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1
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Elsner RA, Shlomchik MJ. Coordinated Regulation of Extrafollicular B Cell Responses by IL-12 and IFNγ. Immunol Rev 2025; 331:e70027. [PMID: 40211749 PMCID: PMC11986407 DOI: 10.1111/imr.70027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
Upon activation, B cells undergo either the germinal center (GC) or extrafollicular (EF) response. While GC are known to generate high-affinity memory B cells and long-lived plasma cells, the role of the EF response is less well understood. Initially, it was thought to be limited to that of a source of fast but lower-quality antibodies until the GC can form. However, recent evidence strongly supports the EF response as an important component of the humoral response to infection. EF responses are now also recognized as a source of pathogenic B cells in autoimmune diseases. The EF response itself is dynamic and regulated by pathways that are only recently being uncovered. We have identified that the cytokine IL-12 acts as a molecular switch, enhancing the EF response and suppressing GC through multiple mechanisms. These include direct effects on both B cells themselves and the coordinated differentiation of helper CD4 T cells. Here, we explore this pathway in relation to other recent advancements in our understanding of the EF response's role and highlight areas for future research. A better understanding of how the EF response forms and is regulated is essential for advancing treatments for many disease states.
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Affiliation(s)
- Rebecca A. Elsner
- Department of ImmunologyUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Mark J. Shlomchik
- Department of ImmunologyUniversity of PittsburghPittsburghPennsylvaniaUSA
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2
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Chaudhari R, Dasgupta M, Kodgire P. Unravelling the Impact of Outer Membrane Protein, OmpA, From S. Typhimurium on Aberrant AID Expression and IgM to IgA Class Switching in Human B-Cells. Immunology 2025. [PMID: 40300848 DOI: 10.1111/imm.13938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 02/12/2025] [Accepted: 04/18/2025] [Indexed: 05/01/2025] Open
Abstract
Salmonella enterica serovar Typhimurium is a Gram-negative bacterium that causes gastrointestinal infection and poses significant public health risks worldwide. This study aims to explore how S. Typhimurium manipulates B-cell function through outer membrane protein A (OmpA). We investigate the effect of OmpA on Raji human B-cells, leading to the induction of activation-induced cytidine deaminase (AID) protein, which plays an important role in generating antibody diversity in B-cells, via initiating the process of somatic hypermutation (SHM) and class switch recombination (CSR). Our key findings demonstrate that OmpA is crucial for inducing aberrant AID expression in B-cells, leading to increased CSR. Interestingly, the increased AID expression was likely due to overexpression of cMYC, an activator for AID expression. Not only was the expression of cMYC elevated, but its occupancy on the aicda locus was raised. Furthermore, increased AID expression induced CSR events, specifically switching to IgA. In summary, our study suggests that OmpA plays a potential role in modulating B-cell regulation and controlling the adaptive immune system. These functional attributes of OmpA implicate its potential as a therapeutic target for combating S. Typhimurium pathogenesis.
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Affiliation(s)
- Rahul Chaudhari
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, Indore, India
| | - Mallar Dasgupta
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, Indore, India
| | - Prashant Kodgire
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, Indore, India
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3
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Homeyer MA, Falck A, Li LY, Prüss H. From immunobiology to intervention: Pathophysiology of autoimmune encephalitis. Semin Immunol 2025; 78:101955. [PMID: 40267699 DOI: 10.1016/j.smim.2025.101955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/02/2025] [Accepted: 04/03/2025] [Indexed: 04/25/2025]
Abstract
Autoimmune encephalitides (AEs) are neurological disorders caused by autoantibodies against neuronal and glial surface proteins. Nearly 20 years after their discovery, AE have evolved from being frequently misdiagnosed and untreated to a growing group of increasingly well-characterized conditions where patients benefit from targeted therapeutic strategies. This narrative review provides an immunological perspective on AE, focusing on NMDAR, CASPR2 and LGI1 encephalitis as the three most common forms of AE associated with anti-neuronal surface autoantibodies. We examine the autoreactive B cell subsets, the tolerance checkpoints that may fail, and the known triggers and predispositions contributing to disease. In addition, we discuss the roles of other immune cells, including T cells and microglia, in the pathogenesis of AE. By analyzing therapeutic strategies and treatment responses we draw insights into AE pathophysiology. Written at a time of transformative therapeutic advancements through cell therapies this work underscores the synergy between detailed immunological research and the development of innovative therapies.
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Affiliation(s)
| | - Alice Falck
- Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Lucie Y Li
- Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Harald Prüss
- Charité - Universitätsmedizin Berlin, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany
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4
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Schacht SS, Graffunder J, Durek P, Wehrenberg J, Siracusa A, Biese C, Mashreghi MF, Thurley K, Bauer L, Hutloff A. Activation and maturation of antigen-specific B cells in nonectopic lung infiltrates are independent of germinal center reactions in the draining lymph node. Cell Mol Immunol 2025:10.1038/s41423-025-01285-8. [PMID: 40210692 DOI: 10.1038/s41423-025-01285-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 02/14/2025] [Accepted: 03/19/2025] [Indexed: 04/12/2025] Open
Abstract
Pulmonary T and B cells are important for protection of this mucosal barrier site. While viral infections lead to the development of ectopic lymphoid structures highly similar to those in germinal centers in secondary lymphoid organs, little is known about how T/B cooperation occurs in the unstructured, diffuse tissue infiltrates characteristic of autoimmune diseases and nonviral infections. Using a mouse model of interstitial lung inflammation, we found that naive B cells are directly activated in lung tissue. Despite the absence of any germinal center-like structures, the interaction of B cells with peripheral T helper cells results in efficient somatic hypermutation and class switching. As antigen-presenting cells, macrophages are critical for this process. Unique B-cell repertoires indicated that the lung response was autonomous from the lung-draining lymph node. Only lung GC-like B cells were switched to IgA and had a broader repertoire, making them ideal candidates for producing broadly neutralizing immunoglobulins against respiratory pathogens.
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Affiliation(s)
| | - Josefine Graffunder
- Chronic Immune Reactions, German Rheumatism Research Centre, A Leibniz Institute, Berlin, Germany
| | - Pawel Durek
- Therapeutic Gene Regulation, German Rheumatism Research Centre, A Leibniz Institute, Berlin, Germany
| | - Jonas Wehrenberg
- Institute of Immunology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Annette Siracusa
- Chronic Immune Reactions, German Rheumatism Research Centre, A Leibniz Institute, Berlin, Germany
| | - Charlotte Biese
- Institute of Immunology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Mir-Farzin Mashreghi
- Therapeutic Gene Regulation, German Rheumatism Research Centre, A Leibniz Institute, Berlin, Germany
- German Center for Child and Adolescent Health (DZKJ), partner site Berlin, Berlin, Germany
| | - Kevin Thurley
- Institute for Experimental Oncology, Biomathematics Division, University Hospital Bonn, Bonn, Germany
| | - Laura Bauer
- Institute of Immunology, University Hospital Schleswig-Holstein, Kiel, Germany
- Chronic Immune Reactions, German Rheumatism Research Centre, A Leibniz Institute, Berlin, Germany
| | - Andreas Hutloff
- Institute of Immunology, University Hospital Schleswig-Holstein, Kiel, Germany.
- Chronic Immune Reactions, German Rheumatism Research Centre, A Leibniz Institute, Berlin, Germany.
- Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, Germany.
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5
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Xin M, Wang A, Ji M, Wu J, Jiang B, Shi M, Song L, Xin Z. Molecular Biology and Functions of T Follicular Helper Cells in Cancer and Immunotherapy. Immune Netw 2025; 25:e7. [PMID: 40342840 PMCID: PMC12056291 DOI: 10.4110/in.2025.25.e7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/22/2024] [Accepted: 01/08/2025] [Indexed: 05/11/2025] Open
Abstract
T follicular helper (Tfh) cells are integral to the germinal center (GC) response and the development of potent humoral immunity. By priming B cells, Tfh cells can initiate both extrafollicular and GC-dependent Ab responses. The dynamic physical interactions between Tfh and B cells constitute the primary platform for Tfh cells to provide essential "help" factors to B cells, as well as for reciprocal signaling from B cells to sustain the helper state of Tfh cells. In recent years, significant advancements have been made in understanding the diverse roles of Tfh cells across various diseases, particularly in cancer. Notably, beyond the classical GC-Tfh cells, it is increasingly recognized that the Tfh cell phenotype is highly heterogeneous and dynamic, which adds complexity to their roles in disease contexts. This review aims to encapsulate progress in Tfh cell biology, with a focus on their role in cancer and immunotherapy.
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Affiliation(s)
- Mengyuan Xin
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
- Medical Science and Technology Innovation Center, Shandong First Medical University, Jinan 250117, China
| | - Antuo Wang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
- Medical Science and Technology Innovation Center, Shandong First Medical University, Jinan 250117, China
| | - Minghao Ji
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Jingru Wu
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Bin Jiang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Mo Shi
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Liang Song
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Zhongwei Xin
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
- Medical Science and Technology Innovation Center, Shandong First Medical University, Jinan 250117, China
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6
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Staniek J, Rizzi M. Signaling Activation and Modulation in Extrafollicular B Cell Responses. Immunol Rev 2025; 330:e70004. [PMID: 39917832 PMCID: PMC11803499 DOI: 10.1111/imr.70004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 01/20/2025] [Indexed: 02/11/2025]
Abstract
The differentiation of naive follicular B cells into either the germinal center (GC) or extrafollicular (EF) pathway plays a critical role in shaping the type, affinity, and longevity of effector B cells. This choice also governs the selection and survival of autoreactive B cells, influencing their potential to enter the memory compartment. During the first 2-3 days following antigen encounter, initially activated B cells integrate activating signals from T cells, Toll-like receptors (TLRs), and cytokines, alongside inhibitory signals mediated by inhibitory receptors. This integration modulates the intensity of signaling, particularly of the PI3K/AKT/mTOR pathway, which plays a central role in guiding developmental decisions. These early signaling events determine whether B cells undergo GC maturation or differentiate rapidly into antibody-secreting cells (ASCs) via the EF pathway. Dysregulation of these signaling pathways-whether through excessive activation or defective regulatory mechanisms-can disrupt the balance between GC and EF fates, predisposing individuals to autoimmunity. Accordingly, aberrant PI3K/AKT/mTOR signaling has been implicated in the defective selection of autoreactive B cells, increasing the risk of autoimmune disease. This review focuses on the signaling events in newly activated B cells, with an emphasis on the induction and regulation of the PI3K/AKT/mTOR pathway. It also highlights gaps in our understanding of how alternative B cell fates are regulated. Both the physiological context and the implications of inborn errors of immunity (IEIs) and complex autoimmune conditions will be discussed in this regard.
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Affiliation(s)
- Julian Staniek
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University Medical Center FreiburgUniversity of FreiburgFreiburgGermany
- Faculty of Medicine, Center for Chronic Immunodeficiency, University Medical Center FreiburgUniversity of FreiburgFreiburgGermany
| | - Marta Rizzi
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University Medical Center FreiburgUniversity of FreiburgFreiburgGermany
- Faculty of Medicine, Center for Chronic Immunodeficiency, University Medical Center FreiburgUniversity of FreiburgFreiburgGermany
- Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and ImmunologyMedical University of ViennaViennaAustria
- CIBSS—Centre for Integrative Biological Signalling StudiesUniversity of FreiburgFreiburgGermany
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7
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Li R, Bao K, Liu C, Ma X, Hua Z, Zhu P, Hou B. Competition propels, rather than limits, the success of low-affinity B cells in the germinal center response. Cell Rep 2025; 44:115334. [PMID: 39955776 DOI: 10.1016/j.celrep.2025.115334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 12/01/2024] [Accepted: 01/29/2025] [Indexed: 02/18/2025] Open
Abstract
The germinal center (GC) sets an environment where antigen-specific B cells are compelled to continuously increase their affinity to compete for the antigen and obtain Tfh help for survival and propagation. Previous studies indicated that low-affinity B cells are disadvantaged in the presence of high-affinity ones, suggesting that competition may lead to the elimination of low-affinity B cells and their descendants. However, using a multivalent virus-mimicking antigen, our study demonstrates that low-affinity B cells not only successfully participate in GC responses alongside high-affinity B cells but also undergo accelerated affinity maturation under the more stringent competition. Furthermore, our cryo-electron-microscopy-based structural analysis reveals that both low-affinity and high-affinity B cells compete for the same antigenic epitope. Although the applicability of this idealized GC competition to true pathogen-induced responses remains uncertain, this change in perspective on the role of competition in low-affinity B cell evolution provides valuable insights for vaccine development.
