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Nguyen AA, Platt CD. Flow Cytometry-based Immune Phenotyping of T and B Lymphocytes in the Evaluation of Immunodeficiency and Immune Dysregulation. Immunol Allergy Clin North Am 2025; 45:189-203. [PMID: 40287168 DOI: 10.1016/j.iac.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
There are approximately 500 congenital disorders that impair immune cell development and/or function. Patients with these disorders may present with a wide range of symptoms, including increased susceptibility to infection, autoimmunity, autoinflammation, lymphoproliferation, and/or atopy. Flow cytometry-based immune phenotyping of T and B lymphocytes plays an essential role in the evaluation of patients with these presentations. In this review, we describe the clinical utility of flow cytometry as part of a comprehensive evaluation of immune function and how this testing may be used as a diagnostic tool to identify underlying aberrant immune pathways, monitor disease activity, and assess infection risk.
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Affiliation(s)
- Alan A Nguyen
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Fegan Building 6th Floor, Boston, MA 02115, USA
| | - Craig D Platt
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, 1 Blackfan Circle, Karp Building 10th Floor, Boston, MA 02115, USA.
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2
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Gagey G, Sorial D, Rasmussen C, Mechai F, Galicier L, Vérine J, Oksenhendler E, Bertinchamp R, Poullot E, Boutboul D. Urogenital Schistosomiasis Mimicking IgG4-RD in a Patient With HIV. Open Forum Infect Dis 2025; 12:ofaf136. [PMID: 40160350 PMCID: PMC11953034 DOI: 10.1093/ofid/ofaf136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 03/13/2025] [Indexed: 04/02/2025] Open
Abstract
This article reports a case of urogenital schistosomiasis mimicking IgG4-related disease (IgG4-RD) in a 47-year-old immunocompromised man with HIV. Initially diagnosed with IgG4-RD, further biopsies revealed schistosoma eggs. Elevated IgG4 levels indicated a Th2 immune response, highlighting its complex role in antischistosomal immunity and the need for careful differential diagnosis.
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Affiliation(s)
- Guillemette Gagey
- Department of Clinical Immunology, Hôpital Saint Louis, AP-HP, Université Paris Cité, Paris, France
| | - Didier Sorial
- Department of Internal Medicine, Hôpital Saint-Camille, Bry-sur-Marne, France
| | - Camille Rasmussen
- Department of Clinical Immunology, Hôpital Saint Louis, AP-HP, Université Paris Cité, Paris, France
| | - Frédéric Mechai
- Department of Infectious Diseases, Hôpital Avicenne, Université Sorbonne Paris Nord, Bobigny, France
| | - Lionel Galicier
- Department of Internal Medicine, Hôpital de la Timone, AP-HM, Marseille, France
| | - Jérôme Vérine
- Department of Pathology, Hôpital Saint Louis, AP-HP, Université Paris Cité, Paris, France
| | - Eric Oksenhendler
- Department of Clinical Immunology, Hôpital Saint Louis, AP-HP, Université Paris Cité, Paris, France
| | - Rémi Bertinchamp
- Department of Internal Medicine, Hôpital Antoine Béclère, Université Paris-Saclay, Clamart, France
| | - Elsa Poullot
- Department of Pathology, Hôpital Henri Mondor, AP-HP, Université Paris Est Créteil, Créteil, France
| | - David Boutboul
- Department of Hematology, Hôpital Cochin, AP-HP, Université Paris Cité, Paris, France
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Wang L, Vulesevic B, Vigano M, As’sadiq A, Kang K, Fernandez C, Samarani S, Anis AH, Ahmad A, Costiniuk CT. The Impact of HIV on B Cell Compartment and Its Implications for COVID-19 Vaccinations in People with HIV. Vaccines (Basel) 2024; 12:1372. [PMID: 39772034 PMCID: PMC11679862 DOI: 10.3390/vaccines12121372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/28/2024] [Accepted: 11/30/2024] [Indexed: 01/11/2025] Open
Abstract
HIV causes intense polyclonal activation of B cells, resulting in increased numbers of spontaneously antibody-secreting cells in the circulation and hypergammaglobulinemia. It is accompanied by significant perturbations in various B cell subsets, such as increased frequencies of immature/transitional B cells, activated memory B cells, atypical memory B cells, short-lived plasmablasts and regulatory B cells, as well as by decreased frequencies of resting memory and resting naïve B cells. Furthermore, both memory and antigen-inexperienced naïve B cells show exhausted and immune-senescent phenotypes. HIV also drives the expansion and functional impairment of CD4+ T follicular helper cells, which provide help to B cells, crucial for the generation of germinal center reactions and production of long-lived plasma and memory B cells. By suppressing viral replication, anti-retroviral therapy reverses the virus-induced perturbations and functional defects, albeit inadequately. Due to HIV's lingering impact on B cells, immune senescence and residual chronic inflammation, people with HIV (PWH), especially immune non-responders, are immunocompromised and mount suboptimal antibody responses to vaccination for SARS-CoV-2. Here, we review how functionally and phenotypically distinct B cell subsets are induced in response to a vaccine and an infection and how HIV infection and anti-retroviral therapy (ART) impact them. We also review the role played by HIV-induced defects and perturbations in B cells in the induction of humoral immune responses to currently used anti-SARS-CoV-2 vaccines in PWH on ART. We also outline different strategies that could potentially enhance the vaccine-induced antibody responses in PWH. The review will provide guidance and impetus for further research to improve the immunogenicity of these vaccines in this human population.
