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1
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Oh T, Woo Y, Kim G, Koo BS, Baek SH, Hwang EH, An YJ, Kim Y, Kim DY, Hong JJ. Spatiotemporal Cellular Dynamics of Germinal Center Reaction in Coronavirus Disease 2019 Lung-Draining Lymph Node Based on Imaging-Based Spatial Transcriptomics. J Transl Med 2025; 105:102180. [PMID: 39522760 DOI: 10.1016/j.labinv.2024.102180] [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: 07/03/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Although lymph node structures may be compromised in severe SARS-CoV-2 infection, the extent and parameters of recovery in convalescing patients remain unclear. Therefore, this study aimed to elucidate the nuances of lymphoid structural recovery and their implications for immunologic memory in nonhuman primates infected with SARS-CoV-2. To do so, we utilized imaging-based spatial transcriptomics to delineate immune cell composition and tissue architecture formation in the lung-draining lymph nodes during primary infection, convalescence, and reinfection from COVID-19. We noted the establishment of a germinal center with memory B cell differentiation within lymphoid follicles during convalescence accompanied by contrasting transcriptome patterns indicative of the acquisition of follicular helper T cells versus the loss of regulatory T cells. Additionally, repopulation of germinal center-like B cells was observed in the medullary niche with accumulating plasma cells along with enhanced transcriptional expression of B cell-activating factor receptor over the course of reinfection. The spatial transcriptome atlas produced herein enhances our understanding of germinal center formation with immune cell dynamics during COVID-19 convalescence and lymphoid structural recovery with transcriptome dynamics following reinfection. These findings have the potential to inform the optimization of vaccine strategies and the development of precise therapeutic interventions in the spatial context.
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Affiliation(s)
- Taehwan Oh
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - YoungMin Woo
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea; KRIBB School of Bioscience, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
| | - Green Kim
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Bon-Sang Koo
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Seung Ho Baek
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Eun-Ha Hwang
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - You Jung An
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Yujin Kim
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Dong-Yeon Kim
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Jung Joo Hong
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea; KRIBB School of Bioscience, Korea University of Science & Technology (UST), Daejeon, Republic of Korea.
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2
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Huang L, Huang Z, Zhang Y, Lin C, Zhao Z, Li R, Saw PE, Xu X. Advances in targeted delivery of mRNA into immune cells for enhanced cancer therapy. Theranostics 2024; 14:5528-5550. [PMID: 39310113 PMCID: PMC11413781 DOI: 10.7150/thno.93745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 06/06/2024] [Indexed: 09/25/2024] Open
Abstract
Messenger RNA (mRNA) therapy has been applied to the treatment of various human diseases including malignant tumors. Increasing evidences have shown that mRNA can enhance the efficacy of cancer immunotherapy by modulating the functions of immune cells and stimulating their activity. However, mRNA is a type of negatively charged biomacromolecules that are susceptible to serum nucleases and cannot readily cross the cell membrane. In the past few decades, various nanoparticles (NPs)-based delivery systems have been rationally designed and developed to facilitate the intracellular uptake and cytosolic delivery of mRNA. More importantly, by means of the specific recognition between the targeting ligands decorated on NP surface and receptors specifically expressed on immune cells, these mRNA delivery systems could be functionalized to target immune cells to further enhance the mRNA-based cancer immunotherapy. In this review, we briefly introduced the advancements of mRNA in cancer therapy, discussed the challenges faced by mRNA delivery, and systematically summarized the recent development in NPs-based mRNA delivery systems targeting various types of immune cells for cancer immunotherapy. The future development of NPs-mediated targeted mRNA delivery and their challenges in clinical translation are also discussed.
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Affiliation(s)
- Linzhuo Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, P. R. China
| | - Zhiquan Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, P. R. China
| | - Yuxuan Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, P. R. China
| | - Chunhao Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, P. R. China
| | - Zixuan Zhao
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, P. R. China
| | - Rong Li
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, P. R. China
| | - Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, P. R. China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, P. R. China
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3
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Huang T, Pi C, Xu X, Feng Y, Zhang J, Gu H, Fang J. Effect of BAFF blockade on the B cell receptor repertoire and transcriptome in a mouse model of systemic lupus erythematosus. Front Immunol 2024; 14:1307392. [PMID: 38264661 PMCID: PMC10803406 DOI: 10.3389/fimmu.2023.1307392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/18/2023] [Indexed: 01/25/2024] Open
Abstract
Introduction Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Anti-B-cell-activating factor (BAFF) therapy effectively depletes B cells and reduces SLE disease activity. This research aimed to evaluate the effect of BAFF blockade on B cell receptor (BCR) repertoire and gene expression. Methods Through next-generation sequencing, we analyzed gene expression and BCR repertoire in MRL/lpr mice that received long-term anti-BAFF therapy. Based on gene expression profiles, we predicted the relative proportion of immune cells using ImmuCellAI-mouse, validating our predictions via flow cytometry and FluoroSpot. Results The loss of BCR repertoire diversity and richness, along with increased clonality and differential frequency distribution of the immunoglobulin heavy chain variable (IGHV) segment gene usage, were observed in BAFF-blockade mice. Meanwhile, the distribution of complementarity-determining region 3 (CDR3) length and CDR3 amino acid usage remained unaffected. BAFF blockade resulted in extensive changes in gene expression, particularly that of genes related to B cells and immunoglobulins. Besides, the tumor necrosis factor (TNF)-α responses and interferon (IFN)-α/γ were downregulated, consistent with the decrease in IFN-γ and TNF-α serum levels following anti-BAFF therapy. In addition, BAFF blockade significantly reduced B cell subpopulations and plasmacytoid dendritic cells, and caused the depletion of antibody-secreting cells. Discussion Our comparative BCR repertoire and transcriptome analyses of MRL/lpr mice subjected to BAFF blockade provide innovative insights into the molecular pathophysiology of SLE.
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Affiliation(s)
- Tao Huang
- School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Chenyu Pi
- School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xiaoqing Xu
- School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yan Feng
- School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jingming Zhang
- School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Hua Gu
- School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jianmin Fang
- School of Life Sciences and Technology, Tongji University, Shanghai, China
- Biomedical Research Center, Tongji University Suzhou Institute, Suzhou, Jiangsu, China
- Department of Neurology, Tongji Hospital, Tongji University, Shanghai, China
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Matz HC, McIntire KM, Ellebedy AH. 'Persistent germinal center responses: slow-growing trees bear the best fruits'. Curr Opin Immunol 2023; 83:102332. [PMID: 37150126 PMCID: PMC10829534 DOI: 10.1016/j.coi.2023.102332] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/06/2023] [Accepted: 04/09/2023] [Indexed: 05/09/2023]
Abstract
Germinal centers (GCs) are key microanatomical sites in lymphoid organs where responding B cells mature and undergo affinity-based selection. The duration of the GC reaction has long been assumed to be relatively brief, but recent studies in humans, nonhuman primates, and mice indicate that GCs can last for weeks to months after initial antigen exposure. This review examines recent studies investigating the factors that influence GC duration, including antigen persistence, T-follicular helper cells, and mode of immunization. Potential mechanisms for how persistent GCs influence the B-cell repertoire are considered. Overall, these studies provide a blueprint for how to design better vaccines that elicit persistent GC responses.
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Affiliation(s)
- Hanover C Matz
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Katherine M McIntire
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Ali H Ellebedy
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA; Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, St. Louis, MO, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, USA.
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5
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Koizumi H, Fujii W, Sanjoba C, Goto Y. BAFF induces CXCR5 expression during B cell differentiation in bone marrow. Biochem Biophys Rep 2023; 34:101451. [PMID: 36926279 PMCID: PMC10011739 DOI: 10.1016/j.bbrep.2023.101451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/22/2023] [Accepted: 03/03/2023] [Indexed: 03/09/2023] Open
Abstract
B cell activating factor (BAFF) plays an important role in antibody production through differentiation and maturation of B cells mainly in secondary lymphoid organs. On the other hand, the role of BAFF in the bone marrow, the primary lymphoid organ of B cell development, has not been well elucidated. Here, effects of BAFF in bone marrow B cell development were examined by using BAFF-deficient mice. When mRNA expression levels of B cell differentiation markers including Cd19, Bcl2, Igμ, Il7r and Cxcr5 were compared between bone marrow of wild-type and BAFF-KO mice, a lower level of Cxcr5 expression was found in the KO mice. Additionally, protein expression of CXCR5 on IgM+ cells in the bone marrow was decreased by BAFF deficiency. In vitro studies also confirmed the effect of BAFF on CXCR5 by IgM+ cells; culturing bone marrow cells from BAFF-KO mice with BAFF in vitro increased the proportion of CXCR5+ cells in IgM+ cells compared with non-treated bone marrow cells. In addition, BAFF synergized with TNF-α and IL-6 to increase the expression of CXCR5+ on IgM+ cells. The BAFF-mediated up-regulation of CXCR5 expression was reproduced by using CD19+ cells purified from BAFF-KO bone marrow cells, suggesting that BAFF directly affects B-lineage cells in bone marrow to promote CXCR5 expression. Together, this study suggests that BAFF has an important role in B cell differentiation in bone marrow by directly inducing CXCR5 expression which affect their migration to secondary lymphoid organs.
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Affiliation(s)
- Hajime Koizumi
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan
| | - Wataru Fujii
- Laboratory of Biomedical Science, Department of Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan
| | - Chizu Sanjoba
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan
| | - Yasuyuki Goto
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan
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6
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Maz MP, Martens JWS, Hannoudi A, Reddy AL, Hile GA, Kahlenberg JM. Recent advances in cutaneous lupus. J Autoimmun 2022; 132:102865. [PMID: 35858957 PMCID: PMC10082587 DOI: 10.1016/j.jaut.2022.102865] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/03/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022]
Abstract
Cutaneous lupus erythematosus (CLE) is an inflammatory and autoimmune skin condition that affects patients with systemic lupus erythematosus (SLE) and exists as an isolated entity without associated SLE. Flares of CLE, often triggered by exposure to ultraviolet (UV) light result in lost productivity and poor quality of life for patients and can be associated with trigger of systemic inflammation. In the past 10 years, the knowledge of CLE etiopathogenesis has grown, leading to promising targets for better therapies. Development of lesions likely begins in a pro-inflammatory epidermis, conditioned by excess type I interferon (IFN) production to undergo increased cell death and inflammatory cytokine production after UV light exposure. The reasons for this inflammatory predisposition are not well-understood, but may be an early event, as ANA + patients without criteria for autoimmune disease exhibit similar (although less robust) findings. Non-lesional skin of SLE patients also exhibits increased innate immune cell infiltration, conditioned by excess IFNs to release pro-inflammatory cytokines, and potentially increase activation of the adaptive immune system. Plasmacytoid dendritic cells are also found in non-lesional skin and may contribute to type I IFN production, although this finding is now being questioned by new data. Once the inflammatory cycle begins, lesional infiltration by numerous other cell populations ensues, including IFN-educated T cells. The heterogeneity amongst lesional CLE subtypes isn't fully understood, but B cells appear to discriminate discoid lupus erythematosus from other subtypes. Continued discovery will provide novel targets for additional therapeutic pursuits. This review will comprehensively discuss the contributions of tissue-specific and immune cell populations to the initiation and propagation of disease.