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Affiliation(s)
- Runhan Li
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Keyan Bao
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Can Liu
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuejing Ma
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhaolin Hua
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Ping Zhu
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Baidong Hou
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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8
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Lehmann PV, Karulin AY, Becza N, Yao L, Liu Z, Chepke J, Maul-Pavicic A, Wolf C, Köppert S, Valente AV, Gorbachev AV, Tary-Lehmann M, Kirchenbaum GA. Theoretical and practical considerations for validating antigen-specific B cell ImmunoSpot assays. J Immunol Methods 2025; 537:113817. [PMID: 39864733 DOI: 10.1016/j.jim.2025.113817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 10/17/2024] [Accepted: 01/20/2025] [Indexed: 01/28/2025]
Abstract
Owing to their ability to reliably detect even very rare antigen-specific B cells in cellular isolates such as peripheral blood mononuclear cells (PBMC), and doing so robustly in a high throughput-compatible manner, B cell ELISPOT/FluoroSpot (collectively "B cell ImmunoSpot") tests have become increasingly attractive for immune monitoring in regulated settings. Presently, there are no guidelines for the qualification and validation of B cell ImmunoSpot assay results. Here, we propose such guidelines, building on the experience acquired from T cell ImmunoSpot testing in an environment adhering to the requirements of regulatory bodies yet taking the unique features of B cell assays into account. A streamlined protocol is proposed that permits the performance of all tests needed for the formal validation of an antigen-specific B cell ImmunoSpot assay in only three experiments, utilizing 2.2 × 107 PBMC per donor. Subsequently, utilizing only 1-2 × 106 PBMC per sample (obtainable from 1 to 2 mL of blood), a validated multiplexed assay enables accurate quantification of the frequency of antigen-specific memory B cell-derived blasts secreting IgM, IgG, IgA or IgE antibodies. Collectively, such multiplexed B cell ImmunoSpot assays offer immense value for B cell immune monitoring programs due to their ease of implementation, scalability, applicability to essentially any antigenic system, economy of PBMC utilization, and last but not least, the high content information gained.
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Affiliation(s)
- Paul V Lehmann
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Alexey Y Karulin
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Noémi Becza
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Lingling Yao
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Zhigang Liu
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Jack Chepke
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Andrea Maul-Pavicic
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Carla Wolf
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Sebastian Köppert
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Alexis V Valente
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Anton V Gorbachev
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Magdalena Tary-Lehmann
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA
| | - Greg A Kirchenbaum
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH 44122, USA.
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9
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Wilbrink R, van der Weele L, Spoorenberg AJPL, de Vries N, Niewold ITG, Verstappen GM, Kroese FGM. B Cell Receptor Repertoire Analysis of the CD21 lo B Cell Compartment in Healthy Individuals, Patients With Sjögren's Disease, and Patients With Radiographic Axial Spondyloarthritis. Eur J Immunol 2025; 55:e202451398. [PMID: 39707660 PMCID: PMC11830390 DOI: 10.1002/eji.202451398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 11/22/2024] [Accepted: 11/27/2024] [Indexed: 12/23/2024]
Abstract
B cells with low or absent expression of CD21 (CD21lo B cells) gained attention due to their expansion in the peripheral blood of patients with immune-mediated, rheumatic diseases. This is not only observed in typical autoimmune diseases like systemic lupus erythematosus and Sjögren's disease (SjD) but also in radiographic axial spondyloarthritis (r-axSpA), which is considered an autoinflammatory disease. To gain more insight into the origins of the heterogeneous CD21lo B-cell population, and its relation to the plasmablast (PB) compartment, we profiled the B-cell-receptor (BCR) repertoire in CD27- and CD27+ fractions of CD21lo B cells and early PBs using next-generation sequencing. Populations were sorted from peripheral blood of healthy individuals, SjD patients, and r-axSpA patients (n = 10 for each group). In healthy individuals and both patient groups, our findings indicate that CD27-CD21lo B cells, which exhibit few mutations in their BCR, may develop into CD27+CD21lo B cells and PBs, both marked by considerably more mutations. Given the known expansion of circulating CD27-CD21lo B cells in SjD and r-axSpA patients and clonal relationships with both CD27+CD21lo B cells and early PBs, these cells might actively contribute to (pathological) immune responses in rheumatic diseases with autoimmune and/or autoinflammatory characteristics.
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MESH Headings
- Humans
- Sjogren's Syndrome/immunology
- Receptors, Antigen, B-Cell/genetics
- Receptors, Antigen, B-Cell/immunology
- Receptors, Antigen, B-Cell/metabolism
- Female
- Adult
- Male
- Middle Aged
- Receptors, Complement 3d/metabolism
- Receptors, Complement 3d/immunology
- Receptors, Complement 3d/genetics
- B-Lymphocytes/immunology
- Axial Spondyloarthritis/immunology
- Axial Spondyloarthritis/diagnostic imaging
- Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism
- Aged
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Affiliation(s)
- Rick Wilbrink
- Department of Rheumatology and Clinical ImmunologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Linda van der Weele
- Department of Rheumatology & Clinical ImmunologyAmsterdam Rheumatology and Immunology Center (ARC)Amsterdam UMC, University of AmsterdamAmsterdamthe Netherlands
| | - Anneke J. P. L. Spoorenberg
- Department of Rheumatology and Clinical ImmunologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Niek de Vries
- Department of Rheumatology & Clinical ImmunologyAmsterdam Rheumatology and Immunology Center (ARC)Amsterdam UMC, University of AmsterdamAmsterdamthe Netherlands
| | - Ilse T. G. Niewold
- Department of Rheumatology & Clinical ImmunologyAmsterdam Rheumatology and Immunology Center (ARC)Amsterdam UMC, University of AmsterdamAmsterdamthe Netherlands
| | - Gwenny M. Verstappen
- Department of Rheumatology and Clinical ImmunologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Frans G. M. Kroese
- Department of Rheumatology and Clinical ImmunologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
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10
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Faliti CE, Mesina M, Choi J, Bélanger S, Marshall MA, Tipton CM, Hicks S, Chappa P, Cardenas MA, Abdel-Hakeem M, Thinnes TC, Cottrell C, Scharer CD, Schief WR, Nemazee D, Woodruff MC, Lindner JM, Sanz I, Crotty S. Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis. Immunity 2024; 57:2772-2789.e8. [PMID: 39612915 PMCID: PMC11675998 DOI: 10.1016/j.immuni.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 06/03/2024] [Accepted: 11/06/2024] [Indexed: 12/01/2024]
Abstract
During antigen-driven responses, B cells can differentiate at extra-follicular (EF) sites or initiate germinal centers (GCs) in processes that involve interactions with T cells. Here, we examined the roles of interleukin (IL)-2 secreted by T helper (Th) cells during cognate interactions with activated B cells. IL-2 boosted the expansion of EF plasma cells and the secretion of low-mutated immunoglobulin G (IgG). Conversely, genetically disrupting IL-2 expression by CD4+ T cells, or IL-2 receptor (CD25) expression by B cells, promoted B cell entry into the GC and high-affinity antibody secretion. Mechanistically, IL-2 induced early mTOR activity, expression of the transcriptional regulator IRF4, and metabolic changes in B cells required to form Blimp-1-expressing plasma cells. Thus, T cell help via IL-2 regulates an mTOR-AKT-Blimp-1 axis in activated B cells, providing insight into the mechanisms that determine EF versus GC fates and positioning IL-2 as an early switch controlling plasma cell versus GC B cell commitment.
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Affiliation(s)
- Caterina E Faliti
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Maria Mesina
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA
| | - Jinyong Choi
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Microbiology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Simon Bélanger
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; VIR Biotechnology, San Francisco, CA 94158, USA
| | - Monique A Marshall
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Christopher M Tipton
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Sakeenah Hicks
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Prashanti Chappa
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | | | | | - Theresa C Thinnes
- Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA
| | - Christopher Cottrell
- Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Christopher D Scharer
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - William R Schief
- Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA
| | - David Nemazee
- Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA
| | - Matthew C Woodruff
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | | | - Ignacio Sanz
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Shane Crotty
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.
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11
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Robinson WH, Younis S, Love ZZ, Steinman L, Lanz TV. Epstein-Barr virus as a potentiator of autoimmune diseases. Nat Rev Rheumatol 2024; 20:729-740. [PMID: 39390260 DOI: 10.1038/s41584-024-01167-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2024] [Indexed: 10/12/2024]
Abstract
The Epstein-Barr virus (EBV) is epidemiologically associated with development of autoimmune diseases, including systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis and multiple sclerosis. Although there is well-established evidence for this association, the underlying mechanistic basis remains incompletely defined. In this Review, we discuss the role of EBV infection as a potentiator of autoimmune rheumatic diseases. We review the EBV life cycle, viral transcription programmes, serological profiles and lytic reactivation. We discuss the epidemiological and mechanistic associations of EBV with systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis and multiple sclerosis. We describe the potential mechanisms by which EBV might promote autoimmunity, including EBV nuclear antigen 1-mediated molecular mimicry of human autoantigens; EBV-mediated B cell reprogramming, including EBV nuclear antigen 2-mediated dysregulation of autoimmune susceptibility genes; EBV and host genetic factors, including the potential for autoimmunity-promoting strains of EBV; EBV immune evasion and insufficient host responses to control infection; lytic reactivation; and other mechanisms. Finally, we discuss the therapeutic implications and potential therapeutic approaches to targeting EBV for the treatment of autoimmune disease.
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Affiliation(s)
- William H Robinson
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
- VA Palo Alto Health Care System, Palo Alto, CA, USA.
| | - Shady Younis
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA
- VA Palo Alto Health Care System, Palo Alto, CA, USA
| | - Zelda Z Love
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA
- VA Palo Alto Health Care System, Palo Alto, CA, USA
| | - Lawrence Steinman
- Department of Neurology and Neurological Sciences and Paediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Tobias V Lanz
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA
- Institute for Immunity Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
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12
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Priest DG, Ebihara T, Tulyeu J, Søndergaard JN, Sakakibara S, Sugihara F, Nakao S, Togami Y, Yoshimura J, Ito H, Onishi S, Muratsu A, Mitsuyama Y, Ogura H, Oda J, Okusaki D, Matsumoto H, Wing JB. Atypical and non-classical CD45RB lo memory B cells are the majority of circulating SARS-CoV-2 specific B cells following mRNA vaccination or COVID-19. Nat Commun 2024; 15:6811. [PMID: 39122676 PMCID: PMC11315995 DOI: 10.1038/s41467-024-50997-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
Resting memory B cells can be divided into classical or atypical groups, but the heterogenous marker expression on activated memory B cells makes similar classification difficult. Here, by longitudinal analysis of mass cytometry and CITE-seq data from cohorts with COVID-19, bacterial sepsis, or BNT162b2 mRNA vaccine, we observe that resting B cell memory consist of classical CD45RB+ memory and CD45RBlo memory, of which the latter contains of two distinct groups of CD11c+ atypical and CD23+ non-classical memory cells. CD45RB levels remain stable in these cells after activation, thereby enabling the tracking of activated B cells and plasmablasts derived from either CD45RB+ or CD45RBlo memory B cells. Moreover, in both COVID-19 patients and mRNA vaccination, CD45RBlo B cells formed the majority of SARS-CoV2 specific memory B cells and correlated with serum antibodies, while CD45RB+ memory are activated by bacterial sepsis. Our results thus identify that stably expressed CD45RB levels can be exploited to trace resting memory B cells and their activated progeny, and suggest that atypical and non-classical CD45RBlo memory B cells contribute to SARS-CoV-2 infection and vaccination.
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Affiliation(s)
- David G Priest
- Laboratory of Human Single Cell Immunology, World Premier International Research Center Initiative Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka, 563-0793, Japan
| | - Takeshi Ebihara
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, 565-0871, Japan
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Janyerkye Tulyeu
- Human Single Cell Immunology Team, Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, 565-0871, Japan
| | - Jonas N Søndergaard
- Human Single Cell Immunology Team, Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, 565-0871, Japan
| | - Shuhei Sakakibara
- Laboratory of Immune Regulation, IFReC, Osaka University, Suita, Osaka, 563-0793, Japan
- Graduate School of Medical Safety Management, Jikei University of Health Care Sciences, Osaka, 532-0003, Japan
| | - Fuminori Sugihara
- Core Instrumentation Facility, Immunology Frontier Research Center and Research Institute for Microbial Disease, Osaka University, Suita, Osaka, 563-0793, Japan
- Research Institute for Microbial Disease, Osaka University, Suita, Osaka, 563-0793, Japan
| | - Shunichiro Nakao
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Yuki Togami
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Jumpei Yoshimura
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Hiroshi Ito
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Shinya Onishi
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Arisa Muratsu
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Yumi Mitsuyama
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
- Division of Trauma and Surgical Critical Care, Osaka General Medical Center, Osaka, 558-8558, Japan
| | - Hiroshi Ogura
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, 565-0871, Japan
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Jun Oda
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, 565-0871, Japan
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Daisuke Okusaki
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, 565-0871, Japan
- Laboratory of Human Immunology (Single Cell Genomics), WPI-IFReC, Osaka University, Suita, 565-0871, Japan
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, 565-0871, Japan
| | - Hisatake Matsumoto
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, 565-0871, Japan.
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
| | - James B Wing
- Laboratory of Human Single Cell Immunology, World Premier International Research Center Initiative Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka, 563-0793, Japan.
- Human Single Cell Immunology Team, Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, 565-0871, Japan.
- Center for Advanced Modalities and DDS (CAMaD), Osaka University, Osaka, Japan.