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Affiliation(s)
- Lixing Wang
- Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada; (L.W.); (C.F.)
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
| | - Branka Vulesevic
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
| | - MariaLuisa Vigano
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
| | - Alia As’sadiq
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
| | - Kristina Kang
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
| | - Cristina Fernandez
- Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada; (L.W.); (C.F.)
| | - Suzanne Samarani
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
| | - Aslam H. Anis
- Centre for Advancing Health Outcomes Centre for Health Evaluation and Outcome Sciences, St. Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada;
| | - Ali Ahmad
- Centre de Recherche, Hôpital Ste Justine, Montréal, QC H3T 1C5, Canada;
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3T 1C5, Canada
| | - Cecilia T. Costiniuk
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
- Division of Infectious Diseases and Chronic Viral Illnesses Service, McGill University Health Centre, Montreal QC H4A 3J1, Canada
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Nguyen AA, Platt CD. Flow Cytometry-based Immune Phenotyping of T and B Lymphocytes in the Evaluation of Immunodeficiency and Immune Dysregulation. Clin Lab Med 2024; 44:479-493. [PMID: 39089753 DOI: 10.1016/j.cll.2024.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
There are approximately 500 congenital disorders that impair immune cell development and/or function. Patients with these disorders may present with a wide range of symptoms, including increased susceptibility to infection, autoimmunity, autoinflammation, lymphoproliferation, and/or atopy. Flow cytometry-based immune phenotyping of T and B lymphocytes plays an essential role in the evaluation of patients with these presentations. In this review, we describe the clinical utility of flow cytometry as part of a comprehensive evaluation of immune function and how this testing may be used as a diagnostic tool to identify underlying aberrant immune pathways, monitor disease activity, and assess infection risk.
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Affiliation(s)
- Alan A Nguyen
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Fegan Building 6th Floor, Boston, MA 02115, USA
| | - Craig D Platt
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, 1 Blackfan Circle, Karp Building 10th Floor, Boston, MA 02115, USA.
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Zhang M, Dai G, Smith DL, Zacco E, Shimoda M, Kumar N, Girling V, Gardner K, Hunt PW, Huang L, Lin J. Interferon-signaling pathways are upregulated in people with HIV with abnormal pulmonary diffusing capacity (DL CO ). AIDS 2024; 38:1523-1532. [PMID: 38819840 PMCID: PMC11239097 DOI: 10.1097/qad.0000000000003946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 03/14/2024] [Accepted: 04/03/2024] [Indexed: 06/01/2024]
Abstract
OBJECTIVE People with HIV (PWH) are at greater risk of developing lung diseases even when they are antiretroviral therapy (ART)-adherent and virally suppressed. The most common pulmonary function abnormality in PWH is that of impaired diffusing capacity of the lungs for carbon monoxide (DL CO ), which is an independent risk factor for increased mortality in PWH. Earlier work has identified several plasma biomarkers of inflammation and immune activation to be associated with decreased DL CO . However, the underpinning molecular mechanisms of HIV-associated impaired DL CO are largely unknown. DESIGN Cross-sectional pilot study with PWH with normal DL CO (values greater than or equal to the lower limit of normal, DL CO ≥ LLN, N = 9) or abnormal DL CO (DL CO < LLN, N = 9). METHODS We compared the gene expression levels of over 900 inflammation and immune exhaustion genes in PBMCs from PWH with normal vs. abnormal DL CO using the NanoString technology. RESULTS We found that 26 genes were differentially expressed in the impaired DL CO group. These genes belong to 4 categories: 1. Nine genes in inflammation and immune activation pathways, 2. seven upregulated genes that are direct targets of the interferon signaling pathway, 3. seven B-cell specific genes that are downregulated, and 4. three miscellaneous genes. These results were corroborated using the bioinformatics tools DAVID (Database for Annotation, Visualization and Integrated Discovery) and GSEA (Gene Sets Enrichment Analysis). CONCLUSION The data provides preliminary evidence for the involvement of sustained interferon signaling as a molecular mechanism for impaired DL CO in PWH.