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Affiliation(s)
- Mitra P Maz
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jacob W S Martens
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Andrew Hannoudi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Alayka L Reddy
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Grace A Hile
- Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - J Michelle Kahlenberg
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109, USA.
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7
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Arulraj T, Binder SC, Meyer-Hermann M. Investigating the Mechanism of Germinal Center Shutdown. Front Immunol 2022; 13:922318. [PMID: 35911680 PMCID: PMC9329532 DOI: 10.3389/fimmu.2022.922318] [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: 04/17/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Germinal centers (GCs) are transient structures where affinity maturation of B cells gives rise to high affinity plasma and memory cells. The mechanism of GC shutdown is unclear, despite being an important phenomenon maintaining immune homeostasis. In this study, we used a mathematical model to identify mechanisms that can independently promote contraction of GCs leading to shutdown. We show that GC shutdown can be promoted by antigen consumption by B cells, antigen masking by soluble antibodies, alterations in follicular dendritic cell (FDC) network area, modulation of immune complex cycling rate constants, alterations in T follicular helper signaling, increased terminal differentiation and reduced B cell division capacity. Proposed mechanisms promoted GC contraction by ultimately decreasing the number of B cell divisions and recycling cells. Based on the in-silico predictions, we suggest a combination of experiments that can be potentially employed by future studies to unravel the mechanistic basis of GC shutdown such as measurements of the density of pMHC presentation of B cells, FDC network size per B cell, fraction of cells expressing differentiation markers. We also show that the identified mechanisms differentially affect the efficiency of GC reaction estimated based on the quantity and quality of resulting antibodies.
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Affiliation(s)
- Theinmozhi Arulraj
- Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Sebastian C. Binder
- Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Michael Meyer-Hermann
- Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany
- *Correspondence: Michael Meyer-Hermann,
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8
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Takeuchi A, Ozawa M, Cui G, Ikuta K, Katakai T. Lymph Node Stromal Cells: Diverse Meshwork Structures Weave Functionally Subdivided Niches. Curr Top Microbiol Immunol 2021; 434:103-121. [PMID: 34850284 DOI: 10.1007/978-3-030-86016-5_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Lymph nodes (LNs) are secondary lymphoid organs that function as the first line of defense against invasive foreign substances. Within the LNs, different types of immune cells are strategically localized to induce immune responses efficiently. Such a sophisticated tissue structure is a complex of functionally specialized niches, constructed by a variety of fibroblastic stromal cells. Elucidating the characteristics and functions of the niches and stromal cells will facilitate comprehension of the immune response induced in the LNs. Three recent studies offered novel insights into specialized stromal cells. In our discussion of these surprisingly diverse stromal cells, we will integrate information from these studies to improve knowledge about the structure and niches of LN.
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Affiliation(s)
- Arata Takeuchi
- Department of Immunology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Madoka Ozawa
- Department of Immunology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Guangwei Cui
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
| | - Koichi Ikuta
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
| | - Tomoya Katakai
- Department of Immunology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.
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9
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Lau AWY, Turner VM, Bourne K, Hermes JR, Chan TD, Brink R. BAFFR controls early memory B cell responses but is dispensable for germinal center function. J Exp Med 2021; 218:211511. [PMID: 33119033 PMCID: PMC7604765 DOI: 10.1084/jem.20191167] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/15/2020] [Accepted: 09/03/2020] [Indexed: 11/04/2022] Open
Abstract
The TNF superfamily ligand BAFF maintains the survival of naive B cells by signaling through its surface receptor, BAFFR. Activated B cells maintain expression of BAFFR after they differentiate into germinal center (GC) or memory B cells (MBCs). However, the functions of BAFFR in these antigen-experienced B cell populations remain unclear. Here, we show that B cell-intrinsic BAFFR does not play a significant role in the survival or function of GC B cells or in the generation of the somatically mutated MBCs derived from them. Instead, BAFF/BAFFR signaling was required to generate the unmutated, GC-independent MBCs that differentiate directly from activated B cell blasts early in the response. Furthermore, amplification of BAFFR signaling in responding B cells did not affect GCs or the generation of GC-derived MBCs but greatly expanded the GC-independent MBC response. Although BAFF/BAFFR signaling specifically controlled the formation of the GC-independent MBC response, both types of MBCs required input from this pathway for optimal long-term survival.
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Affiliation(s)
- Angelica W Y Lau
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Vivian M Turner
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Katherine Bourne
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Jana R Hermes
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Tyani D Chan
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.,St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia
| | - Robert Brink
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.,St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia
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10
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Neys SFH, Rip J, Hendriks RW, Corneth OBJ. Bruton's Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease. Drugs 2021; 81:1605-1626. [PMID: 34609725 PMCID: PMC8491186 DOI: 10.1007/s40265-021-01592-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2021] [Indexed: 12/14/2022]
Abstract
Systemic autoimmune disorders are complex heterogeneous chronic diseases involving many different immune cells. A significant proportion of patients respond poorly to therapy. In addition, the high burden of adverse effects caused by "classical" anti-rheumatic or immune modulatory drugs provides a need to develop more specific therapies that are better tolerated. Bruton's tyrosine kinase (BTK) is a crucial signaling protein that directly links B-cell receptor (BCR) signals to B-cell activation, proliferation, and survival. BTK is not only expressed in B cells but also in myeloid cells, and is involved in many different signaling pathways that drive autoimmunity. This makes BTK an interesting therapeutic target in the treatment of autoimmune diseases. The past decade has seen the emergence of first-line BTK small-molecule inhibitors with great efficacy in the treatment of B-cell malignancies, but with unfavorable safety profiles for use in autoimmunity due to off-target effects. The development of second-generation BTK inhibitors with superior BTK specificity has facilitated the investigation of their efficacy in clinical trials with autoimmune patients. In this review, we discuss the role of BTK in key signaling pathways involved in autoimmunity and provide an overview of the different inhibitors that are currently being investigated in clinical trials of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, as well as available results from completed trials.
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Affiliation(s)
- Stefan F H Neys
- Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Jasper Rip
- Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Rudi W Hendriks
- Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
| | - Odilia B J Corneth
- Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
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11
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Meyer SJ, Steffensen M, Acs A, Weisenburger T, Wadewitz C, Winkler TH, Nitschke L. CD22 Controls Germinal Center B Cell Receptor Signaling, Which Influences Plasma Cell and Memory B Cell Output. THE JOURNAL OF IMMUNOLOGY 2021; 207:1018-1032. [PMID: 34330755 DOI: 10.4049/jimmunol.2100132] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 06/05/2021] [Indexed: 12/23/2022]
Abstract
Germinal center reactions are established during a thymus-dependent immune response. Germinal center (GC) B cells are rapidly proliferating and undergo somatic hypermutation in Ab genes. This results in the production of high-affinity Abs and establishment of long-lived memory cells. GC B cells show lower BCR-induced signaling when compared with naive B cells, but the functional relevance is not clear. CD22 is a member of the Siglec family and functions as an inhibitory coreceptor on B cells. Interestingly, GC B cells downregulate sialic acid forms that serve as high-affinity ligands for CD22, indicating a role for CD22 ligand binding during GC responses. We studied the role of CD22 in the GC with mixed bone marrow chimeric mice and found a disadvantage of CD22-/- GC B cells during the GC reaction. Mechanistic investigations ruled out defects in dark zone/light zone distribution and affinity maturation. Rather, an increased rate of apoptosis in CD22-/- GC B cells was responsible for the disadvantage, also leading to a lower GC output in plasma cells and memory B cells. CD22-/- GC B cells showed a clearly increased calcium response upon BCR stimulation, which was almost absent in wild-type GC B cells. We conclude that the differential expression of the low-affinity cis CD22 ligands in the GC normally results in a strong attenuation of BCR signaling in GC B cells, probably due to higher CD22-BCR interactions. Therefore, attenuation of BCR signaling by CD22 is involved in GC output and B cell fate.
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Affiliation(s)
- Sarah J Meyer
- Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany
| | - Marie Steffensen
- Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany
| | - Andreas Acs
- Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany
| | - Thomas Weisenburger
- Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany
| | - Charlotte Wadewitz
- Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany
| | - Thomas H Winkler
- Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany
| | - Lars Nitschke
- Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany
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12
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Sevdali E, Block Saldana V, Speletas M, Eibel H. BAFF receptor polymorphisms and deficiency in humans. Curr Opin Immunol 2021; 71:103-110. [PMID: 34311146 DOI: 10.1016/j.coi.2021.06.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/24/2021] [Accepted: 06/06/2021] [Indexed: 01/26/2023]
Abstract
The BAFF-receptor (BAFFR) is a member of the TNF-receptor family. It is expressed only by B cells and binds BAFF as single ligand, which activates key signaling pathways regulating essential cellular functions, including survival, protein synthesis, and metabolic fitness. In humans, BAFFR deficiency interrupts B cell development at the transition from immature to mature B cells and causes B lymphopenia, hypogammaglobulinemia, and impaired humoral immune responses. Polymorphisms in TNFRSF13C gene affecting BAFFR oligomerization and signaling have been described in patients with immunodeficiency, autoimmunity and B cell lymphomas. Despite a uniform expression pattern of BAFFR in peripheral mature B cells, depletion of BAFF with neutralizing antibodies in patients with systemic lupus erythematosus does not affect the survival of switched memory B cells. These findings imply a distinct dependency of mature B cell subsets on BAFF/BAFFR interaction and highlight the contribution of BAFFR-derived signals in peripheral B cell development and homeostasis.
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Affiliation(s)
- Eirini Sevdali
- Dept. of Rheumatology and Clinical Immunology and Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Freiburg, Germany
| | - Violeta Block Saldana
- Dept. of Rheumatology and Clinical Immunology and Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Freiburg, Germany
| | - Matthaios Speletas
- Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Hermann Eibel
- Dept. of Rheumatology and Clinical Immunology and Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Freiburg, Germany.