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13
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Houser CL, Fenner KN, Lawrence BP. Timing influences the impact of aryl hydrocarbon receptor activation on the humoral immune response to respiratory viral infection. Toxicol Appl Pharmacol 2024; 489:117010. [PMID: 38901696 PMCID: PMC11240840 DOI: 10.1016/j.taap.2024.117010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/05/2024] [Accepted: 06/15/2024] [Indexed: 06/22/2024]
Abstract
Humoral responses to respiratory viruses, such as influenza viruses, develop over time and are central to protection from repeated infection with the same or similar viruses. Epidemiological and experimental studies have linked exposures to environmental contaminants that bind the aryl hydrocarbon receptor (AHR) with modulated antibody responses to pathogenic microorganisms and common vaccinations. Other studies have prompted investigation into the potential therapeutic applications of compounds that activate AHR. Herein, using two different AHR ligands [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE), to modulate the duration of AHR activity, we show that the humoral response to viral infection is dependent upon the duration and timing of AHR signaling, and that different cellular elements of the response have different sensitivities. When AHR activation was initiated prior to infection with influenza A virus, there was suppression of all measured elements of the humoral response (i.e., the frequency of T follicular helper cells, germinal center B cells, plasma cells, and circulating virus-specific antibody). However, when the timing of AHR activation was adjusted to either early (days -1 to +5 relative to infection) or later (days +5 onwards), then AHR activation affected different aspects of the overall humoral response. These findings highlight the importance of considering the timing of AHR activation in relation to triggering an immune response, particularly when targeting the AHR to manipulate disease processes.
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Affiliation(s)
- Cassandra L Houser
- Department of Microbiology & Immunology, University of Rochester, Rochester NY14642, USA
| | - Kristina N Fenner
- Department of Environmental Medicine, University of Rochester, Rochester NY14642, USA
| | - B Paige Lawrence
- Department of Microbiology & Immunology, University of Rochester, Rochester NY14642, USA; Department of Environmental Medicine, University of Rochester, Rochester NY14642, USA.
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14
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Shao W, Wang Y, Fang Q, Shi W, Qi H. Epigenetic recording of stimulation history reveals BLIMP1-BACH2 balance in determining memory B cell fate upon recall challenge. Nat Immunol 2024; 25:1432-1444. [PMID: 38969872 DOI: 10.1038/s41590-024-01900-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 06/17/2024] [Indexed: 07/07/2024]
Abstract
Memory B cells (MBCs) differentiate into plasma cells (PCs) or germinal centers (GCs) upon antigen recall. How this decision is programmed is not understood. We found that the relative strength between two antagonistic transcription factors, B lymphocyte-induced maturation protein 1 (BLIMP1) and BTB domain and CNC homolog 2 (BACH2), progressively increases in favor of BLIMP1 in antigen-responding B cells through the course of primary responses. MBC subsets that preferentially produce secondary GCs expressed comparatively higher BACH2 but lower BLIMP1 than those predisposed for PC development. Skewing the BLIMP1-BACH2 balance in otherwise fate-predisposed MBC subsets could switch their fate preferences. Underlying the changing BLIMP1-over-BACH2 balance, we observed progressively increased accessibilities at chromatin loci that are specifically opened in PCs, particularly those that contain interferon-sensitive response elements (ISREs) and are controlled by interferon regulatory factor 4 (IRF4). IRF4 is upregulated by B cell receptor, CD40 or innate receptor signaling and it induces graded levels of PC-specifying epigenetic imprints according to the strength of stimulation. By analyzing history-stamped GC B cells, we found progressively increased chromatin accessibilities at PC-specific, IRF4-controlled gene loci over time. Therefore, the cumulative stimulation history of B cells is epigenetically recorded in an IRF4-dependent manner, determines the relative strength between BLIMP1 and BACH2 in individual MBCs and dictates their probabilities to develop into GCs or PCs upon restimulation.
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Affiliation(s)
- Wen Shao
- Tsinghua-Peking Center for Life Sciences, Beijing, China
- Laboratory of Dynamic Immunobiology, Institute for Immunology, Beijing, China
- Department of Basic Medical Sciences, School of Medicine, Beijing, China
- New Cornerstone Science Laboratory, School of Medicine, Tsinghua University, Beijing, China
- Changping Laboratory, Beijing, China
| | - Yifeng Wang
- Tsinghua-Peking Center for Life Sciences, Beijing, China
- Laboratory of Dynamic Immunobiology, Institute for Immunology, Beijing, China
- Department of Basic Medical Sciences, School of Medicine, Beijing, China
- Changping Laboratory, Beijing, China
| | - Qian Fang
- Tsinghua-Peking Center for Life Sciences, Beijing, China
- Laboratory of Dynamic Immunobiology, Institute for Immunology, Beijing, China
- Department of Basic Medical Sciences, School of Medicine, Beijing, China
| | - Wenjuan Shi
- SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, China
| | - Hai Qi
- Tsinghua-Peking Center for Life Sciences, Beijing, China.
- Laboratory of Dynamic Immunobiology, Institute for Immunology, Beijing, China.
- Department of Basic Medical Sciences, School of Medicine, Beijing, China.
- New Cornerstone Science Laboratory, School of Medicine, Tsinghua University, Beijing, China.
- Changping Laboratory, Beijing, China.
- SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, China.
- Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.
- Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China.
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15
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Elsner RA, Smita S, Shlomchik MJ. IL-12 induces a B cell-intrinsic IL-12/IFNγ feed-forward loop promoting extrafollicular B cell responses. Nat Immunol 2024; 25:1283-1295. [PMID: 38862796 PMCID: PMC11992614 DOI: 10.1038/s41590-024-01858-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 04/26/2024] [Indexed: 06/13/2024]
Abstract
While some infections elicit germinal centers, others produce only extrafollicular responses. The mechanisms controlling these dichotomous fates are poorly understood. We identify IL-12 as a cytokine switch, acting directly on B cells to promote extrafollicular and suppress germinal center responses. IL-12 initiates a B cell-intrinsic feed-forward loop between IL-12 and IFNγ, amplifying IFNγ production, which promotes proliferation and plasmablast differentiation from mouse and human B cells, in synergy with IL-12. IL-12 sustains the expression of a portion of IFNγ-inducible genes. Together, they also induce unique gene changes, reflecting both IFNγ amplification and cooperative effects between both cytokines. In vivo, cells lacking both IL-12 and IFNγ receptors are more impaired in plasmablast production than those lacking either receptor alone. Further, B cell-derived IL-12 enhances both plasmablast responses and T helper 1 cell commitment. Thus, B cell-derived IL-12, acting on T and B cells, determines the immune response mode, with implications for vaccines, pathogen protection and autoimmunity.
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Affiliation(s)
- Rebecca A Elsner
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Shuchi Smita
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mark J Shlomchik
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
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16
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Hjálmsdóttir Á, Hasler F, Waeckerle-Men Y, Duda A, López-Deber MP, Pihlgren M, Vukicevic M, Kündig TM, Johansen P. T cell independent antibody responses with class switch and memory using peptides anchored on liposomes. NPJ Vaccines 2024; 9:115. [PMID: 38909055 PMCID: PMC11193769 DOI: 10.1038/s41541-024-00902-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 05/23/2024] [Indexed: 06/24/2024] Open
Abstract
Vaccines generally require T lymphocytes for B-cell activation and immunoglobulin class switching in response to peptide or protein antigens. In the absence of T cells, limited IgG class switch takes place, germinal centers are short-lived, and the B cells lack memory. Here, immunization of mice with liposomes containing 15mer peptides and monophosphoryl lipid A (MPLA) as adjuvant, induced T-cell independent (TI) IgG class switch within three days, as well as germinal center formation. The antibody responses were long-lived, strictly dependent on Toll-like receptor 4 (TLR4) signaling, partly dependent on Bruton's tyrosine kinase (BTK) signal transmission, and independent of signaling through T-cell receptors, MHC class II and inflammasome. The antibody response showed characteristics of both TI type 1 and TI type 2. All IgG subclasses could be boosted months after primary immunization, and the biological function of the secreted antibodies was demonstrated in murine models of allergic anaphylaxis and of bacterial infection. Moreover, antibody responses after immunization with peptide- and MPLA-loaded liposomes could be triggered in neonatal mice and in mice receiving immune-suppressants. This study demonstrates T-cell independent endogenous B-cell memory and recall responses in vivo using a peptide antigen. The stimulation of these antibody responses required a correct and dense assembly and administration of peptide and adjuvant on the surface of liposomes. In the future, TI vaccines may prove beneficial in pathological conditions in which T-cell immunity is compromised through disease or medicines or when rapid, antibody-mediated immune protection is needed.
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Affiliation(s)
| | - Fabio Hasler
- Department of Dermatology, University of Zurich, Zurich, Switzerland
| | | | - Agathe Duda
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | | | - Maria Pihlgren
- AC Immune SA, EPFL Innovation Park EPFL, Lausanne, Switzerland
| | | | - Thomas M Kündig
- Department of Dermatology, University of Zurich, Zurich, Switzerland
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Pål Johansen
- Department of Dermatology, University of Zurich, Zurich, Switzerland.
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
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17
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Qi R, Fu R, Lei X, He J, Jiang Y, Zhang L, Wu Y, Wang S, Guo X, Chen F, Nie M, Yang M, Chen Y, Zeng J, Xu J, Xiong H, Fang M, Que Y, Yao Y, Wang Y, Cao J, Ye H, Zhang Y, Zheng Z, Cheng T, Zhang J, Lin X, Yuan Q, Zhang T, Xia N. Therapeutic vaccine-induced plasma cell differentiation is defective in the presence of persistently high HBsAg levels. J Hepatol 2024; 80:714-729. [PMID: 38336348 DOI: 10.1016/j.jhep.2023.12.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 12/15/2023] [Accepted: 12/29/2023] [Indexed: 02/12/2024]
Abstract
BACKGROUND & AIMS Mechanisms behind the impaired response of antigen-specific B cells to therapeutic vaccination in chronic hepatitis B virus (HBV) infection remain unclear. The development of vaccines or strategies to overcome this obstacle is vital for advancing the management of chronic hepatitis B. METHODS A mouse model, denominated as E6F6-B, was engineered to feature a knock-in of a B-cell receptor (BCR) that specifically recognizes HBsAg. This model served as a valuable tool for investigating the temporal and spatial dynamics of humoral responses following therapeutic vaccination under continuous antigen exposure. Using a suite of immunological techniques, we elucidated the differentiation trajectory of HBsAg-specific B cells post-therapeutic vaccination in HBV carrier mice. RESULTS Utilizing the E6F6-B transfer model, we observed a marked decline in antibody-secreting cells 2 weeks after vaccination. A dysfunctional and atypical pre-plasma cell population (BLIMP-1+ IRF4+ CD40- CD138- BCMA-) emerged, manifested by sustained BCR signaling. By deploying an antibody to purge persistent HBsAg, we effectively prompted the therapeutic vaccine to provoke conventional plasma cell differentiation. This resulted in an enhanced anti-HBs antibody response and facilitated HBsAg clearance. CONCLUSIONS Sustained high levels of HBsAg limit the ability of therapeutic hepatitis B vaccines to induce the canonical plasma cell differentiation necessary for anti-HBs antibody production. Employing a strategy combining antibodies with vaccines can surmount this altered humoral response associated with atypical pre-plasma cells, leading to improved therapeutic efficacy in HBV carrier mice. IMPACT AND IMPLICATIONS Therapeutic vaccines aimed at combatting HBV encounter suboptimal humoral responses in clinical settings, and the mechanisms impeding their effectiveness have remained obscure. Our research, utilizing the innovative E6F6-B mouse transfer model, reveals that the persistence of HBsAg can lead to the emergence of an atypical pre-plasma cell population, which proves to be relevant to the potency of therapeutic HBV vaccines. Targeting the aberrant differentiation process of these atypical pre-plasma cells stands out as a critical strategy to amplify the humoral response elicited by HBV therapeutic vaccines in carrier mouse models. This discovery suggests a compelling avenue for further study in the context of human chronic hepatitis B. Encouragingly, our findings indicate that synergistic therapy combining HBV-specific antibodies with vaccines offers a promising approach that could significantly advance the pursuit of a functional cure for HBV.
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Affiliation(s)
- Ruoyao Qi
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Rao Fu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Xing Lei
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Jinhang He
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Yao Jiang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Liang Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Yangtao Wu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Siling Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Xueran Guo
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Feng Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Meifeng Nie
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Man Yang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Yiyi Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Jing Zeng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China; Department of clinical laboratory, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Jingjing Xu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Hualong Xiong
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Mujin Fang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Yuqiong Que
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Youliang Yao
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Yingbin Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Jiali Cao
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China; Department of clinical laboratory, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Huiming Ye
- Department of clinical laboratory, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Yali Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Zizheng Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Tong Cheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Jun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China
| | - Xu Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
| | - Quan Yuan
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China.
| | - Tianying Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China.
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen 361102, Fujian, China.
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18
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Iborra-Pernichi M, Ruiz García J, Velasco de la Esperanza M, Estrada BS, Bovolenta ER, Cifuentes C, Prieto Carro C, González Martínez T, García-Consuegra J, Rey-Stolle MF, Rupérez FJ, Guerra Rodriguez M, Argüello RJ, Cogliati S, Martín-Belmonte F, Martínez-Martín N. Defective mitochondria remodelling in B cells leads to an aged immune response. Nat Commun 2024; 15:2569. [PMID: 38519473 PMCID: PMC10960012 DOI: 10.1038/s41467-024-46763-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 03/08/2024] [Indexed: 03/25/2024] Open
Abstract
The B cell response in the germinal centre (GC) reaction requires a unique bioenergetic supply. Although mitochondria are remodelled upon antigen-mediated B cell receptor stimulation, mitochondrial function in B cells is still poorly understood. To gain a better understanding of the role of mitochondria in B cell function, here we generate mice with B cell-specific deficiency in Tfam, a transcription factor necessary for mitochondrial biogenesis. Tfam conditional knock-out (KO) mice display a blockage of the GC reaction and a bias of B cell differentiation towards memory B cells and aged-related B cells, hallmarks of an aged immune response. Unexpectedly, blocked GC reaction in Tfam KO mice is not caused by defects in the bioenergetic supply but is associated with a defect in the remodelling of the lysosomal compartment in B cells. Our results may thus describe a mitochondrial function for lysosome regulation and the downstream antigen presentation in B cells during the GC reaction, the dysruption of which is manifested as an aged immune response.