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Affiliation(s)
- Michelle Zhang
- Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine
| | - Guorui Dai
- Department of Biochemistry and Biophysics
| | | | - Emanuela Zacco
- Laboratory for Cell Analysis, Helen Diller Comprehensive Cancer Center
| | | | - Nitasha Kumar
- Core Immunology Lab, Division of Experimental Medicine
| | | | - Kendall Gardner
- Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine
| | | | - Laurence Huang
- Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, CA, USA
| | - Jue Lin
- Department of Biochemistry and Biophysics
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Li P, Wang Q, He Y, Yang C, Zhang Z, Liu Z, Liu B, Yin L, Cui Y, Hu P, Liu Y, Zheng P, Wang W, Qu L, Sun C, Guan S, Feng L, Chen L. Booster vaccination is required to elicit and maintain COVID-19 vaccine-induced immunity in SIV-infected macaques. Emerg Microbes Infect 2023; 12:e2136538. [PMID: 36239345 PMCID: PMC9980405 DOI: 10.1080/22221751.2022.2136538] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
ABSTRACTProlonged infection and possible evolution of SARS-CoV-2 in patients living with uncontrolled HIV-1 infection highlight the importance of an effective vaccination regimen, yet the immunogenicity of COVID-19 vaccines and predictive immune biomarkers have not been well investigated. Herein, we report that the magnitude and persistence of antibody and cell-mediated immunity (CMI) elicited by an Ad5-vectored COVID-19 vaccine are impaired in SIV-infected macaques with high viral loads (> 105 genome copies per ml plasma, SIVhi) but not in macaques with low viral loads (< 105, SIVlow). After a second vaccination, the immune responses are robustly enhanced in all uninfected and SIVlow macaques. These responses also show a moderate increase in 70% SIVhi macaques but decline sharply soon after. Further analysis reveals that decreased antibody and CMI responses are associated with reduced circulating follicular helper T cell (TFH) counts and aberrant CD4/CD8 ratios, respectively, indicating that dysregulation of CD4+ T cells by SIV infection impairs the COVID-19 vaccine-induced immunity. Ad5-vectored COVID-19 vaccine shows no impact on SIV loads or SIV-specific CMI responses. Our study underscores the necessity of frequent booster vaccinations in HIV-infected patients and provides indicative biomarkers for predicting vaccination effectiveness in these patients.
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Affiliation(s)
- Pingchao Li
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China, Pingchao Li State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China; Liqiang Feng
| | - Qian Wang
- State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China
| | - Yizi He
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China,University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Chenchen Yang
- Guangzhou nBiomed Ltd., Guangzhou, People’s Republic of China
| | - Zhengyuan Zhang
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China,University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Zijian Liu
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China,University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Bo Liu
- Guangzhou nBiomed Ltd., Guangzhou, People’s Republic of China
| | - Li Yin
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China,University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Yilan Cui
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China,University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Peiyu Hu
- Guangzhou Laboratory & Bioland Laboratory, Guangzhou, People’s Republic of China
| | - Yichu Liu
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China
| | - Pingqian Zheng
- Guangzhou Laboratory & Bioland Laboratory, Guangzhou, People’s Republic of China
| | - Wei Wang
- Guangzhou Laboratory & Bioland Laboratory, Guangzhou, People’s Republic of China
| | - Linbing Qu
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China
| | - Caijun Sun
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China
| | - Suhua Guan
- Guangzhou nBiomed Ltd., Guangzhou, People’s Republic of China
| | - Liqiang Feng
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China,Guangzhou Laboratory & Bioland Laboratory, Guangzhou, People’s Republic of China
| | - Ling Chen
- State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China,State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China,Guangzhou Laboratory & Bioland Laboratory, Guangzhou, People’s Republic of China,Ling Chen State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, People’s Republic of China
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Dhande JR, Saikia K, Singh DP, Bagul RD, Kulkarni SS, Ghate MV, Thakar MR. Higher frequencies of functional HIV-envelope-specific memory B cells are associated with nonprogressive HIV infection in Indian population. AIDS 2020; 34:1603-1608. [PMID: 32769762 DOI: 10.1097/qad.0000000000002620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE The HIV-1-specific antibodies are being considered for prevention and therapy in HIV infection. For effective antibody response, presence of functionally competent memory B cells (MEBs) is important; however, HIV-infection is known to alter the B-cell functionality. Very limited data are available on the HIV-specific memory B-cell population in HIV-infected Indian population. METHODS In this study, the frequencies of HIV-gp140-specific MEBs were measured in individuals with nonprogressive [long-term-nonprogressors (LTNPs), N = 20] and progressive (N = 19) HIV infection using multicolor flow cytometry. The activation and functional status of these MEBs were assessed as frequencies and mean fluorescence intensity (MFI) of the CD38 and CD40 expression, respectively. RESULTS The percentages of gp140 + MEBs were higher in LTNPs than seen in progressors (P = 0.0475) and associated with higher CD4 cell count (P = 0.0312, r = 0.2833). As compared with the progressors, LTNPs also showed higher functional (CD40+) gp140 + MEBs both frequencies (P < 0.0001) and CD40 MFI (P = 0.0222), whereas the frequencies (<0.0001) and the MFI (P = 0.0047) of CD38 expression was significantly lower. Higher CD4 cell counts and lower plasma viral load values were associated with higher frequencies of CD40+ gp140 + MEBs (P < 0.0001, r = 0.4962) (P = 0.0036, r = -0.4202) and lower frequencies (P = 0.0008, r = -0.4231) and CD38 expression (MFI) (P = 0.004, r = -0.3719) (P = 0.0066, r = 0.4033). CONCLUSION Our study suggests that LTNPs have functional HIV-specific memory B-cell compartment with reduced activation that may lead to effective HIV-specific humoral immune responses contributing to their nondisease progression status. These findings would help in better understanding of the characteristics of the HIV-specific memory B-cell population in nonprogressive HIV infection.