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13
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Arulraj T, Binder SC, Robert PA, Meyer-Hermann M. Germinal Centre Shutdown. Front Immunol 2021; 12:705240. [PMID: 34305944 PMCID: PMC8293096 DOI: 10.3389/fimmu.2021.705240] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 06/24/2021] [Indexed: 12/24/2022] Open
Abstract
Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, ‘normal’ GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question – what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.
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Affiliation(s)
- Theinmozhi Arulraj
- Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Sebastian C Binder
- Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Philippe A Robert
- Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.,Department of Immunology, University of Oslo, Oslo, Norway
| | - Michael Meyer-Hermann
- Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.,Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany
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14
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Jacobs HM, Arkatkar T, Du SW, Scharping NE, Woods J, Li QZ, Hudkins KL, Alpers CE, Rawlings DJ, Jackson SW. TACI haploinsufficiency protects against BAFF-driven humoral autoimmunity in mice. Eur J Immunol 2021; 51:2225-2236. [PMID: 34146342 DOI: 10.1002/eji.202149244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/26/2021] [Accepted: 06/16/2021] [Indexed: 11/06/2022]
Abstract
Polymorphisms in TACI, a BAFF family cytokine receptor, are linked to diverse human immune disorders including common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE). Functional studies of individual variants show modest impacts on surface TACI expression and/or downstream signal transduction, indicating that relatively subtle variation in TACI activity can impact human B-cell biology. However, significant complexity underlies TACI biology, including both positive and negative regulation of physiologic and pathogenic B-cell responses. To model these contradictory events, we compared the functional impact of TACI deletion on separate models of murine SLE driven by T cell-independent and -dependent breaks in B-cell tolerance. First, we studied whether reduced surface TACI expression was sufficient to protect against progressive BAFF-mediated systemic autoimmunity. Strikingly, despite a relatively modest impact on surface TACI levels, TACI haploinsufficiency markedly reduced pathogenic RNA-associated autoantibody titers and conferred long-term protection from BAFF-driven lupus nephritis. In contrast, B cell-intrinsic TACI deletion exerted a limited impact of autoantibody generation in murine lupus characterized by spontaneous germinal center formation and T cell-dependent humoral autoimmunity. Together, these combined data provide new insights into TACI biology and highlight how TACI signals must be tightly regulated during protective and pathogenic B-cell responses.
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Affiliation(s)
| | | | - Samuel W Du
- Seattle Children's Research Institute, Seattle, WA, USA
| | | | | | - Quan-Zhen Li
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Kelly L Hudkins
- Departments of Laboratory Medicine and Pathology, Immunology and Pediatrics, University of Washington School of Medicine, Washington, WA, USA
| | - Charles E Alpers
- Departments of Laboratory Medicine and Pathology, Immunology and Pediatrics, University of Washington School of Medicine, Washington, WA, USA
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15
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Schell SL, Bricker KN, Fike AJ, Chodisetti SB, Domeier PP, Choi NM, Fasnacht MJ, Luckenbill SA, Ziegler SF, Rahman ZSM. Context-Dependent miR-21 Regulation of TLR7-Mediated Autoimmune and Foreign Antigen-Driven Antibody-Forming Cell and Germinal Center Responses. THE JOURNAL OF IMMUNOLOGY 2021; 206:2803-2818. [PMID: 34039637 DOI: 10.4049/jimmunol.2001039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 04/01/2021] [Indexed: 01/03/2023]
Abstract
MicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), although the role of many miRNAs remains poorly understood. Dampening miR-21 activity was previously shown to reduce splenomegaly and blood urea nitrogen levels in SLE-prone mice, but the detailed cellular responses and mechanism of action remains unexplored. In this study, using the TLR7 agonist, imiquimod-induced SLE model, we observed that loss of miR-21 in Sle1b mice prevented the formation of plasma cells and autoantibody-producing Ab-forming cells (AFCs) without a significant effect on the magnitude of the germinal center (GC) response. We further observed reduced dendritic cell and monocyte numbers in the spleens of miR-21-deficient Sle1b mice that were associated with reduced IFN, proinflammatory cytokines, and effector CD4+ T cell responses. RNA sequencing analysis on B cells from miR-21-deficient Sle1b mice revealed reduced activation and response to IFN, and cytokine and target array analysis revealed modulation of numerous miR-21 target genes in response to TLR7 activation and type I IFN stimulation. Our findings in the B6.Sle1bYaa (Sle1b Yaa) spontaneous model recapitulated the miR-21 role in TLR7-induced responses with an additional role in autoimmune GC and T follicular helper responses. Finally, immunization with T-dependent Ag revealed a role for miR-21 in foreign Ag-driven GC and Ab, but not AFC, responses. Our data suggest a potential multifaceted, context-dependent role for miR-21 in autoimmune and foreign Ag-driven AFC and GC responses. Further study is warranted to delineate the cell-intrinsic requirements and mechanisms of miR-21 during infection and SLE development.
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Affiliation(s)
- Stephanie L Schell
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA; and
| | - Kristen N Bricker
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA; and
| | - Adam J Fike
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA; and
| | - Sathi Babu Chodisetti
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA; and
| | | | - Nicholas M Choi
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA; and
| | - Melinda J Fasnacht
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA; and
| | - Sara A Luckenbill
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA; and
| | | | - Ziaur S M Rahman
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA; and
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16
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Elsner RA, Shlomchik MJ. Germinal Center and Extrafollicular B Cell Responses in Vaccination, Immunity, and Autoimmunity. Immunity 2021; 53:1136-1150. [PMID: 33326765 DOI: 10.1016/j.immuni.2020.11.006] [Citation(s) in RCA: 300] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 10/19/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023]
Abstract
Activated B cells participate in either extrafollicular (EF) or germinal center (GC) responses. Canonical responses are composed of a short wave of plasmablasts (PBs) arising from EF sites, followed by GC producing somatically mutated memory B cells (MBC) and long-lived plasma cells. However, somatic hypermutation (SHM) and affinity maturation can take place at both sites, and a substantial fraction of MBC are produced prior to GC formation. Infection responses range from GC responses that persist for months to persistent EF responses with dominant suppression of GCs. Here, we review the current understanding of the functional output of EF and GC responses and the molecular switches promoting them. We discuss the signals that regulate the magnitude and duration of these responses, and outline gaps in knowledge and important areas of inquiry. Understanding such molecular switches will be critical for vaccine development, interpretation of vaccine efficacy and the treatment for autoimmune diseases.
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Affiliation(s)
- Rebecca A Elsner
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15216, USA
| | - Mark J Shlomchik
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15216, USA.
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17
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Suchanek O, Clatworthy MR. Novel strategies to target the humoral alloimmune response. HLA 2020; 96:667-680. [PMID: 33022883 DOI: 10.1111/tan.14092] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/02/2020] [Accepted: 10/03/2020] [Indexed: 12/24/2022]
Abstract
Antibody-mediated rejection (ABMR) represents a major cause of late allograft loss in solid organ transplantation worldwide. This process is driven by donor-specific antibodies (DSA), which develop either de-novo or, in sensitized patients, are preformed at the time of transplantation. Effective targeting of ABMR has been hampered by a lack of robust randomized controlled trials (RCT), required for the regulatory approval of new therapeutics. In this review, we discuss the evidence behind the present "standard" of care and recent progress in the development of novel strategies targeting different aspects of the alloimmune humoral response, including naïve and memory B-cell activation, the germinal centre reaction, plasma cell survival and antibody effector functions. In particular, we focus on co-stimulation blockade and its combination with next-generation proteasome inhibitors, new depleting monoclonal antibodies (anti-CD19, anti-BCMA, anti-CD38, anti-CD138), interleukin-6 blockade, complement inhibition and DSA degradation. These treatment modalities, when used in the appropriate clinical context and combination, have the potential to finally improve long-term allograft survival.
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Affiliation(s)
- Ondrej Suchanek
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Menna R Clatworthy
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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18
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Magliozzi R, Marastoni D, Calabrese M. The BAFF / APRIL system as therapeutic target in multiple sclerosis. Expert Opin Ther Targets 2020; 24:1135-1145. [PMID: 32900236 DOI: 10.1080/14728222.2020.1821647] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The complex system of BAFF (B-cell-activating factor of the TNF family) and APRIL (A proliferation-inducing ligand) has been studied in animal models of autoimmune diseases such as those resembling human systemic lupus erythematosus and Sjogren's syndrome and multiple sclerosis (MS). Accumulating evidence suggests that BAFF and APRIL have a physiological role in B cell immunity regulation, however inappropriate production of these factors may represent a key event which disrupts immune tolerance which is associated with systemic autoimmune diseases. AREAS COVERED We provide an update on the latest studies of the BAFF/APRIL system in multiple sclerosis, as well as on related clinical trials. EXPERT OPINION Experimental and clinical evidence suggests that increased BAFF levels may interfere directly and indirectly with B cell immunity; this can lead to breakdown of immune tolerance, the production of autoantibodies and continuous local intracerebral inflammation and brain tissue destruction. A more comprehensive understanding of the cell/molecular mechanism immune reactions specifically regulated by BAFF/APRIL in MS would better elucidate the specific cell phenotype targeted by actual anti-BAFF/APRIL therapies; this may enable the identification of either specific biomarkers of MS subgroups that would benefit of anti-BAFF/APRIL treatments or new targets of MS-specific anti-BAFF/APRIL therapies.
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Affiliation(s)
- Roberta Magliozzi
- Neurology B, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona , Verona, Italy
| | - Damiano Marastoni
- Neurology B, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona , Verona, Italy
| | - Massimiliano Calabrese
- Neurology B, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona , Verona, Italy
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19
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Chen Y, Yang M, Long D, Li Q, Zhao M, Wu H, Lu Q. Abnormal expression of BAFF and its receptors in peripheral blood and skin lesions from systemic lupus erythematosus patients. Autoimmunity 2020; 53:192-200. [PMID: 32157911 DOI: 10.1080/08916934.2020.1736049] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by abnormal T and B cells. B-cell activating factor (BAFF) has been suggested to play a crucial role in lupus by promoting the proliferation, differentiation, and survival of B cells. Increased serum levels of BAFF have been found in patients with lupus. However, the expression of BAFF and its receptors on immune cells and in skin has not been systematically reported before. Here, we report that SLE patients showed increased levels of BAFF on circulating CD3+ T cells and B-cell maturation antigen (BCMA) on CD14+ monocytes and dramatically increased expression of BAFF in lupus skin lesions compared with those of healthy controls. TACI was undetectable on circulating immune cells. An increased serum level of BAFF was also confirmed in lupus patients in this study. Our findings may provide a better understanding of the pathogenesis and predictors of BAFF antibody treatment response, as well as potential targets for skin therapies.