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Affiliation(s)
- Marta Iborra-Pernichi
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Jonathan Ruiz García
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - María Velasco de la Esperanza
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Belén S Estrada
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Elena R Bovolenta
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Claudia Cifuentes
- Program of Interactions with the Environment, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Cristina Prieto Carro
- Program of Interactions with the Environment, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Tamara González Martínez
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - José García-Consuegra
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - María Fernanda Rey-Stolle
- Centre for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain
| | - Francisco Javier Rupérez
- Centre for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain
| | - Milagros Guerra Rodriguez
- Electron Microscopy Facility, Centro de Biología Molecular "Severo Ochoa, " Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Rafael J Argüello
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Sara Cogliati
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Fernando Martín-Belmonte
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Nuria Martínez-Martín
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
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19
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He Y, Vinuesa CG. Germinal center versus extrafollicular responses in systemic autoimmunity: Who turns the blade on self? Adv Immunol 2024; 162:109-133. [PMID: 38866437 PMCID: PMC7616122 DOI: 10.1016/bs.ai.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2024]
Abstract
Spontaneously formed germinal centers (GCs) have been reported in most mouse models of human autoimmune disease and autoimmune patients, and have long been considered a source of somatically-mutated and thus high affinity autoantibodies, but their role in autoimmunity is becoming increasingly controversial, particularly in the context of systemic autoimmune diseases like lupus. On the one hand, there is good evidence that some pathogenic lupus antibodies have acquired somatic mutations that increase affinity for self-antigens. On the other hand, recent studies that have genetically prevented GC formation, suggest that GCs are dispensable for systemic autoimmunity, pointing instead to pathogenic extrafollicular (EF) B-cell responses. Furthermore, several lines of evidence suggest germinal centers may in fact be somewhat protective in the context of autoimmunity. Here we review how some of the conflicting evidence arose, and current views on the role of GCs in autoimmunity, outlining mechanisms by which GC may eliminate self-reactivity. We also discuss recent advances in understanding extrafollicular B cell subsets that participate in autoimmunity.
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Affiliation(s)
- Yuke He
- China-Australia Centre for Personalised Immunology, Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Carola G Vinuesa
- China-Australia Centre for Personalised Immunology, Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China; Francis Crick Institute, London, United Kingdom.
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20
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Woodruff MC, Faliti CE, Sanz I. Systems biology of B cells in COVID-19. Semin Immunol 2024; 72:101875. [PMID: 38489999 PMCID: PMC11988200 DOI: 10.1016/j.smim.2024.101875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/04/2024] [Accepted: 03/04/2024] [Indexed: 03/17/2024]
Abstract
The integration of multi-'omic datasets into complex systems-wide assessments has become a mainstay in immunologic investigation. This focus on high-dimensional data collection and analysis was on full display in the investigation of COVID-19, the respiratory illness resulting from infection by the novel coronavirus SARS-CoV-2. Particularly in the area of B cell biology, tremendous efforts in both cellular and serologic investigation have resulted in an increasingly detailed mapping of the coordinated effector, memory, and antibody secreting cell responses that underpin the development of humoral immunity in response to primary viral infection. Further, the rapid development and deployment of effective vaccines has allowed for the assessment of developing memory responses across a wide variety of immune contexts, including in patients with compromised immune function. The result has been a period of rapid gains in the understanding of B cell biology unrestricted to the study of COVID-19. Here, we outline the systems-level technologies that have been routinely implemented in these investigations throughout the pandemic, and discuss how their use has led to clear and applicable gains in pursuance of the amelioration of human infectious disease and beyond.
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Affiliation(s)
- Matthew C Woodruff
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
| | - Caterina E Faliti
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
| | - Ignacio Sanz
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
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21
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Becza N, Liu Z, Chepke J, Gao XH, Lehmann PV, Kirchenbaum GA. Assessing the Affinity Spectrum of the Antigen-Specific B Cell Repertoire via ImmunoSpot ®. Methods Mol Biol 2024; 2768:211-239. [PMID: 38502396 DOI: 10.1007/978-1-0716-3690-9_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024]
Abstract
The affinity distribution of the antigen-specific memory B cell (Bmem) repertoire in the body is a critical variable that defines an individual's ability to rapidly generate high-affinity protective antibody specificities. Detailed measurement of antibody affinity so far has largely been confined to studies of monoclonal antibodies (mAbs) and are laborious since each individual mAb needs to be evaluated in isolation. Here, we introduce two variants of the B cell ImmunoSpot® assay that are suitable for simultaneously assessing the affinity distribution of hundreds of individual B cells within a test sample at single-cell resolution using relatively little labor and with high-throughput capacity. First, we experimentally validated that both ImmunoSpot® assay variants are suitable for establishing functional affinity hierarchies using B cell hybridoma lines as model antibody-secreting cells (ASC), each producing mAb with known affinity for a defined antigen. We then leveraged both ImmunoSpot® variants for characterizing the affinity distribution of SARS-CoV-2 Spike-specific ASC in PBMC following COVID-19 mRNA vaccination. Such ImmunoSpot® assays promise to offer tremendous value for future B cell immune monitoring efforts, owing to their ease of implementation, applicability to essentially any antigenic system, economy of PBMC utilization, high-throughput capacity, and suitability for regulated testing.
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Affiliation(s)
- Noémi Becza
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH, USA
| | - Zhigang Liu
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH, USA
| | - Jack Chepke
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH, USA
| | - Xing-Huang Gao
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH, USA
| | - Paul V Lehmann
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH, USA
| | - Greg A Kirchenbaum
- Research & Development Department, Cellular Technology Limited, Shaker Heights, OH, USA.
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22
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Karulin AY, Katona M, Megyesi Z, Kirchenbaum GA, Lehmann PV. Artificial Intelligence-Based Counting Algorithm Enables Accurate and Detailed Analysis of the Broad Spectrum of Spot Morphologies Observed in Antigen-Specific B-Cell ELISPOT and FluoroSpot Assays. Methods Mol Biol 2024; 2768:59-85. [PMID: 38502388 DOI: 10.1007/978-1-0716-3690-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024]
Abstract
Antigen-specific B-cell ELISPOT and multicolor FluoroSpot assays, in which the membrane-bound antigen itself serves as the capture reagent for the antibodies that B cells secrete, inherently result in a broad range of spot sizes and intensities. The diversity of secretory footprint morphologies reflects the polyclonal nature of the antigen-specific B cell repertoire, with individual antibody-secreting B cells in the test sample differing in their affinity for the antigen, fine epitope specificity, and activation/secretion kinetics. To account for these heterogeneous spot morphologies, and to eliminate the need for setting up subjective counting parameters well-by-well, CTL introduces here its cutting-edge deep learning-based IntelliCount™ algorithm within the ImmunoSpot® Studio Software Suite, which integrates CTL's proprietary deep neural network. Here, we report detailed analyses of spots with a broad range of morphologies that were challenging to analyze using standard parameter-based counting approaches. IntelliCount™, especially in conjunction with high dynamic range (HDR) imaging, permits the extraction of accurate, high-content information of such spots, as required for assessing the affinity distribution of an antigen-specific memory B-cell repertoire ex vivo. IntelliCount™ also extends the range in which the number of antibody-secreting B cells plated and spots detected follow a linear function; that is, in which the frequencies of antigen-specific B cells can be accurately established. Introducing high-content analysis of secretory footprints in B-cell ELISPOT/FluoroSpot assays, therefore, fundamentally enhances the depth in which an antigen-specific B-cell repertoire can be studied using freshly isolated or cryopreserved primary cell material, such as peripheral blood mononuclear cells.
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23
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Reyes RA, Batugedara G, Dutta P, Reers AB, Garza R, Ssewanyana I, Jagannathan P, Feeney ME, Greenhouse B, Bol S, Ay F, Bunnik EM. Atypical B cells consist of subsets with distinct functional profiles. iScience 2023; 26:108496. [PMID: 38098745 PMCID: PMC10720271 DOI: 10.1016/j.isci.2023.108496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/30/2023] [Accepted: 11/16/2023] [Indexed: 12/17/2023] Open
Abstract
Atypical B cells are a population of activated B cells that are commonly enriched in individuals with chronic immune activation but are also part of a normal immune response to infection or vaccination. To better define the role of atypical B cells in the human adaptive immune response, we performed single-cell sequencing of transcriptomes, cell surface markers, and B cell receptors in individuals with chronic exposure to the malaria parasite Plasmodium falciparum, a condition known to lead to accumulation of circulating atypical B cells. We identified three previously uncharacterized populations of atypical B cells with distinct transcriptional and functional profiles and observed marked differences among these three subsets in their ability to produce immunoglobulin G upon T-cell-dependent activation. Our findings help explain the conflicting observations in prior studies regarding the function of atypical B cells and highlight their different roles in the adaptive immune response in chronic inflammatory conditions.
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Affiliation(s)
- Raphael A. Reyes
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Gayani Batugedara
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Paramita Dutta
- Centers for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Ashley B. Reers
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Rolando Garza
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Isaac Ssewanyana
- Infectious Disease Research Collaboration, Kampala, Uganda
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Prasanna Jagannathan
- Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA 94305, USA
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| | - Margaret E. Feeney
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94110, USA
| | - Bryan Greenhouse
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA
| | - Sebastiaan Bol
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Ferhat Ay
- Centers for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
| | - Evelien M. Bunnik
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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24
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Matz H, Dooley H. 450 million years in the making: mapping the evolutionary foundations of germinal centers. Front Immunol 2023; 14:1245704. [PMID: 37638014 PMCID: PMC10450919 DOI: 10.3389/fimmu.2023.1245704] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 07/25/2023] [Indexed: 08/29/2023] Open
Abstract
Germinal centers (GCs) are distinct microanatomical structures that form in the secondary lymphoid organs of endothermic vertebrates (i.e., mammals and some birds). Within GCs, B cells undergo a Darwinian selection process to identify clones which can respond to pathogen insult as well as affinity mature the B cell repertoire. The GC response ultimately generates memory B cells and bone marrow plasma cells which facilitate humoral immunological memory, the basis for successful vaccination programs. GCs have not been observed in the secondary lymphoid organs of ectothermic jawed vertebrates (i.e., fishes, reptiles, and amphibians). However, abundant research over the past decades has indicated these organisms can produce antigen specific B cell responses and some degree of affinity maturation. This review examines data demonstrating that the fundamentals of B cell selection may be more conserved across vertebrate phylogeny than previously anticipated. Further, research in both conventional mammalian model systems and comparative models raises the question of what evolutionary benefit GCs provide endotherms if they are seemingly unnecessary for generating the basic functional components of jawed vertebrate humoral adaptive immune responses.
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25
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Vieira MC, Palm AKE, Stamper CT, Tepora ME, Nguyen KD, Pham TD, Boyd SD, Wilson PC, Cobey S. Germline-encoded specificities and the predictability of the B cell response. PLoS Pathog 2023; 19:e1011603. [PMID: 37624867 PMCID: PMC10484431 DOI: 10.1371/journal.ppat.1011603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 09/07/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Antibodies result from the competition of B cell lineages evolving under selection for improved antigen recognition, a process known as affinity maturation. High-affinity antibodies to pathogens such as HIV, influenza, and SARS-CoV-2 are frequently reported to arise from B cells whose receptors, the precursors to antibodies, are encoded by particular immunoglobulin alleles. This raises the possibility that the presence of particular germline alleles in the B cell repertoire is a major determinant of the quality of the antibody response. Alternatively, initial differences in germline alleles' propensities to form high-affinity receptors might be overcome by chance events during affinity maturation. We first investigate these scenarios in simulations: when germline-encoded fitness differences are large relative to the rate and effect size variation of somatic mutations, the same germline alleles persistently dominate the response of different individuals. In contrast, if germline-encoded advantages can be easily overcome by subsequent mutations, allele usage becomes increasingly divergent over time, a pattern we then observe in mice experimentally infected with influenza virus. We investigated whether affinity maturation might nonetheless strongly select for particular amino acid motifs across diverse genetic backgrounds, but we found no evidence of convergence to similar CDR3 sequences or amino acid substitutions. These results suggest that although germline-encoded specificities can lead to similar immune responses between individuals, diverse evolutionary routes to high affinity limit the genetic predictability of responses to infection and vaccination.