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Affiliation(s)
- Jayshree R Dhande
- Department of Immunology and Serology, National AIDS Research Institute, Pune, Maharashtra, India
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Abstract
TB is the leading cause of death from a single infectious agent globally, followed by HIV. Furthermore, TB represents the leading cause of death among people with HIV. HIV is known to cause severe defects in T cell immunity, rendering HIV/TB-coinfected individuals more susceptible to TB disease progression and complicating accurate TB disease diagnosis. Here, we demonstrate that HIV infection is additionally associated with severely compromised antibody responses, particularly in individuals with active TB. Moreover, despite the influence of HIV infection, antibody profiles still allow accurate classification of individuals with active versus latent TB. These findings reveal novel immunologic challenges associated with HIV/TB coinfection and additionally provide a basis with which to leverage the key antibody features identified to potentially combat TB globally via next-generation therapeutic or diagnostic design. Tuberculosis (TB) represents the largest cause of death in human immunodeficiency virus (HIV)-infected individuals in part due to HIV-related CD4+ T cell loss, rendering patients immunocompromised and susceptible to a loss of Mycobacterium tuberculosis control. However, in light of increasing data pointing to a role for humoral immunity in controlling M. tuberculosis infection, here, we aimed to define whether HIV infection also alters the humoral immune response in subjects with active and latent TB. We show that in the setting of active TB, HIV-positive individuals have significantly lower IgG responses to LAM and Ag85 than HIV-negative individuals. Furthermore, significant isotype/subclass-specific differences were frequently observed, with active TB, HIV-positive individuals demonstrating compromised antigen-specific IgM titers. HIV-infected individuals with active TB also exhibited a significant loss of influenza hemagglutinin- and tetanus toxoid-specific antibody titers at the isotype/subclass level, a symptom of broad humoral immune dysfunction likely precipitated by HIV infection. Finally, we illustrated that despite the influence of HIV infection, differences in M. tuberculosis-specific antibody profiles persist between latent and active TB disease. Taken together, these findings reveal significant HIV-associated disruptions of the humoral immune response in HIV/TB-coinfected individuals. IMPORTANCE TB is the leading cause of death from a single infectious agent globally, followed by HIV. Furthermore, TB represents the leading cause of death among people with HIV. HIV is known to cause severe defects in T cell immunity, rendering HIV/TB-coinfected individuals more susceptible to TB disease progression and complicating accurate TB disease diagnosis. Here, we demonstrate that HIV infection is additionally associated with severely compromised antibody responses, particularly in individuals with active TB. Moreover, despite the influence of HIV infection, antibody profiles still allow accurate classification of individuals with active versus latent TB. These findings reveal novel immunologic challenges associated with HIV/TB coinfection and additionally provide a basis with which to leverage the key antibody features identified to potentially combat TB globally via next-generation therapeutic or diagnostic design.
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Mehtani NJ, Rosman L, Moss WJ. Immunogenicity and Safety of the Measles Vaccine in HIV-Infected Children: An Updated Systematic Review. Am J Epidemiol 2019; 188:2240-2251. [PMID: 31210268 DOI: 10.1093/aje/kwz144] [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: 12/30/2018] [Revised: 05/15/2019] [Accepted: 06/05/2019] [Indexed: 01/26/2023] Open
Abstract
Children infected with human immunodeficiency virus (HIV) are at increased risk of measles morbidity and mortality. We searched abstracts from the PubMed, Embase, and Latin American and Caribbean Center on Health Sciences Information databases for articles published from the earliest date available through September 26, 2017. The primary outcome of interest was serological responses to measles vaccine, stratified by HIV infection status. A total of 2,858 potentially eligible articles were identified, and the final review included 12 studies published between 1992 and 2013, 9 of which reported data on vaccine safety. The studies we included represented 3,573 children, of whom at least 335 were infected with HIV, 788 were HIV-exposed but not infected, and 1,478 were unexposed to HIV. Four of the 12 studies found statistically significant reductions in seropositivity among HIV-infected children compared with HIV-uninfected children within 4 months of vaccination (prevalence ratio range, 0.44-0.70), and forest plots provided visual trends of decreasing immunity over time among HIV-infected children in 2 additional studies. No vaccine-related deaths or serious adverse events were reported. This updated review demonstrated limitations of the existing published literature but supported evidence of reduced immunogenicity of measles vaccine among HIV-infected children, supporting the World Health Organization recommendation to revaccinate HIV-infected children against measles following immune reconstitution with combination antiretroviral therapy.