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Affiliation(s)
- Yongjian Chen
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ming Yang
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Di Long
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qianwen Li
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ming Zhao
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Haijing Wu
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qianjin Lu
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
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20
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Borhis G, Trovato M, Ibrahim HM, Isnard S, Le Grand R, Bosquet N, Richard Y. Impact of BAFF Blockade on Inflammation, Germinal Center Reaction and Effector B-Cells During Acute SIV Infection. Front Immunol 2020; 11:252. [PMID: 32194549 PMCID: PMC7061218 DOI: 10.3389/fimmu.2020.00252] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 01/30/2020] [Indexed: 12/14/2022] Open
Abstract
Memory B-cell dysfunctions and inefficient antibody response suggest germinal center (GC) impairments during HIV/SIV infection with possible contribution of overproduced B-cell activating factor (BAFF). To address this question, we compared proportions and functions of various B-cell subsets and follicular helper T-cells (TFH) in untreated (Placebo) and BR3-Fc treated (Treated) SIV-infected macaques. From day 2 post-infection (dpi), Treated macaques received one weekly injection of BR3-Fc molecule, a soluble BAFF antagonist, for 4 weeks. Whereas, the kinetics of CD4+ T-cell loss and plasma viral loads were comparable in both groups, BAFF blockade delayed the peak of inflammatory cytokines (CXCL10, IFNα), impaired the renewal of plasmacytoid dendritic cells and fostered the decline of plasma CXCL13 titers after 14 dpi. In Treated macaques, proportions of total and naïve B-cells were reduced in blood and spleen whereas SIV-induced loss of marginal zone (MZ) B-cells was only accentuated in blood and terminal ileum. Proportions of spleen GC B-cells and TFH were similar in both groups, with CD8+ T-cells and rare Foxp3+ being present in spleen GC. Regardless of treatment, sorted TFH produced similar levels of IL21, CXCL13, and IFNγ but no IL2, IL4, or BAFF and exhibited similar capacities to support IgG production by autologous or heterologous B-cells. Consistently, most TFH were negative for BAFF-R and TACI. Higher proportions of resting and atypical (CD21lo) memory B-cells were present in Treated macaques compared to Placebo. In both groups, we found higher levels of BAFF-R expression on MZ and resting memory B-cells but low levels on atypical memory B-cells. TACI was present on 20-30% of MZ, resting and atypical memory B-cells in Placebo macaques. BAFF blockade decreased TACI expression on these B-cell subsets as well as titers of SIV-specific and vaccine-specific antibodies arguing for BAFF being mandatory for plasma cell survival. Irrespective of treatment, GC B-cells expressed BAFF-R at low level and were negative for TACI. In addition to key information on spleen BAFF-R and TACI expression, our data argue for BAFF contributing to the GC reaction in terminal ileum but being dispensable for the generation of atypical memory B-cells and GC reaction in spleen during T-dependent response against SIV.
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Affiliation(s)
- Gwenoline Borhis
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
| | - Maria Trovato
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
| | - Hany M. Ibrahim
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
| | - Stephane Isnard
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
| | - Roger Le Grand
- CEA, Université Paris Sud, INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department/IBFJ, Fontenay-aux-Roses, France
| | - Nathalie Bosquet
- CEA, Université Paris Sud, INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department/IBFJ, Fontenay-aux-Roses, France
| | - Yolande Richard
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
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Jackson SW, Davidson A. BAFF inhibition in SLE-Is tolerance restored? Immunol Rev 2019; 292:102-119. [PMID: 31562657 PMCID: PMC6935406 DOI: 10.1111/imr.12810] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023]
Abstract
The B cell activating factor (BAFF) inhibitor, belimumab, is the first biologic drug approved for the treatment of SLE, and exhibits modest, but durable, efficacy in decreasing disease flares and organ damage. BAFF and its homolog APRIL are TNF-like cytokines that support the survival and differentiation of B cells at distinct developmental stages. BAFF is a crucial survival factor for transitional and mature B cells that acts as rheostat for the maturation of low-affinity autoreactive cells. In addition, BAFF augments innate B cell responses via complex interactions with the B cell receptor (BCR) and Toll like receptor (TLR) pathways. In this manner, BAFF impacts autoreactive B cell activation via extrafollicular pathways and fine tunes affinity selection within germinal centers (GC). Finally, BAFF and APRIL support plasma cell survival, with differential impacts on IgM- and IgG-producing populations. Therapeutically, BAFF and combined BAFF/APRIL inhibition delays disease onset in diverse murine lupus strains, although responsiveness to BAFF inhibition is model dependent, in keeping with heterogeneity in clinical responses to belimumab treatment in humans. In this review, we discuss the mechanisms whereby BAFF/APRIL signals promote autoreactive B cell activation, discuss whether altered selection accounts for therapeutic benefits of BAFF inhibition, and address whether new insights into BAFF/APRIL family complexity can be exploited to improve human lupus treatments.
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Affiliation(s)
- Shaun W Jackson
- Seattle Children's Research Institute, Seattle, WA, USA
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
| | - Anne Davidson
- Feinstein Institutes for Medical Research, Manhasset, NY, USA
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22
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Molecular structure, expression, and bioactivity of B-cell-activating factor of the TNF family (BAFF) and its receptor BAFF-R in cats (Felis catus). Mol Immunol 2019; 112:59-71. [PMID: 31078117 DOI: 10.1016/j.molimm.2019.04.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 04/30/2019] [Indexed: 01/06/2023]
Abstract
B-cell survival depends on signals induced by binding of B-cell activating factor (BAFF) to its receptor (BAFF-R). In this study, the full-length cDNAs of cat BAFF (cBAFF) and BAFF-R (cBAFF-R) were amplified from the spleen by reverse transcription PCR. The open reading frame of cBAFF cDNA encodes a protein of 285 amino acids containing a predicted transmembrane domain and a furin protease cleavage site, similar to mammalian, avian, and reptile BAFFs. The cBAFF-R gene encodes a 189 amino acid protein. Real-time quantitative PCR analyses revealed that the two genes are predominantly expressed in the spleen. csBAFF, EGFP/csBAFF, and cBAFF-R were efficiently expressed in Escherichia coli BL21 (DE3), as confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting analyses. After purification, the EGFP/csBAFF fusion protein showed a fluorescence spectrum similar to that of EGFP. Confocal laser scanning microscopy showed that EGFP/csBAFF bound to its receptor. In vitro, csBAFF promoted the survival of cat and mouse splenic B cells with/without a priming agent (Staphylococcus aureus Cowan 1, SAC) or anti-mouse IgM. Furthermore, it stimulated the survival of mouse B cells, similar to msBAFF. Recombinant cBAFF-R blocked the function of sBAFF in vitro. These findings indicate that csBAFF plays an important role in the survival of cat B cells and has functional cross reactivity between cats and other mammals, and suggest a role for the BAFF-BAFF-R system in regulating B-cell survival. Therefore, BAFF and BAFF-R show promise for enhancing the immune systems of animals.
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23
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Carrillo-Ballesteros FJ, Oregon-Romero E, Franco-Topete RA, Govea-Camacho LH, Cruz A, Muñoz-Valle JF, Bustos-Rodríguez FJ, Pereira-Suárez AL, Palafox-Sánchez CA. B-cell activating factor receptor expression is associated with germinal center B-cell maintenance. Exp Ther Med 2019; 17:2053-2060. [PMID: 30783477 PMCID: PMC6364250 DOI: 10.3892/etm.2019.7172] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 11/23/2018] [Indexed: 12/30/2022] Open
Abstract
B-cell activating factor (BAFF) is a major cytokine that regulates B-cell survival, maturation and differentiation through its binding with its receptors: BAFF receptor (BAFF-R), transmembrane activator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA). These receptors have been demonstrated to be involved in tertiary lymphoid structure formation; however, their role in germinal centers (GCs) has remained elusive. The aim of the present study was to determine the expression profiles of BAFF and its receptors in secondary lymphoid tissues. Tonsils resected due to chronic tonsillitis were used as lymphoid tissues. To confirm the presence of GCs identified based on their typical structure, CD21 antibody staining was employed. The expression of BAFF, BAFF-R, TACI and BCMA was assessed by immunohistochemistry. BAFF was highly expressed in all regions of the follicle, but the highest BAFF expression was detected in the mantle zone (MZ). A high expression of BAFF-R was observed on lymphocytes in the MZ in comparison with the other regions (~80%; P<0.05), which was co-localizated with BAFF (r=0.646; P<0.001), in the MZ. TACI and BCMA exhibited similar expression among the different zones of the GCs, and co-localization with BAFF was observed inside the follicle, mainly in the dark zone. The present results indicate that BAFF is implicated in the maintenance of GCs. BAFF-R overexpression in the MZ, co-localizated with BAFF, suggests that these proteins constitute the principal pathway for the maintenance of the naïve B-cell population. Furthermore, TACI and BCMA have a role in the GC, where processes of B-cell selection, proliferation and differentiation into immunoglobulin-secreting plasma cells occur.
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Affiliation(s)
- Francisco Josué Carrillo-Ballesteros
- Research Institute of Biomedical Sciences, Department of Medical Clinics, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Edith Oregon-Romero
- Research Institute of Biomedical Sciences, Department of Medical Clinics, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Ramon Antonio Franco-Topete
- Department of Microbiology and Pathology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Luis Humberto Govea-Camacho
- Department of Otorhinolaryngology, West National Medical Center, Mexican Institute of Social Security, Guadalajara, Jalisco 44340, México
| | - Alvaro Cruz
- Research Institute of Biomedical Sciences, Department of Medical Clinics, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - José Francisco Muñoz-Valle
- Research Institute of Biomedical Sciences, Department of Medical Clinics, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Felipe Jesús Bustos-Rodríguez
- Department of Microbiology and Pathology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Ana Laura Pereira-Suárez
- Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Claudia Azucena Palafox-Sánchez
- Research Institute of Biomedical Sciences, Department of Medical Clinics, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, México
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Rose WA, Okragly AJ, Hu NN, Daniels MR, Martin AP, Koh YT, Kikly K, Benschop RJ. Interleukin-33 Contributes Toward Loss of Tolerance by Promoting B-Cell-Activating Factor of the Tumor-Necrosis-Factor Family (BAFF)-Dependent Autoantibody Production. Front Immunol 2018; 9:2871. [PMID: 30574145 PMCID: PMC6292404 DOI: 10.3389/fimmu.2018.02871] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 11/21/2018] [Indexed: 01/13/2023] Open
Abstract
Breaking tolerance is a key event leading to autoimmunity, but the exact mechanisms responsible for this remain uncertain. Here we show that the alarmin IL-33 is able to drive the generation of autoantibodies through induction of the B cell survival factor BAFF. A temporary, short-term increase in IL-33 results in a primary (IgM) response to self-antigens. This transient DNA-specific autoantibody response was dependent on the induction of BAFF. Notably, radiation resistant cells and not myeloid cells, such as neutrophils or dendritic cells were the major source of BAFF and were critical in driving the autoantibody response. Chronic exposure to IL-33 elicited dramatic increases in BAFF levels and resulted in elevated numbers of B and T follicular helper cells as well as germinal center formation. We also observed class-switching from an IgM to an IgG DNA-specific autoantibody response. Collectively, the results provide novel insights into a potential mechanism for breaking immune-tolerance via IL-33-mediated induction of BAFF.