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Affiliation(s)
- Marcos C. Vieira
- Department of Ecology and Evolution, University of Chicago, Chicago, United States of America
| | - Anna-Karin E. Palm
- Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States of America
| | - Christopher T. Stamper
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Committee on Immunology, University of Chicago, Chicago, United States of America
| | - Micah E. Tepora
- Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States of America
| | - Khoa D. Nguyen
- Department of Pathology, Stanford University School of Medicine, Stanford, United States of America
| | - Tho D. Pham
- Department of Pathology, Stanford University School of Medicine, Stanford, United States of America
| | - Scott D. Boyd
- Department of Pathology, Stanford University School of Medicine, Stanford, United States of America
| | - Patrick C. Wilson
- Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States of America
- Gale and Ira Drukier Institute for Children’s Health, Weill Cornell Medicine, New York City, United States of America
| | - Sarah Cobey
- Department of Ecology and Evolution, University of Chicago, Chicago, United States of America
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26
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Lam JH, Baumgarth N. Toll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses. Nat Commun 2023; 14:3979. [PMID: 37407556 DOI: 10.1038/s41467-023-39734-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 06/27/2023] [Indexed: 07/07/2023] Open
Abstract
Extrafollicular plasmablast responses (EFRs) are considered to generate antibodies of low affinity that offer little protection from infections. Paradoxically, high avidity antigen-B cell receptor engagement is thought to be the main driver of B cell differentiation, whether in EFRs or slower-developing germinal centers (GCs). Here we show that influenza infection rapidly induces EFRs, generating protective antibodies via Toll-like receptor (TLR)-mediated mechanisms that are both B cell intrinsic and extrinsic. B cell-intrinsic TLR signals support antigen-stimulated B cell survival, clonal expansion, and the differentiation of B cells via induction of IRF4, the master regulator of B cell differentiation, through activation of NF-kB c-Rel. Provision of sustained TLR4 stimulation after immunization shifts the fate of virus-specific B cells towards EFRs instead of GCs, prompting rapid antibody production and improving their protective capacity over antigen/alum administration alone. Thus, inflammatory signals act as B cell fate-determinants for the rapid generation of protective antiviral extrafollicular responses.
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Affiliation(s)
- Jonathan H Lam
- Graduate Group in Immunology, University of California Davis, Davis, USA
- Center for Immunology and Infectious Diseases, University of California Davis, Davis, USA
- Dept. Pathology, Microbiology and Immunology, University of California Davis, Davis, USA
| | - Nicole Baumgarth
- Graduate Group in Immunology, University of California Davis, Davis, USA.
- Center for Immunology and Infectious Diseases, University of California Davis, Davis, USA.
- Dept. Pathology, Microbiology and Immunology, University of California Davis, Davis, USA.
- W. Harry Feinstone Dept Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, E4135, Baltimore, MD, 21205, USA.
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Gonzales C, Liang Y, Fisher J, Card G, Sun J, Soong L. Alterations in germinal center formation and B cell activation during severe Orientia tsutsugamushi infection in mice. PLoS Negl Trop Dis 2023; 17:e0011090. [PMID: 37146079 PMCID: PMC10191367 DOI: 10.1371/journal.pntd.0011090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 05/17/2023] [Accepted: 04/17/2023] [Indexed: 05/07/2023] Open
Abstract
Scrub typhus is a poorly studied but life-threatening disease caused by the intracellular bacterium Orientia tsutsugamushi (Ot). Cellular and humoral immunity in Ot-infected patients is not long-lasting, waning as early as one-year post-infection; however, its underlying mechanisms remain unclear. To date, no studies have examined germinal center (GC) or B cell responses in Ot-infected humans or experimental animals. This study was aimed at evaluating humoral immune responses at acute stages of severe Ot infection and possible mechanisms underlying B cell dysfunction. Following inoculation with Ot Karp, a clinically dominant strain known to cause lethal infection in C57BL/6 mice, we measured antigen-specific antibody titers, revealing IgG2c as the dominant isotype induced by infection. Splenic GC responses were evaluated by immunohistology, co-staining for B cells (B220), T cells (CD3), and GCs (GL-7). Organized GCs were evident at day 4 post-infection (D4), but they were nearly absent at D8, accompanied by scattered T cells throughout splenic tissues. Flow cytometry revealed comparable numbers of GC B cells and T follicular helper (Tfh) cells at D4 and D8, indicating that GC collapse was not due to excessive death of these cell subtypes at D8. B cell RNAseq analysis revealed significant differences in expression of genes associated with B cell adhesion and co-stimulation at D8 versus D4. The significant downregulation of S1PR2 (a GC-specific adhesion gene) was most evident at D8, correlating with disrupted GC formation. Signaling pathway analysis uncovered downregulation of 71% of B cell activation genes at D8, suggesting attenuation of B cell activation during severe infection. This is the first study showing the disruption of B/T cell microenvironment and dysregulation of B cell responses during Ot infection, which may help understand the transient immunity associated with scrub typhus.
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Affiliation(s)
- Casey Gonzales
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Yuejin Liang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - James Fisher
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Galen Card
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Jiaren Sun
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Lynn Soong
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America
- Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, United States of America
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28
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Rivera CE, Zhou Y, Chupp DP, Yan H, Fisher AD, Simon R, Zan H, Xu Z, Casali P. Intrinsic B cell TLR-BCR linked coengagement induces class-switched, hypermutated, neutralizing antibody responses in absence of T cells. SCIENCE ADVANCES 2023; 9:eade8928. [PMID: 37115935 PMCID: PMC10146914 DOI: 10.1126/sciadv.ade8928] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 03/23/2023] [Indexed: 05/03/2023]
Abstract
Maturation of antibody responses entails somatic hypermutation (SHM), class-switch DNA recombination (CSR), plasma cell differentiation, and generation of memory B cells, and it is thought to require T cell help. We showed that B cell Toll-like receptor 4 (TLR4)-B cell receptor (BCR) (receptor for antigen) coengagement by 4-hydroxy-3-nitrophenyl acetyl (NP)-lipopolysaccharide (LPS) (Escherichia coli lipid A polysaccharide O-antigen) or TLR5-BCR coengagement by Salmonella flagellin induces mature antibody responses to NP and flagellin in Tcrβ-/-Tcrδ-/- and NSG/B mice. TLR-BCR coengagement required linkage of TLR and BCR ligands, "linked coengagement." This induced B cell CSR/SHM, germinal center-like differentiation, clonal expansion, intraconal diversification, plasma cell differentiation, and an anamnestic antibody response. In Tcrβ-/-Tcrδ-/- mice, linked coengagement of TLR4-BCR by LPS or TLR5-BCR by flagellin induced protective antibodies against E. coli or Salmonella Typhimurium. Our findings unveiled a critical role of B cell TLRs in inducing neutralizing antibody responses, including those to microbial pathogens, without T cell help.
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Affiliation(s)
- Carlos E. Rivera
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA
| | - Yulai Zhou
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA
| | - Daniel P. Chupp
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA
| | - Hui Yan
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA
| | - Amanda D. Fisher
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA
| | - Raphael Simon
- Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Hong Zan
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA
| | - Zhenming Xu
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA
| | - Paolo Casali
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA
- Department of Medicine, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA
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29
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Marcial-Juárez E, Pérez-Toledo M, Nayar S, Pipi E, Alshayea A, Persaud R, Jossi SE, Lamerton R, Barone F, Henderson IR, Cunningham AF. Salmonella infection induces the reorganization of follicular dendritic cell networks concomitant with the failure to generate germinal centers. iScience 2023; 26:106310. [PMID: 36950118 PMCID: PMC10025972 DOI: 10.1016/j.isci.2023.106310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/07/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
Germinal centers (GCs) are sites where plasma and memory B cells form to generate high-affinity, Ig class-switched antibodies. Specialized stromal cells called follicular dendritic cells (FDCs) are essential for GC formation. During systemic Salmonella Typhimurium (STm) infection GCs are absent, whereas extensive extrafollicular and switched antibody responses are maintained. The mechanisms that underpin the absence of GC formation are incompletely understood. Here, we demonstrate that STm induces a reversible disruption of niches within the splenic microenvironment, including the T and B cell compartments and the marginal zone. Alongside these effects after infection, mature FDC networks are strikingly absent, whereas immature FDC precursors, including marginal sinus pre-FDCs (MadCAM-1+) and perivascular pre-FDCs (PDGFRβ+) are enriched. As normal FDC networks re-establish, extensive GCs become detectable throughout the spleen. Therefore, the reorganization of FDC networks and the loss of GC responses are key, parallel features of systemic STm infections.
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Affiliation(s)
- Edith Marcial-Juárez
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
| | - Marisol Pérez-Toledo
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
| | - Saba Nayar
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
| | - Elena Pipi
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
| | - Areej Alshayea
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
| | - Ruby Persaud
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
| | - Sian E. Jossi
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
| | - Rachel Lamerton
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
| | - Francesca Barone
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, UK and Sandwell and West Birmingham Trust, Birmingham, West Midlands, B15 2TH, United Kingdom
| | - Ian R. Henderson
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia
| | - Adam F. Cunningham
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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30
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Kibler A, Seifert M, Budeus B. Age-related changes of the human splenic marginal zone B cell compartment. Immunol Lett 2023; 256-257:59-65. [PMID: 37044264 DOI: 10.1016/j.imlet.2023.04.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 03/24/2023] [Accepted: 04/07/2023] [Indexed: 04/14/2023]
Abstract
In this review, we will summarize the growing body of knowledge on the age-related changes of human splenic B cell composition and molecular evidence of immune maturation and discuss the contribution of these changes on splenic protective function. From birth on, the splenic marginal zone (sMZ) contains a specialized B cell subpopulation, which recruits and archives memory B cells from immune responses throughout the organism. The quality of sMZ B cell responses is augmented by germinal center (GC)-dependent maturation of memory B cells during childhood, however, in old age, these mechanisms likely contribute to waning of splenic protective function.
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Affiliation(s)
- Artur Kibler
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany
| | - Marc Seifert
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany; Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Germany.
| | - Bettina Budeus
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany
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31
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Gauthier J, Grégoire M, Reizine F, Lesouhaitier M, Desvois Y, Ghukasyan G, Moreau C, Amé P, Tarte K, Tadié JM, Delaloy C. Citrulline enteral administration markedly reduces immunosuppressive extrafollicular plasma cell differentiation in a preclinical model of sepsis. Eur J Immunol 2023; 53:e2250154. [PMID: 36564641 DOI: 10.1002/eji.202250154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/22/2022] [Accepted: 12/21/2022] [Indexed: 12/25/2022]
Abstract
The sustained immunosuppression associated with severe sepsis favors an increased susceptibility to secondary infections and remains incompletely understood. Plasmablast and plasma cell subsets, whose primary function is to secrete antibodies, have emerged as important suppressive populations that expand during sepsis. In particular, sepsis supports CD39hi plasmablast metabolic reprogramming associated with adenosine-mediated suppressive activity. Arginine deficiency has been linked to an increased risk of secondary infections in sepsis. Overcoming arginine shortage by citrulline administration efficiently improves sepsis-induced immunosuppression and secondary infections in the cecal ligation and puncture murine model. Here, we aimed to determine the impact of citrulline administration on B cell suppressive responses in sepsis. We demonstrate that restoring arginine bioavailability through citrulline administration markedly reduces the dominant extrafollicular B cell response, decreasing the immunosuppressive LAG3+ and CD39+ plasma cell populations, and restoring splenic follicles. At the molecular level, the IRF4/MYC-mediated B cell reprogramming required for extrafollicular plasma cell differentiation is shunted in the splenic B cells of mice fed with citrulline. Our study reveals a prominent impact of nutrition on B cell responses and plasma cell differentiation and further supports the development of citrulline-based clinical studies to prevent sepsis-associated immune dysfunction.
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Affiliation(s)
| | - Murielle Grégoire
- UMR INSERM S1236, LabEx IGO, Univ Rennes, EFS, Rennes, France
- CHU Rennes, SITI Laboratory, Pôle Biologie, Rennes, France
| | - Florian Reizine
- UMR INSERM S1236, LabEx IGO, Univ Rennes, EFS, Rennes, France
- CHU Rennes, SITI Laboratory, Pôle Biologie, Rennes, France
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | - Mathieu Lesouhaitier
- UMR INSERM S1236, LabEx IGO, Univ Rennes, EFS, Rennes, France
- CHU Rennes, SITI Laboratory, Pôle Biologie, Rennes, France
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | - Yoni Desvois
- UMR INSERM S1236, LabEx IGO, Univ Rennes, EFS, Rennes, France
| | | | - Caroline Moreau
- CHU Rennes, Laboratoire de Biochimie, Pôle Biologie, Rennes, France
- Univ Rennes, INSERM, EHESP, IRSET, UMR S1085, Rennes, France
| | - Patricia Amé
- UMR INSERM S1236, LabEx IGO, Univ Rennes, EFS, Rennes, France
- CHU Rennes, SITI Laboratory, Pôle Biologie, Rennes, France
| | - Karin Tarte
- UMR INSERM S1236, LabEx IGO, Univ Rennes, EFS, Rennes, France
- CHU Rennes, SITI Laboratory, Pôle Biologie, Rennes, France
| | - Jean-Marc Tadié
- UMR INSERM S1236, LabEx IGO, Univ Rennes, EFS, Rennes, France
- CHU Rennes, SITI Laboratory, Pôle Biologie, Rennes, France
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | - Céline Delaloy
- UMR INSERM S1236, LabEx IGO, Univ Rennes, EFS, Rennes, France
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32
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Sollid LM, Iversen R. Tango of B cells with T cells in the making of secretory antibodies to gut bacteria. Nat Rev Gastroenterol Hepatol 2023; 20:120-128. [PMID: 36056203 DOI: 10.1038/s41575-022-00674-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/27/2022] [Indexed: 02/03/2023]
Abstract
Polymeric IgA and IgM are transported across the epithelial barrier from plasma cells in the lamina propria to exert a function in the gut lumen as secretory antibodies. Many secretory antibodies are reactive with the gut bacteria, and mounting evidence suggests that these antibodies are important for the host to control gut bacterial communities. However, we have incomplete knowledge of how bacteria-reactive secretory antibodies are formed. Antibodies from gut plasma cells often show bacterial cross-species reactivity, putting the degree of specificity behind anti-bacterial antibody responses into question. Such cross-species reactive antibodies frequently recognize non-genome-encoded membrane glycan structures. On the other hand, the T cell epitopes are peptides encoded in the bacterial genomes, thereby allowing a higher degree of predictable specificity on the T cell side of anti-bacterial immune responses. In this Perspective, we argue that the production of bacteria-reactive secretory antibodies is mainly controlled by the antigen specificity of T cells, which provide help to B cells. To be able to harness this system (for instance, for manipulation with vaccines), we need to obtain insight into the bacterial epitopes recognized by T cells in addition to characterizing the reactivity of the antibodies.