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Affiliation(s)
- Nicky J Mehtani
- Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Lori Rosman
- Welch Medical Library, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - William J Moss
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
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10
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Baroncelli S, Maria Galluzzo C, Liotta G, Orlando S, Ciccacci F, Andreotti M, Mpwhere R, Luhanga R, Sagno JB, Amici R, Marazzi MC, Giuliano M. IgG abnormalities in HIV-positive Malawian women initiating antiretroviral therapy during pregnancy persist after 24 months of treatment. Int J Infect Dis 2019; 88:1-7. [PMID: 31499207 DOI: 10.1016/j.ijid.2019.09.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/27/2019] [Accepted: 09/03/2019] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Hypergammaglobulinemia and anomalies in the IgG subclass distribution are common in HIV-infected individuals and persist even after many years of antiretroviral therapy (ART). The aim of this study was to investigate the IgG profile and dynamics in pregnant HIV-infected Malawian women in the Option B era. METHODS Thirty-seven treatment-naive women received ART from the third trimester of pregnancy to 6 months post delivery (end of the breastfeeding period). ART continuation (group C) or interruption (group I) was then decided on the basis of the CD4+ cell count at enrolment (>350 or ≤350/μl). Total IgG and IgG subclasses were determined in maternal serum using a nephelometric assay at baseline and at 6 and 24 months postpartum. RESULTS At enrolment, 36/37 women had IgG levels >15g/l and there was a predominance of the IgG1 isotype (more than 90%) in parallel with underrepresentation of IgG2 (5.0%). After 6 months of ART, both groups showed a significant median decrease in total IgG (-3.1g/l in group I, -3.5g/l in group C) and in IgG1 (-4.0g/l and -3.6g/l, respectively), but only a modest recovery in IgG2 levels (+0.16 in group I, +0.14g/l in group C). At month 24, hypergammaglobulinemia was still present in 73.7% of women in group C, although a significant reduction was observed in total IgG level and in IgG1 and IgG3 subclasses (p<0.0001 in all cases). IgG2 levels did not show any significant change. In group I at 24 months, total IgG and IgG subclasses had returned to levels comparable to those at baseline. CONCLUSIONS The beneficial effects of 24 months of ART appear to be limited in the B-cell compartment, with an incomplete reduction of total IgG levels and no recovery of IgG2 depletion. A short ART period did not have significant effects on IgG abnormalities in women who interrupted treatment.
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Affiliation(s)
- Silvia Baroncelli
- National Centre for Global Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
| | - Clementina Maria Galluzzo
- National Centre for Global Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Giuseppe Liotta
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy
| | - Stefano Orlando
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy
| | - Fausto Ciccacci
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy
| | - Mauro Andreotti
- National Centre for Global Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Robert Mpwhere
- DREAM Program, Community of S. Egidio, PO Box 30355, Blantyre, Malawi
| | - Richard Luhanga
- DREAM Program, Community of S. Egidio, PO Box 30355, Blantyre, Malawi
| | | | - Roberta Amici
- National Centre for Global Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | | | - Marina Giuliano
- National Centre for Global Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
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11
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Dhande J, Salunke P, Kulkarni A, Ghate M, Thakar M. Short Communication: Nonprogressive HIV-1 Infection Is Associated with Expansion of IL-21R Expressing Class-Switched Memory B Cells. AIDS Res Hum Retroviruses 2019; 35:729-733. [PMID: 31044603 DOI: 10.1089/aid.2019.0015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
HIV perturbs the functionality of B cells resulting in defective humoral responses. As efficient humoral immune responses are important in controlling HIV-disease progression, we characterized the memory B cell population for its subsets and their activation (CD38 expression) and functional [interleukin (IL)-21R expression] profile in individuals with nonprogressive [long-term nonprogressors (LTNPs), N = 16] and progressive HIV disease (progressors, N = 16) along with 10 HIV uninfected healthy controls (HCs). The frequencies of total memory B cells were similar in HCs and HIV-infected individuals, whereas the frequencies of unswitched memory B (UMB) cells and CD38+ UMB cells were significantly higher in progressors than LTNPs and HCs (p < .03). LTNPs showed higher frequencies of class-switched memory B (SMB) cells and IL-21R expressing SMB cells than seen in progressors (p = .019), which were similar to that seen in HCs. The %UMB cells correlated inversely (p = .0002, r = -0.6053) and %SMB cells correlated positively (p = .0005, r = 0.5804) with CD4 count. IL-21/IL-21R interaction is required for class switching of B cells and differentiation into antibody-secreting plasma cells. The higher expression of IL-21R on class SMB cells from LTNPs might be resulting in efficient plasma cell differentiation and the functional humoral immune response that might be responsible for mounting efficient antibody response against the encountered infections. The more insights in this area might be required to further understand the role of IL-21R expressing class SMB cells in HIV infection.