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Affiliation(s)
- William A Rose
- Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
| | - Angela J Okragly
- Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
| | - Ningjie N Hu
- Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
| | - Montanea R Daniels
- Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
| | - Andrea P Martin
- Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
| | - Yi Ting Koh
- Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
| | - Kristine Kikly
- Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
| | - Robert J Benschop
- Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
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25
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Smulski CR, Eibel H. BAFF and BAFF-Receptor in B Cell Selection and Survival. Front Immunol 2018; 9:2285. [PMID: 30349534 PMCID: PMC6186824 DOI: 10.3389/fimmu.2018.02285] [Citation(s) in RCA: 231] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/14/2018] [Indexed: 12/16/2022] Open
Abstract
The BAFF-receptor (BAFFR) is encoded by the TNFRSF13C gene and is one of the main pro-survival receptors in B cells. Its function is impressively documented in humans by a homozygous deletion within exon 2, which leads to an almost complete block of B cell development at the stage of immature/transitional B cells. The resulting immunodeficiency is characterized by B-lymphopenia, agammaglobulinemia, and impaired humoral immune responses. However, different from mutations affecting pathway components coupled to B cell antigen receptor (BCR) signaling, BAFFR-deficient B cells can still develop into IgA-secreting plasma cells. Therefore, BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.
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Affiliation(s)
- Cristian R Smulski
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Freiburg, Germany
| | - Hermann Eibel
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Freiburg, Germany
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26
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B cell therapy in ANCA-associated vasculitis: current and emerging treatment options. Nat Rev Rheumatol 2018; 14:580-591. [DOI: 10.1038/s41584-018-0065-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 07/10/2018] [Indexed: 12/19/2022]
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27
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Papa I, Vinuesa CG. Synaptic Interactions in Germinal Centers. Front Immunol 2018; 9:1858. [PMID: 30150988 PMCID: PMC6099157 DOI: 10.3389/fimmu.2018.01858] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 07/27/2018] [Indexed: 12/27/2022] Open
Abstract
The germinal center (GC) is a complex, highly dynamic microanatomical niche that allows the generation of high-affinity antibody-producing plasma cells and memory B cells. These cells constitute the basis of long-lived highly protective antibody responses. For affinity maturation to occur, B cells undergo multiple rounds of proliferation and mutation of the genes that encode the immunoglobulin V region followed by selection by specialized T cells called follicular helper T (TFH) cells. In order to achieve this result, the GC requires spatially and temporally coordinated interactions between the different cell types, including B and T lymphocytes and follicular dendritic cells. Cognate interactions between TFH and GC B cells resemble cellular connections and synaptic communication within the nervous system, which allow signals to be transduced rapidly and effectively across the synaptic cleft. Such immunological synapses are particularly critical in the GC where the speed of T–B cell interactions is faster and their duration shorter than at other sites. In addition, the antigen-based specificity of cognate interactions in GCs is critical for affinity-based selection in which B cells compete for T cell help so that rapid modulation of the signaling threshold determines the outcome of the interaction. In the context of GCs, which contain large numbers of cells in a highly compacted structure, focused delivery of signals across the interacting cells becomes particularly important. Promiscuous or bystander delivery of positive selection signals could potentially lead to the appearance of long-lived self-reactive B cell clones. Cytokines, cytotoxic granules, and more recently neurotransmitters have been shown to be transferred from TFH to B cells upon cognate interactions. This review describes the current knowledge on immunological synapses occurring during GC responses including the type of granules, their content, and function in TFH-mediated help to B cells.
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Affiliation(s)
- Ilenia Papa
- John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia
| | - Carola G Vinuesa
- John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia
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28
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Arkatkar T, Jacobs HM, Du SW, Li QZ, Hudkins KL, Alpers CE, Rawlings DJ, Jackson SW. TACI deletion protects against progressive murine lupus nephritis induced by BAFF overexpression. Kidney Int 2018; 94:728-740. [PMID: 29907458 DOI: 10.1016/j.kint.2018.03.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 03/12/2018] [Accepted: 03/15/2018] [Indexed: 11/26/2022]
Abstract
B cells are known to promote the pathogenesis of systemic lupus erythematosus (SLE) via the production of pathogenic anti-nuclear antibodies. However, the signals required for autoreactive B cell activation and the immune mechanisms whereby B cells impact lupus nephritis pathology remain poorly understood. The B cell survival cytokine B cell activating factor of the TNF Family (BAFF) has been implicated in the pathogenesis of SLE and lupus nephritis in both animal models and human clinical studies. Although the BAFF receptor has been predicted to be the primary BAFF family receptor responsible for BAFF-driven humoral autoimmunity, in the current study we identify a critical role for signals downstream of Transmembrane Activator and CAML Interactor (TACI) in BAFF-dependent lupus nephritis. Whereas transgenic mice overexpressing BAFF develop progressive membranoproliferative glomerulonephritis, albuminuria and renal dysfunction, TACI deletion in BAFF-transgenic mice provided long-term (about 1 year) protection from renal disease. Surprisingly, disease protection in this context was not explained by complete loss of glomerular immune complex deposits. Rather, TACI deletion specifically reduced endocapillary, but not mesangial, immune deposits. Notably, although excess BAFF promoted widespread breaks in B cell tolerance, BAFF-transgenic antibodies were enriched for RNA- relative to DNA-associated autoantigen reactivity. These RNA-associated autoantibody specificities were specifically reduced by TACI or Toll-like receptor 7 deletion. Thus, our study provides important insights into the autoantibody specificities driving proliferative lupus nephritis, and suggests that TACI inhibition may be novel and effective treatment strategy in lupus nephritis.
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Affiliation(s)
- Tanvi Arkatkar
- Seattle Children's Research Institute, Seattle, Washington, USA
| | - Holly M Jacobs
- Seattle Children's Research Institute, Seattle, Washington, USA
| | - Samuel W Du
- Seattle Children's Research Institute, Seattle, Washington, USA
| | - Quan-Zhen Li
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Kelly L Hudkins
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA
| | - Charles E Alpers
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA
| | - David J Rawlings
- Seattle Children's Research Institute, Seattle, Washington, USA; Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA; Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA
| | - Shaun W Jackson
- Seattle Children's Research Institute, Seattle, Washington, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
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29
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Neely HR, Guo J, Flowers EM, Criscitiello MF, Flajnik MF. "Double-duty" conventional dendritic cells in the amphibian Xenopus as the prototype for antigen presentation to B cells. Eur J Immunol 2018; 48:430-440. [PMID: 29235109 DOI: 10.1002/eji.201747260] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/20/2017] [Accepted: 12/07/2017] [Indexed: 12/19/2022]
Abstract
Two populations of dendritic cells (DCs) are found in mammals, one derived from hematopoietic precursors (conventional/cDC), and another derived from mesenchymal precursors, the follicular DC (FDC); the latter is specialized for antigen presentation to B cells, and has only been definitively demonstrated in mammals. Both cDC and FDC are necessary for induction of germinal centers (GC) and GC-dependent class switch recombination (CSR) and somatic hypermutation (SHM). We demonstrate that in Xenopus, an amphibian in which immunoglobulin CSR and SHM occur without GC formation, a single type of DC has properties of both cDC and FDC, including high expression of MHC class II for the former and display of native antigen at the cell surface for the latter. Our data confirm that the advent of FDC functionality preceded emergence of bona fide FDC, which was in turn crucial for the development of GC formation and efficient affinity maturation in mammals.
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Affiliation(s)
- Harold R Neely
- Department of Microbiology and Immunology, University of Maryland Baltimore, Baltimore, MD, USA.,Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - Jacqueline Guo
- Department of Microbiology and Immunology, University of Maryland Baltimore, Baltimore, MD, USA
| | - Emily M Flowers
- Department of Microbiology and Immunology, University of Maryland Baltimore, Baltimore, MD, USA
| | | | - Martin F Flajnik
- Department of Microbiology and Immunology, University of Maryland Baltimore, Baltimore, MD, USA
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30
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Abstract
Germinal centers (GCs) are dynamic microenvironments that form in the secondary lymphoid organs and generate somatically mutated high-affinity antibodies necessary to establish an effective humoral immune response. Tight regulation of GC responses is critical for maintaining self-tolerance. GCs can arise in the absence of purposeful immunization or overt infection (called spontaneous GCs, Spt-GCs). In autoimmune-prone mice and patients with autoimmune disease, aberrant regulation of Spt-GCs is thought to promote the development of somatically mutated pathogenic autoantibodies and the subsequent development of autoimmunity. The mechanisms that control the formation of Spt-GCs and promote systemic autoimmune diseases remain an open question and the focus of ongoing studies. Here, we discuss the most current studies on the role of Spt-GCs in autoimmunity.
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Affiliation(s)
- Phillip P Domeier
- a Department of Microbiology and Immunology, Penn State College of Medicine , USA
| | - Stephanie L Schell
- a Department of Microbiology and Immunology, Penn State College of Medicine , USA
| | - Ziaur S M Rahman
- a Department of Microbiology and Immunology, Penn State College of Medicine , USA
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31
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Schell SL, Soni C, Fasnacht MJ, Domeier PP, Cooper TK, Rahman ZSM. Mer Receptor Tyrosine Kinase Signaling Prevents Self-Ligand Sensing and Aberrant Selection in Germinal Centers. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2017; 199:4001-4015. [PMID: 29118245 DOI: 10.4049/jimmunol.1700611] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 10/11/2017] [Indexed: 04/04/2025]
Abstract
Mer tyrosine kinase (Mer) signaling maintains immune tolerance by clearing apoptotic cells (ACs) and inducing immunoregulatory signals. We previously showed that Mer-deficient mice (Mer-/-) have increased germinal center (GC) responses, T cell activation, and AC accumulation within GCs. Accumulated ACs in GCs can undergo necrosis and release self-ligands, which may influence the outcome of a GC response and selection. In this study, we generated Mer-/- mice with a global MyD88, TLR7, or TLR9 deficiency and cell type-specific MyD88 deficiency to study the functional correlation between Mer and TLRs in the development of GC responses and autoimmunity. We found that GC B cell-intrinsic sensing of self-RNA, but not self-DNA, released from dead cells accumulated in GCs drives enhanced GC responses in Mer-/- mice. Although self-ligands directly affect GC B cell responses, the loss of Mer in dendritic cells promotes enhanced T cell activation and proinflammatory cytokine production. To study the impact of Mer deficiency on the development of autoimmunity, we generated autoimmune-prone B6.Sle1b mice deficient in Mer (Sle1bMer-/-). We observed accelerated autoimmunity development even under conditions where Sle1bMer-/- mice did not exhibit increased AC accumulation in GCs compared with B6.Sle1b mice, indicating that Mer immunoregulatory signaling in APCs regulates B cell selection and autoimmunity. We further found significant expansion, retention, and class-switching of autoreactive B cells in GCs under conditions where ACs accumulated in GCs of Sle1bMer-/- mice. Altogether, both the phagocytic and immunomodulatory functions of Mer regulate GC responses to prevent the development of autoimmunity.