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Affiliation(s)
- Ludvig M Sollid
- K.G. Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. .,Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
| | - Rasmus Iversen
- K.G. Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. .,Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
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33
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Bessho S, Grando KCM, Kyrylchuk K, Miller A, Klein-Szanto AJ, Zhu W, Gallucci S, Tam V, Tükel Ç. Systemic exposure to bacterial amyloid curli alters the gut mucosal immune response and the microbiome, exacerbating Salmonella-induced arthritis. Gut Microbes 2023; 15:2221813. [PMID: 37317012 PMCID: PMC10269392 DOI: 10.1080/19490976.2023.2221813] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 05/30/2023] [Accepted: 05/31/2023] [Indexed: 06/16/2023] Open
Abstract
The Salmonella biofilm-associated amyloid protein, curli, is a dominant instigator of systemic inflammation and autoimmune responses following Salmonella infection. Systemic curli injections or infection of mice with Salmonella Typhimurium induce the major features of reactive arthritis, an autoimmune disorder associated with Salmonella infection in humans. In this study, we investigated the link between inflammation and microbiota in exacerbating autoimmunity. We studied C57BL/6 mice from two sources, Taconic Farms and Jackson Labs. Mice from Taconic Farms have been reported to have higher basal levels of the inflammatory cytokine IL - 17 than do mice from Jackson Labs due to the differences in their microbiota. When we systemically injected mice with purified curli, we observed a significant increase in diversity in the microbiota of Jackson Labs mice but not in that of the Taconic mice. In Jackson Labs, mice, the most striking effect was the expansion of Prevotellaceae. Furthermore, there were increases in the relative abundance of the family Akkermansiaceae and decreases in families Clostridiaceae and Muribaculaceae in Jackson Labs mice. Curli treatment led to significantly aggravated immune responses in the Taconic mice compared to Jackson Labs counterparts. Expression and production of IL - 1β, a cytokine known to promote IL - 17 production, as well as expression of Tnfa increased in the gut mucosa of Taconic mice in the first 24 hours after curli injections, which correlated with significant increases in the number of neutrophils and macrophages in the mesenteric lymph nodes. A significant increase in the expression of Ccl3 in colon and cecum of Taconic mice injected with curli was detected. Taconic mice injected with curli also had elevated levels of inflammation in their knees. Overall, our data suggest that autoimmune responses to bacterial ligands, such as curli, are amplified in individuals with a microbiome that promote inflammation.
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Affiliation(s)
- Shingo Bessho
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Kaitlyn C. M. Grando
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Kathrine Kyrylchuk
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Amanda Miller
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | | | - Wenhan Zhu
- Department of Pathology Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Stefania Gallucci
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Vincent Tam
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Çagla Tükel
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
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Zimmerman LM. Adaptive Immunity in Reptiles: Conventional Components but Unconventional Strategies. Integr Comp Biol 2022; 62:1572-1583. [PMID: 35482599 DOI: 10.1093/icb/icac022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/25/2022] [Accepted: 04/25/2022] [Indexed: 01/05/2023] Open
Abstract
Recent studies have established that the innate immune system of reptiles is broad and robust, but the question remains: What role does the reptilian adaptive immune system play? Conventionally, adaptive immunity is described as involving T and B lymphocytes that display variable receptors, is highly specific, improves over the course of the response, and produces a memory response. While reptiles do have B and T lymphocytes that utilize variable receptors, their adaptive response is relatively non-specific, generates a prolonged antibody response, and does not produce a typical memory response. This alternative adaptive strategy may allow reptiles to produce a broad adaptive response that complements a strong innate system. Further studies into reptile adaptive immunity cannot only clarify outstanding questions on the reptilian immune system but can shed light on a number of important immunological concepts, including the evolution of the immune system and adaptive immune responses that take place outside of germinal centers.
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35
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Nguyen DC, Lamothe PA, Woodruff MC, Saini AS, Faliti CE, Sanz I, Lee FE. COVID-19 and plasma cells: Is there long-lived protection? Immunol Rev 2022; 309:40-63. [PMID: 35801537 PMCID: PMC9350162 DOI: 10.1111/imr.13115] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Infection with SARS-CoV-2, the etiology of the ongoing COVID-19 pandemic, has resulted in over 450 million cases with more than 6 million deaths worldwide, causing global disruptions since early 2020. Memory B cells and durable antibody protection from long-lived plasma cells (LLPC) are the mainstay of most effective vaccines. However, ending the pandemic has been hampered by the lack of long-lived immunity after infection or vaccination. Although immunizations offer protection from severe disease and hospitalization, breakthrough infections still occur, most likely due to new mutant viruses and the overall decline of neutralizing antibodies after 6 months. Here, we review the current knowledge of B cells, from extrafollicular to memory populations, with a focus on distinct plasma cell subsets, such as early-minted blood antibody-secreting cells and the bone marrow LLPC, and how these humoral compartments contribute to protection after SARS-CoV-2 infection and immunization.
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Affiliation(s)
- Doan C. Nguyen
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
| | - Pedro A. Lamothe
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
| | - Matthew C. Woodruff
- Division of Rheumatology, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
- Emory Autoimmunity Center of ExcellenceEmory UniversityAtlantaGeorgiaUSA
- Lowance Center for Human ImmunologyEmory UniversityAtlantaGeorgiaUSA
| | - Ankur S. Saini
- Division of Rheumatology, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
- Emory Autoimmunity Center of ExcellenceEmory UniversityAtlantaGeorgiaUSA
- Lowance Center for Human ImmunologyEmory UniversityAtlantaGeorgiaUSA
| | - Caterina E. Faliti
- Division of Rheumatology, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
- Lowance Center for Human ImmunologyEmory UniversityAtlantaGeorgiaUSA
| | - Ignacio Sanz
- Division of Rheumatology, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
- Emory Autoimmunity Center of ExcellenceEmory UniversityAtlantaGeorgiaUSA
- Lowance Center for Human ImmunologyEmory UniversityAtlantaGeorgiaUSA
| | - Frances Eun‐Hyung Lee
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
- Lowance Center for Human ImmunologyEmory UniversityAtlantaGeorgiaUSA
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36
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Wang Y, Tian Q, Ye L. The Differentiation and Maintenance of SARS-CoV-2-Specific Follicular Helper T Cells. Front Cell Infect Microbiol 2022; 12:953022. [PMID: 35909969 PMCID: PMC9329515 DOI: 10.3389/fcimb.2022.953022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Upon acute viral infection, virus-specific CD4+ T cells differentiate into either TH1 cells or follicular helper T (TFH) cells. The molecular pathways governing such bimodal cell fate commitment remain elusive. Additionally, effector virus-specific TFH cells further differentiate into corresponding memory population, which confer long-term protection against re-infection of same viruses by providing immediate help to virus-specific memory B cells. Currently, the molecular mechanisms underlying the long-term maintenance of memory TFH cells are largely unknown. In this review, we discuss current understanding of early differentiation of virus-specific effector TFH cells and long-term maintenance of virus-specific memory TFH cells in mouse models of viral infection and patients of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
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Affiliation(s)
- Yifei Wang
- Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Qin Tian
- Dermatology Hospital, Southern Medical University, Guangzhou, China
- Institute of Immunology, The People’s Liberation Army (PLA), Third Military Medical University, Chongqing, China
| | - Lilin Ye
- Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
- Institute of Immunology, The People’s Liberation Army (PLA), Third Military Medical University, Chongqing, China
- *Correspondence: Lilin Ye,
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37
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Lee T, Kim Y, Kim HJ, Ha NY, Lee S, Chin B, Cho NH. Acute Surge of Atypical Memory and Plasma B-Cell Subsets Driven by an Extrafollicular Response in Severe COVID-19. Front Cell Infect Microbiol 2022; 12:909218. [PMID: 35899045 PMCID: PMC9309264 DOI: 10.3389/fcimb.2022.909218] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 06/13/2022] [Indexed: 11/20/2022] Open
Abstract
Background Despite the use of vaccines and therapeutics against the coronavirus disease 2019 (COVID-19) pandemic, this severe disease has been a critical burden on public health, whereas the pathogenic mechanism remains elusive. Recently, accumulating evidence underscores the potential role of the aberrant B-cell response and humoral immunity in disease progression, especially in high-risk groups. Methods Using single-cell RNA (scRNA) sequencing analysis, we investigated transcriptional features of B-cell population in peripheral blood from COVID-19 patients and compared them, according to clinical severity and disease course, against a public B-cell dataset. Results We confirmed that acute B cells differentiate into plasma cells, particularly in severe patients, potentially through enhanced extrafollicular (EF) differentiation. In severe groups, the elevated plasma B-cell response displayed increased B-cell receptor (BCR) diversity, as well as higher levels of anti–severe acute respiratory syndrome coronavirus 2 (anti–SARS-CoV-2) spike antibodies in plasma, than those in moderate cases, suggesting more robust and heterogeneous plasma cell response in severe COVID-19 patients. Trajectory analysis identified a differentiation pathway for the EF B-cell response from active naïve to atypical memory B cells (AM2), in addition to the emergence of an aberrant plasma cell subset (PC2), which was associated with COVID-19 progression and severity. The AM2 and PC2 subsets surged in the acute phase of the severe disease and presented multiple inflammatory features, including higher cytokine expression and humoral effector function, respectively. These features differ from other B-cell subsets, suggesting a pathogenic potential for disease progression. Conclusion The acute surge of AM2 and PC2 subsets with lower somatic hypermutation and higher inflammatory features may be driven by the EF B-cell response during the acute phase of severe COVID-19 and may represent one of the critical drivers in disease severity.
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Affiliation(s)
- Taeseob Lee
- Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea
- Discovery department, Biomarker Laboratory, Geninus Inc., Seoul, South Korea
| | - Yuri Kim
- Institute of Endemic Diseases, Medical Research Center, Seoul National University, Seoul, South Korea
| | - Hyun Je Kim
- College of Medicine, Genome Medicine Institute, Seoul National University, Seoul, South Korea
| | - Na-Young Ha
- Institute of Endemic Diseases, Medical Research Center, Seoul National University, Seoul, South Korea
- School of Medicine, Biomedical Research Institute, Chungnam National University, Daejeon, South Korea
| | - Siyoung Lee
- Discovery department, Biomarker Laboratory, Geninus Inc., Seoul, South Korea
| | - BumSik Chin
- Department of Internal Medicine, National Medical Center, Seoul, South Korea
- *Correspondence: Nam-Hyuk Cho, ; BumSik Chin,
| | - Nam-Hyuk Cho
- Institute of Endemic Diseases, Medical Research Center, Seoul National University, Seoul, South Korea
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, South Korea
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, South Korea
- Bundang Hospital, Seoul National University, Seongnam, South Korea
- Wide River Institute of Immunology, Seoul National University, Hongcheon, South Korea
- *Correspondence: Nam-Hyuk Cho, ; BumSik Chin,
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38
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Courey-Ghaouzi AD, Kleberg L, Sundling C. Alternative B Cell Differentiation During Infection and Inflammation. Front Immunol 2022; 13:908034. [PMID: 35812395 PMCID: PMC9263372 DOI: 10.3389/fimmu.2022.908034] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/30/2022] [Indexed: 01/02/2023] Open
Abstract
Long-term protective immunity to infectious disease depends on cell-mediated and humoral immune responses. Induction of a strong humoral response relies on efficient B cell activation and differentiation to long-lived plasma cells and memory B cells. For many viral or bacterial infections, a single encounter is sufficient to induce such responses. In malaria, the induction of long-term immunity can take years of pathogen exposure to develop, if it occurs at all. This repeated pathogen exposure and suboptimal immune response coincide with the expansion of a subset of B cells, often termed atypical memory B cells. This subset is present at low levels in healthy individuals as well but it is observed to expand in an inflammatory context during acute and chronic infection, autoimmune diseases or certain immunodeficiencies. Therefore, it has been proposed that this subset is exhausted, dysfunctional, or potentially autoreactive, but its actual role has remained elusive. Recent reports have provided new information regarding both heterogeneity and expansion of these cells, in addition to indications on their potential role during normal immune responses to infection or vaccination. These new insights encourage us to rethink how and why they are generated and better understand their role in our complex immune system. In this review, we will focus on recent advances in our understanding of these enigmatic cells and highlight the remaining gaps that need to be filled.