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Affiliation(s)
- Jayshree Dhande
- Departments of Immunology and Serology, National AIDS Research Institute, Pune, India
| | - Pooja Salunke
- Departments of Immunology and Serology, National AIDS Research Institute, Pune, India
| | - Archana Kulkarni
- Departments of Immunology and Serology, National AIDS Research Institute, Pune, India
| | - Manisha Ghate
- Departments of Immunology and Serology, National AIDS Research Institute, Pune, India
| | - Madhuri Thakar
- Departments of Immunology and Serology, National AIDS Research Institute, Pune, India
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12
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Yoon HA, Nakouzi A, Chang CC, Kuniholm MH, Carreño LJ, Wang T, Ndung’u T, Lewin SR, French MA, Pirofski LA. Association Between Plasma Antibody Responses and Risk for Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome. J Infect Dis 2019; 219:420-428. [PMID: 30010905 PMCID: PMC6325352 DOI: 10.1093/infdis/jiy447] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 07/13/2018] [Indexed: 01/12/2023] Open
Abstract
Background Initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected individuals with cryptococcal meningitis places them at risk for Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS). The relationship between antibody immunity and C-IRIS risk has not been investigated. Methods We compared plasma levels of immunoglobulins, C. neoformans glucuronoxylomannan (GXM) capsule-specific and laminarin (Lam)-binding IgM and IgG, and percentages of peripheral blood total and memory B cells between 27 HIV-infected patients with CM who developed C-IRIS and 63 who did not, and evaluated associations of these parameters with risk of C-IRIS. Results Prior to initiation of ART, plasma IgM, Lam-binding IgM (Lam-IgM), Lam-IgG, and GXM-IgM levels were significantly lower in patients who developed C-IRIS than those who did not. Multivariate analysis revealed significant inverse associations between C-IRIS and IgM (P = .0003), Lam-IgM (P = .0005), Lam-IgG (P = .002), and GXM-IgM (P = .002) independent of age, sex, HIV viral load, CD4+ T-cell count, and cerebrospinal fluid fungal burden. There were no associations between C-IRIS and total or memory B cells. Discussion Antibody profiles that include plasma IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM may have value in furthering our understanding of C-IRIS pathogenesis and hold promise as candidate biomarkers of C-IRIS risk.
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Affiliation(s)
- Hyun Ah Yoon
- Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York
| | - Antonio Nakouzi
- Department of Microbiology and Immunology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York
| | - Christina C Chang
- Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
| | - Mark H Kuniholm
- Department of Epidemiology and Biostatistics, University at Albany, Rensselaer, New York
| | - Leandro J Carreño
- Millennium Institute on Immunology and Immunotherapy, Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Tao Wang
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York
| | - Thumbi Ndung’u
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal
- Africa Health Research Institute, Durban, South Africa
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge
- Max Planck Institute for Infection Biology, Berlin, Germany
| | - Sharon R Lewin
- Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
- The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital
| | - Martyn A French
- University of Western Australia Medical School and School of Biomedical Sciences, Perth, Australia
| | - Liise-anne Pirofski
- Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York
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13
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Nicholson LK, Pratap H, Bowers E, Gunzburger E, Bandi SR, Gardner EM, Palmer BE, Wright T, Kittelson J, Janoff EN. Effective B cell activation in vitro during viremic HIV-1 infection with surrogate T cell stimulation. Immunobiology 2018; 223:839-849. [PMID: 30219203 PMCID: PMC6264910 DOI: 10.1016/j.imbio.2018.08.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 08/09/2018] [Accepted: 08/19/2018] [Indexed: 02/07/2023]
Abstract
Identifying HIV-1-associated B cell defects and responses to activation may direct interventions to circumvent their impaired antibody responses to infection and vaccines. Among 34 viremic HIV-1-infected and 20 seronegative control adults, we measured baseline frequencies and activation of B and T cell subsets, expression of activation-induced cytidine deaminase (AID), potential determinants of B cell activation in vivo and B and T cell responses in vitro. At baseline, HIV-1 infection was associated with increased IgM memory and decreased anergic cell frequencies, as well as increased activation in all 10 B cell subsets compared with controls. HIV-1 status, TFH activation, and BAFF were significant potential drivers of B cell activation. Despite high baseline activation among HIV-1-infected subjects, stimulation in vitro with combined surrogates for antigen (anti-IgM), cognate (CD40 ligand) and soluble T cell factors (IL-4) elicited comparable B cell activation, transitions from naïve to class-switched memory cells and AID expression in both groups. In summary, viremic HIV-1 infection perturbs circulating B cell subsets and activation at each stage of B cell maturation. However, that appropriate stimulation of B cells elicits effective activation and maturation provides impetus for advancing vaccine development to prevent secondary infections by circumventing early B cell defects.