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Affiliation(s)
- Stephanie L Schell
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033; and
| | - Chetna Soni
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033; and
| | - Melinda J Fasnacht
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033; and
| | - Phillip P Domeier
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033; and
| | - Timothy K Cooper
- Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Ziaur S M Rahman
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033; and
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32
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Giordano D, Draves KE, Young LB, Roe K, Bryan MA, Dresch C, Richner JM, Diamond MS, Gale M, Clark EA. Protection of mice deficient in mature B cells from West Nile virus infection by passive and active immunization. PLoS Pathog 2017; 13:e1006743. [PMID: 29176765 PMCID: PMC5720816 DOI: 10.1371/journal.ppat.1006743] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 12/07/2017] [Accepted: 11/10/2017] [Indexed: 01/02/2023] Open
Abstract
B cell activating factor receptor (BAFFR)-/- mice have a profound reduction in mature B cells, but unlike μMT mice, they have normal numbers of newly formed, immature B cells. Using a West Nile virus (WNV) challenge model that requires antibodies (Abs) for protection, we found that unlike wild-type (WT) mice, BAFFR-/- mice were highly susceptible to WNV and succumbed to infection within 8 to 12 days after subcutaneous virus challenge. Although mature B cells were required to protect against lethal infection, infected BAFFR-/- mice had reduced WNV E-specific IgG responses and neutralizing Abs. Passive transfer of immune sera from previously infected WT mice rescued BAFFR-/- and fully B cell-deficient μMT mice, but unlike μMT mice that died around 30 days post-infection, BAFFR-/- mice survived, developed WNV-specific IgG Abs and overcame a second WNV challenge. Remarkably, protective immunity could be induced in mature B cell-deficient mice. Administration of a WNV E-anti-CD180 conjugate vaccine 30 days prior to WNV infection induced Ab responses that protected against lethal infection in BAFFR-/- mice but not in μMT mice. Thus, the immature B cells present in BAFFR-/- and not μMT mice contribute to protective antiviral immunity. A CD180-based vaccine may promote immunity in immunocompromised individuals.
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Affiliation(s)
- Daniela Giordano
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
- * E-mail:
| | - Kevin E. Draves
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Lucy B. Young
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Kelsey Roe
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Marianne A. Bryan
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Christiane Dresch
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Justin M. Richner
- Departments of Medicine, Molecular Microbiology, Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America
| | - Michael S. Diamond
- Departments of Medicine, Molecular Microbiology, Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America
- The Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, Missouri, United States of America
- Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, United States of America
| | - Michael Gale
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
- Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, United States of America
| | - Edward A. Clark
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
- Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, United States of America
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Borhis G, Trovato M, Chaoul N, Ibrahim HM, Richard Y. B-Cell-Activating Factor and the B-Cell Compartment in HIV/SIV Infection. Front Immunol 2017; 8:1338. [PMID: 29163465 PMCID: PMC5663724 DOI: 10.3389/fimmu.2017.01338] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 10/03/2017] [Indexed: 12/12/2022] Open
Abstract
With the goal to design effective HIV vaccines, intensive studies focused on broadly neutralizing antibodies, which arise in a fraction of HIV-infected people. Apart from identifying new vulnerability sites in the viral envelope proteins, these studies have shown that a fraction of these antibodies are produced by self/poly-reactive B-cells. These findings prompted us to revisit the B-cell differentiation and selection process during HIV/SIV infection and to consider B-cells as active players possibly shaping the helper T-cell program within germinal centers (GCs). In this context, we paid a particular attention to B-cell-activating factor (BAFF), a key cytokine in B-cell development and immune response that is overproduced during HIV/SIV infection. As it does in autoimmune diseases, BAFF excess might contribute to the abnormal rescue of self-reactive B-cells at several checkpoints of the B-cell development and impair memory B-cell generation and functions. In this review, we first point out what is known about the functions of BAFF/a proliferation-inducing ligand and their receptors [B-cell maturation, transmembrane activator and CAML interactor (TACI), and BAFF-R], in physiological and pathophysiological settings, in mice and humans. In particular, we highlight recent results on the previously underappreciated regulatory functions of TACI and on the highly regulated production of soluble TACI and BAFF-R that act as decoy receptors. In light of recent data on BAFF, TACI, and BAFF-R, we then revisit the altered phenotypes and functions of B-cell subsets during the acute and chronic phase of HIV/SIV infection. Given the atypical phenotype and reduced functions of memory B-cells in HIV/SIV infection, we particularly discuss the GC reaction, a key checkpoint where self-reactive B-cells are eliminated and pathogen-specific memory B-cells and plasmablasts/cells are generated in physiological settings. Through its capacity to differentially bind and process BAFF-R and TACI on GC B-cells and possibly on follicular helper T-cells, BAFF appears as a key regulator of the physiological GC reaction. Its local excess during HIV/SIV infection could play a key role in B-cell dysregulations.
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Affiliation(s)
- Gwenoline Borhis
- INSERM u1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- Université Paris-Descartes, Paris, France
| | - Maria Trovato
- INSERM u1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- Université Paris-Descartes, Paris, France
| | - Nada Chaoul
- Commissariat à l’Energie Atomique, Institut des maladies Emergentes et Thérapies innovantes, Service d’Immuno-Virologie, Fontenay-aux Roses, France
| | - Hany M. Ibrahim
- INSERM u1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- Université Paris-Descartes, Paris, France
| | - Yolande Richard
- INSERM u1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- Université Paris-Descartes, Paris, France
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34
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Abstract
The two ligands B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) and the three receptors BAFF receptor (BAFF-R), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) are members of the "BAFF system molecules." BAFF system molecules are primarily involved in B cell homeostasis. The relevance of BAFF system molecules in host responses to microbial assaults has been investigated in clinical studies and in mice deficient for each of these molecules. Many microbial products modulate the expression of these molecules. Data from clinical studies suggest a correlation between increased expression levels of BAFF system molecules and elevated B cell responses. Depending on the pathogen, heightened B cell responses may strengthen the host response or promote susceptibility. Whereas pathogen-mediated increases in the expression levels of the ligands and/or the receptors appear to promote microbial clearance, certain pathogens have evolved to ablate B cell responses by suppressing the expression of TACI and/or BAFF-R on B cells. Other than its well-established role in B cell responses, the TACI-mediated activation of macrophages is also implicated in resistance to intracellular pathogens. An improved understanding of the role that BAFF system molecules play in infection may assist in devising novel strategies for vaccine development.
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Affiliation(s)
- Jiro Sakai
- Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Mustafa Akkoyunlu
- Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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35
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Mourik BC, Lubberts E, de Steenwinkel JEM, Ottenhoff THM, Leenen PJM. Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases. Front Immunol 2017; 8:294. [PMID: 28424682 PMCID: PMC5380685 DOI: 10.3389/fimmu.2017.00294] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 03/01/2017] [Indexed: 01/04/2023] Open
Abstract
The classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research.
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Affiliation(s)
- Bas C Mourik
- Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Erik Lubberts
- Department of Rheumatology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jurriaan E M de Steenwinkel
- Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
| | - Pieter J M Leenen
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
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36
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Wensveen FM, Slinger E, van Attekum MH, Brink R, Eldering E. Antigen-affinity controls pre-germinal center B cell selection by promoting Mcl-1 induction through BAFF receptor signaling. Sci Rep 2016; 6:35673. [PMID: 27762293 PMCID: PMC5071843 DOI: 10.1038/srep35673] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 09/30/2016] [Indexed: 12/23/2022] Open
Abstract
Upon antigen encounter, the responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity. Already before formation of the germinal center, activated B cells of low-affinity are negatively selected in a process that is molecularly not well understood. In this study, we investigated the mechanism behind pre-GC affinity-mediated B cell selection. We applied affinity mutants of HEL antigen and found that rapidly after activation B cells become highly dependent on the cytokine BAFF. Moreover, expression of BAFF receptor CD268 is regulated in a BCR-affinity dependent fashion. High affinity responses via BAFF correlated with PI3K activation, which controlled expression of the pro-survival protein Mcl-1, and thereby increased survival. In the presence of excess BAFF, or in absence of the Mcl-1 antagonist Noxa, more low-affinity B cells survived the first two days after antigen encounter. This resulted in increased numbers of antigen-specific B cells of low affinity upon immunization and reduced the overall affinity of cells that contributed to the germinal center reaction. Our findings elucidate a crucial molecular pathway of B cell selection in the earliest phases of activation by identifying a novel link between BCR affinity and BAFF-R signaling towards Mcl-1.