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Affiliation(s)
- Alan-Dine Courey-Ghaouzi
- Division of Infectious Diseases, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Linn Kleberg
- Division of Infectious Diseases, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Christopher Sundling
- Division of Infectious Diseases, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- *Correspondence: Christopher Sundling,
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39
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Pellegrini JM, Gorvel JP, Mémet S. Immunosuppressive Mechanisms in Brucellosis in Light of Chronic Bacterial Diseases. Microorganisms 2022; 10:1260. [PMID: 35888979 PMCID: PMC9324529 DOI: 10.3390/microorganisms10071260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 01/27/2023] Open
Abstract
Brucellosis is considered one of the major zoonoses worldwide, constituting a critical livestock and human health concern with a huge socio-economic burden. Brucella genus, its etiologic agent, is composed of intracellular bacteria that have evolved a prodigious ability to elude and shape host immunity to establish chronic infection. Brucella's intracellular lifestyle and pathogen-associated molecular patterns, such as its specific lipopolysaccharide (LPS), are key factors for hiding and hampering recognition by the immune system. Here, we will review the current knowledge of evading and immunosuppressive mechanisms elicited by Brucella species to persist stealthily in their hosts, such as those triggered by their LPS and cyclic β-1,2-d-glucan or involved in neutrophil and monocyte avoidance, antigen presentation impairment, the modulation of T cell responses and immunometabolism. Attractive strategies exploited by other successful chronic pathogenic bacteria, including Mycobacteria, Salmonella, and Chlamydia, will be also discussed, with a special emphasis on the mechanisms operating in brucellosis, such as granuloma formation, pyroptosis, and manipulation of type I and III IFNs, B cells, innate lymphoid cells, and host lipids. A better understanding of these stratagems is essential to fighting bacterial chronic infections and designing innovative treatments and vaccines.
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40
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Patel SR, Lundgren TS, Baldwin WH, Cox C, Parker ET, Healey JF, Jajosky RP, Zerra PE, Josephson CD, Doering CB, Stowell SR, Meeks SL. Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway. Front Immunol 2022; 13:880829. [PMID: 35634288 PMCID: PMC9132091 DOI: 10.3389/fimmu.2022.880829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/12/2022] [Indexed: 11/13/2022] Open
Abstract
Humoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal center (GC) dependent process. However, clinical observations suggest that the nature of the immune response to FVIII may differ between patients. While some patients produce persistent low or high inhibitor titers, others generate a transient response. Moreover, FVIII reactive memory B cells are only detectable in some patients with sustained inhibitor titers. The determinants regulating the type of immune response a patient develops, let alone how the immune response differs in these patients remains incompletely understood. One hypothesis is that polymorphisms within immunoregulatory genes alter the underlying immune response to FVIII, and thereby the inhibitor response. Consistent with this, studies report that inhibitor titers to FVIII differ in animals with the same F8 pathogenic variant but completely distinct backgrounds; though, how these genetic disparities affect the immune response to FVIII remains to be investigated. Given this, we sought to mechanistically dissect how genetics impact the underlying immune response to FVIII. In particular, as the risk of producing inhibitors is weakly associated with differences in HLA, we hypothesized that genetic factors other than HLA influence the immune response to FVIII and downstream inhibitor formation. Our data demonstrate that FVIII deficient mice encoding the same MHC and F8 variant produce disparate inhibitor titers, and that the type of inhibitor response formed associates with the ability to generate GCs. Interestingly, the formation of antibodies through a GC or non-GC pathway does not appear to be due to differences in CD4 T cell immunity, as the CD4 T cell response to an immunodominant epitope in FVIII was similar in these mice. These results indicate that genetics can impact the process by which inhibitors develop and may in part explain the apparent propensity of patients to form distinct inhibitor responses. Moreover, these data highlight an underappreciated immunological pathway of humoral immunity to FVIII and lay the groundwork for identification of biomarkers for the development of approaches to tolerize against FVIII.
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Affiliation(s)
- Seema R Patel
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States
| | - Taran S Lundgren
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States.,Graduate Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, United States
| | - Wallace Hunter Baldwin
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States
| | - Courtney Cox
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States
| | - Ernest T Parker
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States
| | - John F Healey
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States
| | - Ryan P Jajosky
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Patricia E Zerra
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States.,Center for Transfusion Medicine and Cellular Therapies, Department of Laboratory Medicine and Pathology, Emory University School of Medicine, Atlanta, GA, United States
| | - Cassandra D Josephson
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States
| | - Christopher B Doering
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States
| | - Sean R Stowell
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Shannon L Meeks
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United States
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41
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Abstract
The tumor microenvironment (TME) is a heterogeneous, complex organization composed of tumor, stroma, and endothelial cells that is characterized by cross talk between tumor and innate and adaptive immune cells. Over the last decade, it has become increasingly clear that the immune cells in the TME play a critical role in controlling or promoting tumor growth. The function of T lymphocytes in this process has been well characterized. On the other hand, the function of B lymphocytes is less clear, although recent data from our group and others have strongly indicated a critical role for B cells in antitumor immunity. There are, however, a multitude of populations of B cells found within the TME, ranging from naive B cells all the way to terminally differentiated plasma cells and memory B cells. Here, we characterize the role of B cells in the TME in both animal models and patients, with an emphasis on dissecting how B cell heterogeneity contributes to the immune response to cancer.
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Affiliation(s)
- Stephanie M Downs-Canner
- Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Jeremy Meier
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA;
| | - Benjamin G Vincent
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; .,Bioinformatics and Computational Biology Program, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.,Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Jonathan S Serody
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; .,Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
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42
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Delvecchio FR, Goulart MR, Fincham REA, Bombadieri M, Kocher HM. B cells in pancreatic cancer stroma. World J Gastroenterol 2022; 28:1088-1101. [PMID: 35431504 PMCID: PMC8985484 DOI: 10.3748/wjg.v28.i11.1088] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/18/2021] [Accepted: 02/19/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a disease with high unmet clinical need. Pancreatic cancer is also characterised by an intense fibrotic stroma, which harbours many immune cells. Studies in both human and animal models have demonstrated that the immune system plays a crucial role in modulating tumour onset and progression. In human pancreatic ductal adenocarcinoma, high B-cell infiltration correlates with better patient survival. Hence, B cells have received recent interest in pancreatic cancer as potential therapeutic targets. However, the data on the role of B cells in murine models is unclear as it is dependent on the pancreatic cancer model used to study. Nevertheless, it appears that B cells do organise along with other immune cells such as a network of follicular dendritic cells (DCs), surrounded by T cells and DCs to form tertiary lymphoid structures (TLS). TLS are increasingly recognised as sites for antigen presentation, T-cell activation, B-cell maturation and differentiation in plasma cells. In this review we dissect the role of B cells and provide directions for future studies to harness the role of B cells in treatment of human pancreatic cancer.
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Affiliation(s)
- Francesca Romana Delvecchio
- William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
- Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Michelle R Goulart
- Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | | | - Michele Bombadieri
- William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Hemant M Kocher
- Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
- Barts and the London HPB Centre, Barts Health NHS Trust, London E1 1BB, United Kingdom
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43
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Biram A, Liu J, Hezroni H, Davidzohn N, Schmiedel D, Khatib-Massalha E, Haddad M, Grenov A, Lebon S, Salame TM, Dezorella N, Hoffman D, Abou Karam P, Biton M, Lapidot T, Bemark M, Avraham R, Jung S, Shulman Z. Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation. Immunity 2022; 55:442-458.e8. [PMID: 35182483 DOI: 10.1016/j.immuni.2022.01.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 10/11/2021] [Accepted: 01/18/2022] [Indexed: 02/07/2023]
Abstract
Consecutive exposures to different pathogens are highly prevalent and often alter the host immune response. However, it remains unknown how a secondary bacterial infection affects an ongoing adaptive immune response elicited against primary invading pathogens. We demonstrated that recruitment of Sca-1+ monocytes into lymphoid organs during Salmonella Typhimurium (STm) infection disrupted pre-existing germinal center (GC) reactions. GC responses induced by influenza, plasmodium, or commensals deteriorated following STm infection. GC disruption was independent of the direct bacterial interactions with B cells and instead was induced through recruitment of CCR2-dependent Sca-1+ monocytes into the lymphoid organs. GC collapse was associated with impaired cellular respiration and was dependent on TNFα and IFNγ, the latter of which was essential for Sca-1+ monocyte differentiation. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon severe bacterial infection is induced at the expense of antibody-mediated immunity.
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Affiliation(s)
- Adi Biram
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
| | - Jingjing Liu
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Hadas Hezroni
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Natalia Davidzohn
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Dominik Schmiedel
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Eman Khatib-Massalha
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Montaser Haddad
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Amalie Grenov
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Sacha Lebon
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Tomer Meir Salame
- Department of Life Science Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Nili Dezorella
- Electron Microscopy Unit, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Dotan Hoffman
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Paula Abou Karam
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Moshe Biton
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Tsvee Lapidot
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Mats Bemark
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg SE-405 30, Sweden
| | - Roi Avraham
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Steffen Jung
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Ziv Shulman
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
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44
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Boothby MR, Brookens SK, Raybuck AL, Cho SH. Supplying the trip to antibody production-nutrients, signaling, and the programming of cellular metabolism in the mature B lineage. Cell Mol Immunol 2022; 19:352-369. [PMID: 34782762 PMCID: PMC8591438 DOI: 10.1038/s41423-021-00782-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/16/2021] [Indexed: 12/26/2022] Open
Abstract
The COVID pandemic has refreshed and expanded recognition of the vital role that sustained antibody (Ab) secretion plays in our immune defenses against microbes and of the importance of vaccines that elicit Ab protection against infection. With this backdrop, it is especially timely to review aspects of the molecular programming that govern how the cells that secrete Abs arise, persist, and meet the challenge of secreting vast amounts of these glycoproteins. Whereas plasmablasts and plasma cells (PCs) are the primary sources of secreted Abs, the process leading to the existence of these cell types starts with naive B lymphocytes that proliferate and differentiate toward several potential fates. At each step, cells reside in specific microenvironments in which they not only receive signals from cytokines and other cell surface receptors but also draw on the interstitium for nutrients. Nutrients in turn influence flux through intermediary metabolism and sensor enzymes that regulate gene transcription, translation, and metabolism. This review will focus on nutrient supply and how sensor mechanisms influence distinct cellular stages that lead to PCs and their adaptations as factories dedicated to Ab secretion. Salient findings of this group and others, sometimes exhibiting differences, will be summarized with regard to the journey to a distinctive metabolic program in PCs.
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Affiliation(s)
- Mark R Boothby
- Department of Pathology, Microbiology & Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Department of Medicine, Rheumatology & Immunology Division, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Cancer Biology Program, Vanderbilt University, Nashville, TN, 37232, USA.
- Vanderbilt Institute of Infection, Inflammation, and Immunology, Nashville, TN, 37232, USA.
| | - Shawna K Brookens
- Department of Pathology, Microbiology & Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Cancer Biology Program, Vanderbilt University, Nashville, TN, 37232, USA
| | - Ariel L Raybuck
- Department of Pathology, Microbiology & Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Sung Hoon Cho
- Department of Pathology, Microbiology & Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Vanderbilt Institute of Infection, Inflammation, and Immunology, Nashville, TN, 37232, USA
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45
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Song W, Antao OQ, Condiff E, Sanchez GM, Chernova I, Zembrzuski K, Steach H, Rubtsova K, Angeletti D, Lemenze A, Laidlaw BJ, Craft J, Weinstein JS. Development of Tbet- and CD11c-expressing B cells in a viral infection requires T follicular helper cells outside of germinal centers. Immunity 2022; 55:290-307.e5. [PMID: 35090581 PMCID: PMC8965751 DOI: 10.1016/j.immuni.2022.01.002] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 10/27/2021] [Accepted: 01/04/2022] [Indexed: 12/31/2022]
Abstract
Tbet+CD11c+ B cells arise during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Here, we examined the developmental requirements of this B cell subset. In acute infection, T follicular helper (Tfh) cells, but not Th1 cells, drove Tbet+CD11c+ B cell generation through proximal delivery of help. Tbet+CD11c+ B cells developed prior to germinal center (GC) formation, exhibiting phenotypic and transcriptional profiles distinct from GC B cells. Fate tracking revealed that most Tbet+CD11c+ B cells developed independently of GC entry and cell-intrinsic Bcl6 expression. Tbet+CD11c+ and GC B cells exhibited minimal repertoire overlap, indicating distinct developmental pathways. As the infection resolved, Tbet+CD11c+ B cells localized to the marginal zone where splenic retention depended on integrins LFA-1 and VLA-4, forming a competitive memory subset that contributed to antibody production and secondary GC seeding upon rechallenge. Therefore, Tbet+CD11c+ B cells comprise a GC-independent memory subset capable of rapid and robust recall responses.
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Affiliation(s)
- Wenzhi Song
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Olivia Q Antao
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Emily Condiff
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Gina M Sanchez
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Irene Chernova
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Krzysztof Zembrzuski
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Holly Steach
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Kira Rubtsova
- Department of Biomedical Research, National Jewish Health, Denver, CO, USA
| | - Davide Angeletti
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Alexander Lemenze
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Brian J Laidlaw
- Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Joe Craft
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
| | - Jason S Weinstein
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA.