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Affiliation(s)
- Lindsay K Nicholson
- Mucosal and Vaccine Research Program Colorado (MAVRC), United States; Departments of Medicine, University of Colorado Denver, Aurora, CO, United States; Denver Veterans Affairs Medical Center, Denver, CO, United States
| | - Harsh Pratap
- Mucosal and Vaccine Research Program Colorado (MAVRC), United States; Departments of Medicine, University of Colorado Denver, Aurora, CO, United States; Denver Veterans Affairs Medical Center, Denver, CO, United States
| | - Elisabeth Bowers
- Mucosal and Vaccine Research Program Colorado (MAVRC), United States; Departments of Medicine, University of Colorado Denver, Aurora, CO, United States; Denver Veterans Affairs Medical Center, Denver, CO, United States
| | - Elise Gunzburger
- Departments of Biostatistics, University of Colorado Denver, Aurora, CO, United States
| | - Srinivasa R Bandi
- Mucosal and Vaccine Research Program Colorado (MAVRC), United States; Departments of Medicine, University of Colorado Denver, Aurora, CO, United States
| | - Edward M Gardner
- Departments of Medicine, University of Colorado Denver, Aurora, CO, United States; Denver Health and Hospital Authority, Denver, CO, United States
| | - Brent E Palmer
- Mucosal and Vaccine Research Program Colorado (MAVRC), United States; Departments of Medicine, University of Colorado Denver, Aurora, CO, United States
| | - Timothy Wright
- Denver Health and Hospital Authority, Denver, CO, United States
| | - John Kittelson
- Mucosal and Vaccine Research Program Colorado (MAVRC), United States; Departments of Biostatistics, University of Colorado Denver, Aurora, CO, United States
| | - Edward N Janoff
- Mucosal and Vaccine Research Program Colorado (MAVRC), United States; Departments of Medicine, University of Colorado Denver, Aurora, CO, United States; Denver Veterans Affairs Medical Center, Denver, CO, United States.
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14
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Decreased percentage of memory B cells is independently associated with increased susceptibility to infection in patients on maintenance hemodialysis. Int Urol Nephrol 2018; 50:2081-2090. [PMID: 30276601 DOI: 10.1007/s11255-018-1977-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 09/05/2018] [Indexed: 12/13/2022]
Abstract
PURPOSE Infection is a common complication and cause of death in patients on maintenance hemodialysis (MHD). B lymphocytes, which are an important component of the immune system, play a significant role in defending against pathogen invasion. However, in patients on MHD, the connection between infection and B cell subsets remains largely unknown. Our study aims to clarify the potential role of the distribution of B cell subsets in the infection process in patients on MHD. METHODS In this cross-sectional study, basic information was collected from 175 patients on MHD from July 2016 to July 2017 at Zhongshan Hospital, Fudan University. The distributions of the B cell subsets in patients with and without infection were analyzed using flow cytometry to determine the role of B lymphocyte subsets in the infection process in patients on MHD. RESULTS Among the 175 patients, 45 suffered from infection. The respiratory tract was the most common infection site, accounting for 67.86% of all infections. After adjustment using multivariate logistic regression models, memory B cells [per 1% increase, odds ratio [95% confidence interval (CI)]: 0.949 (0.915, 0.984), P < 0.01], switched memory B cells [per 1% increase, odds ratio (95% CI): 0.939 (0.898, 0.982), P < 0.01], naïve B cells [per 1% increase, odds ratio (95% CI): 1.042 (1.009, 1.075), P < 0.05] and IgG titers [per 1 g/L increase, odds ratio (95% CI): 0.779 (0.630, 0.963), P < 0.05] were independent risk factors for infection in dialysis patients. CONCLUSION A decrease in memory B cells is independently associated with an increased risk of infection in patients on dialysis.
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15
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Singh R, Mukherjee A, Singla M, Vajpayee M, Negi N, Kabra SK, Lodha R, Das BK. Impact of HIV infection and highly active antiretroviral therapy (HAART) on B cell subpopulations in children. J Med Virol 2018; 90:1222-1231. [PMID: 29575050 DOI: 10.1002/jmv.25074] [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: 11/13/2017] [Accepted: 03/15/2018] [Indexed: 01/01/2023]
Abstract
B-cells play an important role in defending children against various infections. In view of scare data, we undertook this prospective cohort study to describe B cell compartment in HIV infected children (<5 years of age) and the effect of HAART on B cell subpopulations. HIV infected children (<5 years) from Pediatric HIV services of the Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, were recruited (April 2012-December 2015). The enrolled HIV-1 infected children (n = 59) were followed up regularly for 12 months; healthy controls (n = 51) included HIV uninfected children with no major illness. Flow cytometry was performed on fresh EDTA-treated blood samples to characterize B cell subpopulations. In HIV-infected children, marked depletion of naive (P = 0.003), non-switched memory (P = 0.02), mature (P = 0.0005), resting memory (P < 0.0001) B cells, and expansion of double negative memory (P < 0.0001), activated memory (P < 0.0001) and tissue like memory (P < 0.0001) B cells were observed as compared to healthy controls. In children started on HAART, at the end of 12 months of therapy, frequencies of non-switched memory (P = 0.04), switched memory (P = 0.01), and resting memory (P = 0.003) B cells were lower; activated memory (P = 0.04), and tissue-like memory (P = 0.0001) B cells were still higher than healthy controls. HIV infection resulted in reduced memory B cells in HIV infected children. Following HAART, there was normalization of some B cell subpopulations. The study emphasizes the need of re-vaccination in HIV infected children to maintain the memory B cell pool and adequate humoral immune response against infections.