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Affiliation(s)
- Felix M Wensveen
- Department of Experimental Immunology, Academic Medical Center, 1105AZ, Amsterdam, The Netherlands
| | - Erik Slinger
- Department of Experimental Immunology, Academic Medical Center, 1105AZ, Amsterdam, The Netherlands
| | - Martijn Ha van Attekum
- Department of Experimental Immunology, Academic Medical Center, 1105AZ, Amsterdam, The Netherlands
| | - Robert Brink
- Immunology Division, Garvan Institute of Medical Research, NSW 2010, Darlinghurst, Australia
| | - Eric Eldering
- Department of Experimental Immunology, Academic Medical Center, 1105AZ, Amsterdam, The Netherlands
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Cieniewicz B, Santana AL, Minkah N, Krug LT. Interplay of Murine Gammaherpesvirus 68 with NF-kappaB Signaling of the Host. Front Microbiol 2016; 7:1202. [PMID: 27582728 PMCID: PMC4987367 DOI: 10.3389/fmicb.2016.01202] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 07/19/2016] [Indexed: 11/13/2022] Open
Abstract
Herpesviruses establish a chronic infection in the host characterized by intervals of lytic replication, quiescent latency, and reactivation from latency. Murine gammaherpesvirus 68 (MHV68) naturally infects small rodents and has genetic and biologic parallels with the human gammaherpesviruses (gHVs), Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus. The murine gammaherpesvirus model pathogen system provides a platform to apply cutting-edge approaches to dissect the interplay of gammaherpesvirus and host determinants that enable colonization of the host, and that shape the latent or lytic fate of an infected cell. This knowledge is critical for the development of novel therapeutic interventions against the oncogenic gHVs. The nuclear factor kappa B (NF-κB) signaling pathway is well-known for its role in the promotion of inflammation and many aspects of B cell biology. Here, we review key aspects of the virus lifecycle in the host, with an emphasis on the route that the virus takes to gain access to the B cell latency reservoir. We highlight how the murine gammaherpesvirus requires components of the NF-κB signaling pathway to promote replication, latency establishment, and maintenance of latency. These studies emphasize the complexity of gammaherpesvirus interactions with NF-κB signaling components that direct innate and adaptive immune responses of the host. Importantly, multiple facets of NF-κB signaling have been identified that might be targeted to reduce the burden of gammaherpesvirus-associated diseases.
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Affiliation(s)
- Brandon Cieniewicz
- Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook NY, USA
| | - Alexis L Santana
- Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook NY, USA
| | - Nana Minkah
- Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook NY, USA
| | - Laurie T Krug
- Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook NY, USA
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Abstract
The major impediment to drug development for systemic lupus erythematosus (SLE) is its heterogeneity. The unpredictable manner in which lupus targets different organs at varying intensity makes the study of new drugs and the optimization of their administration extremely difficult. With the advent of novel, targeted biologic agents for SLE, it can be hoped that more strategic, lupus-relevant immune modulation will lead to safer and more effective treatments. Two alternative new approaches to lupus treatment are reviewed. The first involves selective inhibition of a single protein (BLyS), which may play a central role in host defense and in the pathogenesis of SLE. Although this approach is finely targeted to the inhibition of a single protein which is known to be upregulated in SLE patients, the positioning of BLyS at a critical hub in the immune response suggests that more global adverse repercussions on immunity might still occur. The second strategy is the use of peptides designed to specifically induce tolerance in limited autoreactive immune responses. Immune repercussions might, at least in theory, be almost nonexistent with this kind of approach. Concerns that limited induction of tolerance might have equally limited impact on the complex immune disorder of SLE are not borne out in preliminary murine data. Specific development programs are ongoing using both of these strategies and have recently entered human trials.
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Affiliation(s)
- J T Merrill
- Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
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Ding J, Zhang W, Haskett S, Pellerin A, Xu S, Petersen B, Jandreski L, Hamann S, Reynolds TL, Zheng TS, Mingueneau M. BAFF overexpression increases lymphocytic infiltration in Sjögren's target tissue, but only inefficiently promotes ectopic B-cell differentiation. Clin Immunol 2016; 169:69-79. [PMID: 27352977 DOI: 10.1016/j.clim.2016.06.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 06/19/2016] [Accepted: 06/23/2016] [Indexed: 12/28/2022]
Abstract
B-cell activating factor (BAFF) levels are increased in rheumatoid arthritis, lupus and primary Sjögren's syndrome (pSS). However, BAFF contribution to pathogenesis is not completely understood. In pSS, immune infiltration of the salivary and lacrimal glands leads to xerostomia and xerophtalmia. Glandular B cell hyperactivation, differentiation into germinal center (GC)-like structures and plasma cell accumulation are histopathological hallmarks that were attributed to increased BAFF. Here, we experimentally tested this hypothesis by overexpressing BAFF in a mouse model of pSS. BAFF overexpression enhanced lymphocytic infiltration and MHCII expression on B cells. Increased BAFF also induced B cell differentiation into GC B cells within the autoimmune target tissue. However, even in these conditions, GC B cells only accounted for <1% of glandular B cells, demonstrating that BAFF is not efficiently promoting ectopic GC formation in pSS and warranting further investigation of therapeutics targeting both BAFF and the related TNF-family member APRIL.
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Affiliation(s)
- Jian Ding
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Wei Zhang
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Scott Haskett
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Alex Pellerin
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Shanqin Xu
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Britta Petersen
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Luke Jandreski
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Stefan Hamann
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Taylor L Reynolds
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Timothy S Zheng
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States
| | - Michael Mingueneau
- Immunology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States.
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Domeier PP, Chodisetti SB, Soni C, Schell SL, Elias MJ, Wong EB, Cooper TK, Kitamura D, Rahman ZSM. IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. J Exp Med 2016; 213:715-32. [PMID: 27069112 PMCID: PMC4854731 DOI: 10.1084/jem.20151722] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/18/2016] [Indexed: 12/15/2022] Open
Abstract
Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell-intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell-specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell-intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell-dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen-driven, GC and Tfh cell responses. Together, our data define a novel B cell-intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.
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Affiliation(s)
- Phillip P Domeier
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Sathi Babu Chodisetti
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Chetna Soni
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Stephanie L Schell
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Melinda J Elias
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Eric B Wong
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Timothy K Cooper
- Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033 Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Daisuke Kitamura
- Research Institute for Biomedical Sciences, Tokyo University of Science, 162 0825 Tokyo, Japan
| | - Ziaur S M Rahman
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
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Sakaguchi N, Maeda K. Germinal Center B-Cell-Associated Nuclear Protein (GANP) Involved in RNA Metabolism for B Cell Maturation. Adv Immunol 2016; 131:135-86. [PMID: 27235683 DOI: 10.1016/bs.ai.2016.02.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Germinal center B-cell-associated nuclear protein (GANP) is upregulated in germinal center B cells against T-cell-dependent antigens in mice and humans. In mice, GANP depletion in B cells impairs antibody affinity maturation. Conversely, its transgenic overexpression augments the generation of high-affinity antigen-specific B cells. GANP associates with AID in the cytoplasm, shepherds AID into the nucleus, and augments its access to the rearranged immunoglobulin (Ig) variable (V) region of the genome in B cells, thereby precipitating the somatic hypermutation of V region genes. GANP is also upregulated in human CD4(+) T cells and is associated with APOBEC3G (A3G). GANP interacts with A3G and escorts it to the virion cores to potentiate its antiretroviral activity by inactivating HIV-1 genomic cDNA. Thus, GANP is characterized as a cofactor associated with AID/APOBEC cytidine deaminase family molecules in generating diversity of the IgV region of the genome and genetic alterations of exogenously introduced viral targets. GANP, encoded by human chromosome 21, as well as its mouse equivalent on chromosome 10, contains a region homologous to Saccharomyces Sac3 that was characterized as a component of the transcription/export 2 (TREX-2) complex and was predicted to be involved in RNA export and metabolism in mammalian cells. The metabolism of RNA during its maturation, from the transcription site at the chromosome within the nucleus to the cytoplasmic translation apparatus, needs to be elaborated with regard to acquired and innate immunity. In this review, we summarize the current knowledge on GANP as a component of TREX-2 in mammalian cells.
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Affiliation(s)
- N Sakaguchi
- WPI Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan; Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
| | - K Maeda
- WPI Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan; Laboratory of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
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Boneparth A, Woods M, Huang W, Akerman M, Lesser M, Davidson A. The Effect of BAFF Inhibition on Autoreactive B-Cell Selection in Murine Systemic Lupus Erythematosus. Mol Med 2016; 22:173-182. [PMID: 26882090 DOI: 10.2119/molmed.2016.00022] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 02/08/2016] [Indexed: 12/15/2022] Open
Abstract
The goal of this study was to determine how B-cell-activating factor of the TNF family (BAFF) availability influences selection of the autoreactive B-cell repertoire in NZB/W and NZW/BXSB lupus-prone mice bearing the site-directed heavy-chain transgene 3H9 that encodes for anti-dsDNA and anti-cardiolipin (CL) autoantibodies. We used a bone marrow chimera system in which autoreactive 3H9 transgenic B cells were allowed to mature in competition with wild-type cells and could be identified by green fluorescent protein. The light-chain repertoire associated with the 3H9 heavy chain in naive and antigen-activated B-cell subsets was assessed using single-cell polymerase chain reaction. We found that deletion of autoreactive transgenic B cells occurred in the bone marrow of both strains regardless of BAFF availability, and there were only modest and physiologically non-relevant effects on the naive B-cell repertoire. BAFF inhibition had different effects on selection of the germinal center repertoire in the two strains. In the NZW/BXSB strain, BAFF inhibition phenocopied the loss of one TLR7 allele in that it influenced the selection of 3H9-encoded autoreactive B cells in the germinal center but did not prevent somatic mutation. In the NZB/W strain, BAFF inhibition did not alter the selection of 3H9-encoded B cells in the germinal center, but it influenced selection of a subset of germinal center cells into the plasma cell compartment. Our data underscore the complexity of regulation of the autoreactive B-cell repertoire by BAFF and may help to explain the heterogeneity of responses observed after BAFF inhibition in humans.
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Affiliation(s)
- Alexis Boneparth
- Center for Autoimmunity, Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Megan Woods
- Center for Autoimmunity, Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Weiqing Huang
- Center for Autoimmunity, Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Meredith Akerman
- Musculoskeletal Diseases and Biostatistics Unit, Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Martin Lesser
- Musculoskeletal Diseases and Biostatistics Unit, Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Anne Davidson
- Center for Autoimmunity, Feinstein Institute for Medical Research, Manhasset, New York, United States of America
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Kang S, Keener AB, Jones SZ, Benschop RJ, Caro-Maldonado A, Rathmell JC, Clarke SH, Matsushima GK, Whitmire JK, Vilen BJ. IgG-Immune Complexes Promote B Cell Memory by Inducing BAFF. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2016; 196:196-206. [PMID: 26621863 PMCID: PMC4684997 DOI: 10.4049/jimmunol.1402527] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Accepted: 10/28/2015] [Indexed: 01/10/2023]
Abstract
Memory B cell responses are vital for protection against infections but must also be regulated to prevent autoimmunity. Cognate T cell help, somatic hypermutation, and affinity maturation within germinal centers (GCs) are required for high-affinity memory B cell formation; however, the signals that commit GC B cells to the memory pool remain unclear. In this study, we identify a role for IgG-immune complexes (ICs), FcγRs, and BAFF during the formation of memory B cells in mice. We found that early secretion of IgG in response to immunization with a T-dependent Ag leads to IC-FcγR interactions that induce dendritic cells to secrete BAFF, which acts at or upstream of Bcl-6 in activated B cells. Loss of CD16, hematopoietic cell-derived BAFF, or blocking IC:FcγR regions in vivo diminished the expression of Bcl-6, the frequency of GC and memory B cells, and secondary Ab responses. BAFF also contributed to the maintenance and/or expansion of the follicular helper T cell population, although it was dispensable for their formation. Thus, early Ab responses contribute to the optimal formation of B cell memory through IgG-ICs and BAFF. Our work defines a new role for FcγRs in GC and memory B cell responses.