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46
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Chen JS, Chow RD, Song E, Mao T, Israelow B, Kamath K, Bozekowski J, Haynes WA, Filler RB, Menasche BL, Wei J, Alfajaro MM, Song W, Peng L, Carter L, Weinstein JS, Gowthaman U, Chen S, Craft J, Shon JC, Iwasaki A, Wilen CB, Eisenbarth SC. High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells. Sci Immunol 2022; 7:eabl5652. [PMID: 34914544 PMCID: PMC8977051 DOI: 10.1126/sciimmunol.abl5652] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
T follicular helper (TFH) cells are the conventional drivers of protective, germinal center (GC)–based antiviral antibody responses. However, loss of TFH cells and GCs has been observed in patients with severe COVID-19. As T cell–B cell interactions and immunoglobulin class switching still occur in these patients, noncanonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both TFH-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Although TFH-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. We found by epitope mapping and B cell receptor sequencing that TFH cells focused the B cell response, and therefore, in the absence of TFH cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.
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Affiliation(s)
- Jennifer S. Chen
- Department of Laboratory Medicine, Yale University School of Medicine; New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | - Ryan D. Chow
- Department of Genetics, Yale University School of Medicine; New Haven, CT, USA
- Systems Biology Institute, Yale University; West Haven, CT, USA
| | - Eric Song
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | - Tianyang Mao
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | - Benjamin Israelow
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine; New Haven, CT, USA
| | | | | | | | - Renata B. Filler
- Department of Laboratory Medicine, Yale University School of Medicine; New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | - Bridget L. Menasche
- Department of Laboratory Medicine, Yale University School of Medicine; New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | - Jin Wei
- Department of Laboratory Medicine, Yale University School of Medicine; New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | - Mia Madel Alfajaro
- Department of Laboratory Medicine, Yale University School of Medicine; New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | - Wenzhi Song
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | - Lei Peng
- Department of Genetics, Yale University School of Medicine; New Haven, CT, USA
- Systems Biology Institute, Yale University; West Haven, CT, USA
| | - Lauren Carter
- Institute for Protein Design, University of Washington; Seattle, WA, USA
| | - Jason S. Weinstein
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School; Newark, NJ, USA
| | - Uthaman Gowthaman
- Deparment of Pathology, University of Massachusetts Medical School; Worcester, MA, USA
| | - Sidi Chen
- Department of Genetics, Yale University School of Medicine; New Haven, CT, USA
- Systems Biology Institute, Yale University; West Haven, CT, USA
| | - Joe Craft
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | | | - Akiko Iwasaki
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
- Howard Hughes Medical Institute; Chevy Chase, MD, USA
| | - Craig B. Wilen
- Department of Laboratory Medicine, Yale University School of Medicine; New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
| | - Stephanie C. Eisenbarth
- Department of Laboratory Medicine, Yale University School of Medicine; New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine; New Haven, CT, USA
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Broketa M, Bruhns P. Single-Cell Technologies for the Study of Antibody-Secreting Cells. Front Immunol 2022; 12:821729. [PMID: 35173713 PMCID: PMC8841722 DOI: 10.3389/fimmu.2021.821729] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 12/29/2021] [Indexed: 01/05/2023] Open
Abstract
Antibody-secreting cells (ASC), plasmablasts and plasma cells, are terminally differentiated B cells responsible for large-scale production and secretion of antibodies. ASC are derived from activated B cells, which may differentiate extrafollicularly or form germinal center (GC) reactions within secondary lymphoid organs. ASC therefore consist of short-lived, poorly matured plasmablasts that generally secrete lower-affinity antibodies, or long-lived, highly matured plasma cells that generally secrete higher-affinity antibodies. The ASC population is responsible for producing an immediate humoral B cell response, the polyclonal antibody repertoire, as well as in parallel building effective humoral memory and immunity, or potentially driving pathology in the case of autoimmunity. ASC are phenotypically and transcriptionally distinct from other B cells and further distinguishable by morphology, varied lifespans, and anatomical localization. Single cell analyses are required to interrogate the functional and transcriptional diversity of ASC and their secreted antibody repertoire and understand the contribution of individual ASC responses to the polyclonal humoral response. Here we summarize the current and emerging functional and molecular techniques for high-throughput characterization of ASC with single cell resolution, including flow and mass cytometry, spot-based and microfluidic-based assays, focusing on functional approaches of the secreted antibodies: specificity, affinity, and secretion rate.
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Affiliation(s)
- Matteo Broketa
- Institut Pasteur, Université de Paris, INSERM UMR 1222, Unit of Antibodies in Therapy and Pathology, Paris, France
- Sorbonne Université, Collège doctoral, Paris, France
| | - Pierre Bruhns
- Institut Pasteur, Université de Paris, INSERM UMR 1222, Unit of Antibodies in Therapy and Pathology, Paris, France
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Feldman J, Bals J, Altomare CG, St. Denis K, Lam EC, Hauser BM, Ronsard L, Sangesland M, Moreno TB, Okonkwo V, Hartojo N, Balazs AB, Bajic G, Lingwood D, Schmidt AG. Naive human B cells engage the receptor binding domain of SARS-CoV-2, variants of concern, and related sarbecoviruses. Sci Immunol 2021; 6:eabl5842. [PMID: 34648356 PMCID: PMC8720485 DOI: 10.1126/sciimmunol.abl5842] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Initial exposure to a pathogen elicits an adaptive immune response to control and eradicate the threat. Interrogating the abundance and specificity of the naive B cell repertoire drives understanding of how to mount protective responses. Here, we isolated naive B cells from eight seronegative human donors targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD). Single-cell B cell receptor (BCR) sequencing identified diverse gene usage and no restriction on complementarity determining region length. A subset of recombinant antibodies produced by naive B cell precursors bound to SARS-CoV-2 RBD and engaged circulating variants including B.1.1.7, B.1.351, and B.1.617.2, as well as preemergent bat-derived coronaviruses RaTG13, SHC104, and WIV1. By structural characterization of a naive antibody in complex with SARS-CoV-2 spike, we identified a conserved mode of recognition shared with infection-induced antibodies. We found that representative naive antibodies could signal in a B cell activation assay, and by using directed evolution, we could select for a higher-affinity RBD interaction, conferred by a single amino acid change. The minimally mutated, affinity-matured antibodies also potently neutralized SARS-CoV-2. Understanding the SARS-CoV-2 RBD–specific naive repertoire may inform potential responses capable of recognizing future SARS-CoV-2 variants or emerging coronaviruses, enabling the development of pan-coronavirus vaccines aimed at engaging protective germline responses.
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Affiliation(s)
- Jared Feldman
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Julia Bals
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Clara G. Altomare
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Kerri St. Denis
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Evan C. Lam
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Blake M. Hauser
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Larance Ronsard
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Maya Sangesland
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | | | - Vintus Okonkwo
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Nathania Hartojo
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | | | - Goran Bajic
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Daniel Lingwood
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Aaron G. Schmidt
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
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49
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Kuley R, Draves KE, Fuller DH, Giltiay NV, Clark EA, Giordano D. B cell activating factor (BAFF) from neutrophils and dendritic cells is required for protective B cell responses against Salmonella typhimurium infection. PLoS One 2021; 16:e0259158. [PMID: 34705890 PMCID: PMC8550399 DOI: 10.1371/journal.pone.0259158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/13/2021] [Indexed: 01/01/2023] Open
Abstract
Mice lacking B cells are more susceptible to S. typhimurium infection. How B cells contribute to protective immunity against Salmonella and what signals drive their activation are still unclear. Neutrophils (Nphs), monocytes (MOs), and dendritic cells (DCs) are involved in early immune responses to control the initial replication of S. typhimurium. These cells can produce B cell activating factor (BAFF) required for mature B cell survival and may help regulate B cell responses during Salmonella infection. Using BAFF reporter mice (BAFF-RFP+/-), we discovered that an i.p. infection with a virulent strain of S. typhimurium increased BAFF expression in splenic conventional DCs (cDC) and inflammatory Ly6Chi MOs/DCs four days post-infection. S. typhimurium infection induced the release of BAFF from Nphs, a decrease of BAFF-RFP expression and expansion of BAFF-RFP+ Nphs in the spleen and peritoneal cavity. After S. typhimurium infection, serum BAFF levels and immature and mature B cell subsets and plasma cells increased substantially. Conditional knockout (cKO) mice lacking BAFF in either Nphs or cDCs compared to control Bafffl/fl mice had reduced up-regulation of systemic BAFF levels and reduced expansion of mature and germinal center B cell subsets after infection. Importantly, the cKO mice lacking BAFF from either Nphs or cDCs had impaired induction of Salmonella-specific IgM Abs, and were more susceptible to S. typhimurium infection. Thus, Nphs and cDCs are major cellular sources of BAFF driving B cell responses, required for mounting optimal protective immunity against lethal Salmonella infection.
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Affiliation(s)
- Runa Kuley
- Department of Medicine, Division of Rheumatology, University of Washington, Seattle, Washington, United States of America
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
- * E-mail: (RK); (DG)
| | - Kevin E. Draves
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
| | - Deborah H. Fuller
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
| | - Natalia V. Giltiay
- Department of Medicine, Division of Rheumatology, University of Washington, Seattle, Washington, United States of America
| | - Edward A. Clark
- Department of Medicine, Division of Rheumatology, University of Washington, Seattle, Washington, United States of America
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
| | - Daniela Giordano
- Department of Medicine, Division of Rheumatology, University of Washington, Seattle, Washington, United States of America
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
- * E-mail: (RK); (DG)
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50
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Braddom AE, Bol S, Gonzales SJ, Reyes RA, Musinguzi K, Nankya F, Ssewanyana I, Greenhouse B, Bunnik EM. B Cell Receptor Repertoire Analysis in Malaria-Naive and Malaria-Experienced Individuals Reveals Unique Characteristics of Atypical Memory B Cells. mSphere 2021; 6:e0072621. [PMID: 34523978 PMCID: PMC8550134 DOI: 10.1128/msphere.00726-21] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 08/31/2021] [Indexed: 11/24/2022] Open
Abstract
Malaria, caused by parasites of the Plasmodium genus, is responsible for significant morbidity and mortality globally. Chronic Plasmodium falciparum exposure affects the B cell compartment, leading to the accumulation of atypical memory B cells (atMBCs). IgM-positive (IgM+) and IgG+ atMBCs have not been compared in-depth in the context of malaria, nor is it known if atMBCs in malaria-experienced individuals are different from phenotypically similar B cells in individuals with no known history of Plasmodium exposure. To address these questions, we characterized the B cell receptor (BCR) repertoire of naive B cells (NBCs), IgM+ and IgG+ classical MBCs (cMBCs), and IgM+ and IgG+ atMBCs from 13 malaria-naive American adults and 7 malaria-experienced Ugandan adults. Our results demonstrate that P. falciparum exposure mainly drives changes in atMBCs. In comparison to malaria-naive adults, the BCR repertoire of Plasmodium-exposed adults showed increased levels of somatic hypermutation in the heavy chain V region in IgM+ and IgG+ atMBCs, shorter heavy chain complementarity-determining region 3 (HCDR3) in IgG+ atMBCs, and increased usage of IGHV3-73 in IgG+ cMBCs and both IgM+ and IgG+ atMBCs. Irrespective of Plasmodium exposure, IgM+ atMBCs closely resembled NBCs, while IgG+ atMBCs resembled IgG+ cMBCs. Physicochemical properties of the HCDR3 seemed to be intrinsic to cell type and independent of malaria experience. The resemblance between atMBCs from Plasmodium-exposed and naive adults suggests similar differentiation pathways regardless of chronic antigen exposure. Moreover, these data demonstrate that IgM+ and IgG+ atMBCs are distinct populations that should be considered separately in future analyses. IMPORTANCE Malaria, caused by Plasmodium parasites, still contributes to a high global burden of disease, mainly in children under 5 years of age. Chronic and recurrent Plasmodium infections affect the development of B cell memory against the parasite and promote the accumulation of atypical memory B cells (atMBCs), which have an unclear function in the immune response. Understanding where these cells originate from and whether they are beneficial in the immune response to Plasmodium will help inform vaccination development efforts. We found differences in B cell receptor (BCR) properties of atMBCs between malaria-naive and malaria-experienced adults that are suggestive of divergent selection processes, resulting in more somatic hypermutation and differential immunoglobulin heavy chain V (IGHV) gene usage. Despite these differences, atMBCs from malaria-naive and malaria-experienced adults also showed many similarities in BCR characteristics, such as physicochemical properties of the HCDR3 region, suggesting that atMBCs undergo similar differentiation pathways in response to different pathogens. Our study provides new insights into the effects of malaria experience on the B cell compartment and the relationships between atMBCs and other B cell populations.
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Affiliation(s)
- Ashley E. Braddom
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Sebastiaan Bol
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - S. Jake Gonzales
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Raphael A. Reyes
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | | | | | - Isaac Ssewanyana
- Infectious Disease Research Collaboration, Kampala, Uganda
- London School of Hygiene and Tropical Medicine, London, UK
| | - Bryan Greenhouse
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
| | - Evelien M. Bunnik
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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