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Affiliation(s)
- SunAh Kang
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Amanda B Keener
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Shannon Z Jones
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | | | | | - Jeffrey C Rathmell
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710
| | - Stephen H Clarke
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Glenn K Matsushima
- Neuroscience Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and
| | - Jason K Whitmire
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Barbara J Vilen
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
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45
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Pietrosimone KM, Liu P. Contributions of neutrophils to the adaptive immune response in autoimmune disease. World J Transl Med 2015; 4:60-68. [PMID: 27042404 PMCID: PMC4816207 DOI: 10.5528/wjtm.v4.i3.60] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 10/01/2015] [Accepted: 11/25/2015] [Indexed: 02/05/2023] Open
Abstract
Neutrophils are granulocytic cytotoxic leukocytes of the innate immune system that activate during acute inflammation. Neutrophils can also persist beyond the acute phase of inflammation to impact the adaptive immune response during chronic inflammation. In the context of the autoimmune disease, neutrophils modulating T and B cell functions by producing cytokines and chemokines, forming neutrophil extracellular traps, and acting as or priming antigen presentation cells. Thus, neutrophils are actively involved in chronic inflammation and tissue damage in autoimmune disease. Using rheumatoid arthritis as an example, this review focuses on functions of neutrophils in adaptive immunity and the therapeutic potential of these cells in the treatment of autoimmune disease and chronic inflammation.
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46
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Zhang JX, Song R, Sang M, Sun SQ, Ma L, Zhang J, Zhang SQ. Molecular and functional characterization of BAFF from the Yangtze alligator (Alligator sinensis, Alligatoridae). ZOOLOGY 2015; 118:325-33. [DOI: 10.1016/j.zool.2015.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 02/27/2015] [Accepted: 03/26/2015] [Indexed: 12/24/2022]
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47
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Yang K, Xiao K, Huang H, Lu S, Zhong J, Ansari AR, Khaliq H, Song H, Liu H, Peng K. Molecular cloning, expression and bioactivity of B cell activating factor (BAFF) in African ostrich. Int Immunopharmacol 2015; 28:686-694. [PMID: 26256697 DOI: 10.1016/j.intimp.2015.07.043] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 07/15/2015] [Accepted: 07/30/2015] [Indexed: 12/28/2022]
Abstract
B cell activating factor (BAFF), which belongs to the tumor necrosis factor (TNF) family, is testified to play a critical role in B cell survival, proliferation, maturation and immunoglobulin secretion. In the present study, the cDNA of open reading frame (ORF) in African ostrich (Struthio camelus) BAFF (designated OsBAFF) was cloned by reverse transcription-PCR (RT-PCR). The OsBAFF gene encodes a 288-amino acid protein containing a predicted transmembrane domain and a putative furin protease cleavage site like BAFFs from chicken (cBAFF), quail (qBAFF), duck (dBAFF), goose (gBAFF) and dove (doBAFF). RT-PCR analysis showed that the OsBAFF gene is strongly expressed in the bursa of Fabricius, thymus, spleen, and bone marrow. The soluble OsBAFF had been cloned into pET28a. SDS-PAGE and Western blotting analysis confirmed that the soluble fusion protein His-OsBAFF was efficiently expressed in Escherichia coli Rosset (DE3). In vitro, purified OsBAFF was not only able to promote the survival of African ostrich bursal lymphocytes, but also able to co-stimulate proliferation of mouse splenic B cells. The expression of OsBAFF in lymphocyte cells was higher than the control after LPS stimulation. These findings indicated that OsBAFF plays an important role in survival and proliferation of African ostrich bursal lymphocytes, which may provide valuable information for research into the immune system of African ostrich and OsBAFF may serve as a potential immunologic factor for enhancing immunological efficacy in African ostrich and any other birds.
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Affiliation(s)
- Keli Yang
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China; Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, Hubei, PR China
| | - Ke Xiao
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China
| | - Haibo Huang
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China
| | - Shun Lu
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China
| | - Juming Zhong
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China; College of Veterinary Medicine, Auburn University, Auburn 36849, AL, USA
| | - Abdur Rahman Ansari
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China
| | - Haseeb Khaliq
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China
| | - Hui Song
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China
| | - Huazhen Liu
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China
| | - Kemei Peng
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, PR China.
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48
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Woods M, Zou YR, Davidson A. Defects in Germinal Center Selection in SLE. Front Immunol 2015; 6:425. [PMID: 26322049 PMCID: PMC4536402 DOI: 10.3389/fimmu.2015.00425] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 08/03/2015] [Indexed: 01/01/2023] Open
Abstract
Germinal centers (GCs) are the primary site at which clonal expansion and affinity maturation of B cells occur. B cells encounter antigen and receive T cell help in the GC light zone (LZ) and then migrate to the dark zone where they proliferate and undergo somatic mutation before cycling back to the LZ for further rounds of selection. Tolerance to autoantigens is frequently lost de novo as GC B cells undergo class switching and somatic mutation. This loss of tolerance is regulated by a variety of mechanisms including cell death, failure to compete for T cell help, and failure to differentiate into effector cells. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nucleic acid antigens. While defects in tolerance occur in the naïve repertoire of SLE patients, pathogenic autoantibodies also arise in the GC by somatic mutation from non-autoreactive precursors. Several B cell defects contribute to the loss of GC tolerance in SLE, including polymorphisms of genes encoded by the Sle1 locus, excess TLR7 signaling, defects in FcRIIB expression, or defects of B cell apoptosis. Extrinsic soluble factors, such as Type-1 IFN and B cell-activating factor, or an increased number of T follicular helper cells in the GC also alter B cell-negative selection. Finally, defects in clearance of apoptotic debris within the GC result in BCR-mediated internalization of nucleic acid containing material and stimulation of autoantibody production by endosomal TLR-driven mechanisms.
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Affiliation(s)
- Megan Woods
- Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research , New York, NY , USA
| | - Yong-Rui Zou
- Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research , New York, NY , USA
| | - Anne Davidson
- Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research , New York, NY , USA
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Brightbill HD, Jackman JK, Suto E, Kennedy H, Jones C, Chalasani S, Lin Z, Tam L, Roose-Girma M, Balazs M, Austin CD, Lee WP, Wu LC. Conditional Deletion of NF-κB-Inducing Kinase (NIK) in Adult Mice Disrupts Mature B Cell Survival and Activation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2015; 195:953-64. [PMID: 26116508 DOI: 10.4049/jimmunol.1401514] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 05/30/2015] [Indexed: 01/19/2023]
Abstract
NF-κB-inducing kinase (NIK) is a primary regulator of the noncanonical NF-κB signaling pathway, which plays a vital role downstream of BAFF, CD40L, lymphotoxin, and other inflammatory mediators. Germline deletion or inactivation of NIK in mice results in the defective development of B cells and secondary lymphoid organs, but the role of NIK in adult animals has not been studied. To address this, we generated mice containing a conditional allele of NIK. Deletion of NIK in adult mice results in decreases in B cell populations in lymph nodes and spleen, similar to what is observed upon blockade of BAFF. Consistent with this, B cells from mice in which NIK is acutely deleted fail to respond to BAFF stimulation in vitro and in vivo. In addition, mice with induced NIK deletion exhibit a significant decrease in germinal center B cells and serum IgA, which is indicative of roles for NIK in additional pathways beyond BAFF signaling. Our conditional NIK-knockout mice may be broadly useful for assessing the postdevelopmental and cell-specific roles of NIK and the noncanonical NF-κB pathway in mice.
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Affiliation(s)
- Hans D Brightbill
- Department of Immunology, Genentech Inc., South San Francisco, CA 94080;
| | - Janet K Jackman
- Department of Immunology, Genentech Inc., South San Francisco, CA 94080
| | - Eric Suto
- Department of Translational Immunology, Genentech Inc., South San Francisco, CA 94080
| | - Heather Kennedy
- Department of Pathology, Genentech Inc., South San Francisco, CA 94080; and
| | - Charles Jones
- Department of Pathology, Genentech Inc., South San Francisco, CA 94080; and
| | - Sreedevi Chalasani
- Department of Pathology, Genentech Inc., South San Francisco, CA 94080; and
| | - Zhonghua Lin
- Department of Translational Immunology, Genentech Inc., South San Francisco, CA 94080
| | - Lucinda Tam
- Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080
| | - Meron Roose-Girma
- Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080
| | - Mercedesz Balazs
- Department of Translational Immunology, Genentech Inc., South San Francisco, CA 94080
| | - Cary D Austin
- Department of Pathology, Genentech Inc., South San Francisco, CA 94080; and
| | - Wyne P Lee
- Department of Translational Immunology, Genentech Inc., South San Francisco, CA 94080
| | - Lawren C Wu
- Department of Immunology, Genentech Inc., South San Francisco, CA 94080;
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50
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Wong EB, Soni C, Chan AY, Domeier PP, Shwetank, Abraham T, Limaye N, Khan TN, Elias MJ, Chodisetti SB, Wakeland EK, Rahman ZSM. B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance. THE JOURNAL OF IMMUNOLOGY 2015; 194:4130-43. [PMID: 25801429 DOI: 10.4049/jimmunol.1403023] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 02/16/2015] [Indexed: 12/22/2022]
Abstract
Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated, and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint are not clear. In this study, we generated several bacterial artificial chromosome-transgenic mice that overexpress C57BL/6 (B6) alleles of different SLAM family genes on an autoimmune-prone B6.Sle1b background. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the spontaneously developed GC response and autoantibody production compared with B6.Sle1b mice. These data suggest a prominent role for Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance, leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling and a lower frequency of B cell-T cell conjugates; the reverse is seen in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared with B6 controls. Our study establishes a central role for GC B cell-specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity.
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Affiliation(s)
- Eric B Wong
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Chetna Soni
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Alice Y Chan
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
| | - Phillip P Domeier
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Shwetank
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Thomas Abraham
- Department of Research Resources, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Nisha Limaye
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
| | - Tahsin N Khan
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Melinda J Elias
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Sathi Babu Chodisetti
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Edward K Wakeland
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
| | - Ziaur S M Rahman
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
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