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Affiliation(s)
- Ravinder Singh
- Department of Pediatrics, AIIMS, New Delhi, Delhi, India.,Department of Microbiology, AIIMS, New Delhi, Delhi, India
| | | | - Mohit Singla
- Department of Pediatrics, AIIMS, New Delhi, Delhi, India
| | - Madhu Vajpayee
- Department of Microbiology, AIIMS, New Delhi, Delhi, India
| | - Neema Negi
- Department of Microbiology, AIIMS, New Delhi, Delhi, India
| | - Sushil K Kabra
- Department of Pediatrics, AIIMS, New Delhi, Delhi, India
| | - Rakesh Lodha
- Department of Pediatrics, AIIMS, New Delhi, Delhi, India
| | - Bimal K Das
- Department of Microbiology, AIIMS, New Delhi, Delhi, India
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16
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Higher Transplacental Pathogen-Specific Antibody Transfer Among Pregnant Women Randomized to Triple Antiretroviral Treatment Versus Short Course Zidovudine. Pediatr Infect Dis J 2018; 37:246-252. [PMID: 28834955 PMCID: PMC5807132 DOI: 10.1097/inf.0000000000001749] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND HIV-1 infection may impair transplacental antibody transfer to infants. The impact of highly active antiretroviral treatment (ART) given during pregnancy on transplacental antibody transport is unknown. METHODS HIV-1 infected pregnant women with CD4 counts between 200 - 500 were randomized to short-course zidovudine (ZDV) or triple ART at 32 weeks gestation for prevention of mother-to-child HIV-1 transmission. Levels of maternal antibody against measles, pneumococcus and rotavirus at delivery, and antibody transfer to the baby through cord blood, were compared between trial arms. RESULTS Overall, 141 and 148 women were randomized to triple ART and ZDV, respectively; cord blood was available for a subset (n = 20 in triple ART and n = 22 in ZDV). Maternal antibody levels to all pathogens during pregnancy and at delivery were not significantly different between arms. Within each arm, antibody levels at delivery were lower than at enrolment. For all antibodies, a woman's levels before delivery were an important predictor of amount transferred to her infant. Women on triple ART transferred higher levels of pathogen-specific antibodies when compared with women on short course ZDV. CONCLUSIONS Women on triple ART transferred higher levels of pathogen-specific antibodies compared with women on ZDV alone.
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17
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Kong F, Feng B, Zhang H, Rao H, Wang J, Cong X, Wei L. Abnormal phenotypic features of IgM+B cell subsets in patients with chronic hepatitis C virus infection. Exp Ther Med 2017; 14:1846-1852. [PMID: 28810658 DOI: 10.3892/etm.2017.4682] [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: 09/24/2015] [Accepted: 04/24/2017] [Indexed: 02/04/2023] Open
Abstract
Hepatitis C virus (HCV) infection is associated with B cell abnormality; however the phenotypic profiles of immunoglobulin (Ig)M+B cell subsets in patients with HCV infection remain unclear. In the current study, the effect of HCV infection on IgM+B cell subsets was evaluated. The percentages, as well as the differentiation and activation features of peripheral IgM+B naive subsets [cluster of differentiation (CD)27-IgM+B cells] and IgM+B memory subsets (CD27+IgM+B cells) were assessed using flow cytometry in 27 patients with chronic hepatitis C (CHC) and 20 healthy controls (HCs). The frequency of CD27+IgM+B memory subsets detected in patients with CHC was significantly higher than that in HCs (P<0.05). Although the frequency of CD27-IgM+B naive subsets was similar in both groups, there was a significantly higher proportion of CD5+B cells detected in the CD27-IgM+B subsets of patients with CHC compared with HCs (P<0.05). Among CD27-IgM+B subsets, abnormal differentiation was associated with HCV infection, with significantly increased percentages of IgD+B cells and CD38+B cells in patients with CHC compared with HCs (P<0.05). In CD27+IgM+B memory subsets, the abnormality of cell differentiation was associated with a significantly increased percentage of CD38+B cells in patients with CHC compared with HCs (P<0.05). In addition, the percentage of activated CD27+IgM+B subsets in patients with CHC were significantly higher than those observed in HCs (P<0.05). The number of CD27-IgD+IgM+B, CD27-CD38+IgM+B and CD27+CD38+IgM+B cells were negatively correlated with HCV RNA in patients with CHC. These results suggest that HCV infection contributes to abnormalities in the percentage, differentiation and activation of IgM+B cell subsets and may disrupt the immune response mediated by IgM+B cells.
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Affiliation(s)
- Fanyun Kong
- Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Peking University Hepatology Institute, Beijing 100044, P.R. China.,Department of Pathogenic Biology and Immunity, Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Bo Feng
- Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Peking University Hepatology Institute, Beijing 100044, P.R. China
| | - Henghui Zhang
- Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Peking University Hepatology Institute, Beijing 100044, P.R. China
| | - Huiying Rao
- Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Peking University Hepatology Institute, Beijing 100044, P.R. China
| | - Jianghua Wang
- Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Peking University Hepatology Institute, Beijing 100044, P.R. China
| | - Xu Cong
- Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Peking University Hepatology Institute, Beijing 100044, P.R. China
| | - Lai Wei
- Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Peking University Hepatology Institute, Beijing 100044, P.R. China
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18
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Production of IgG antibodies to pneumococcal polysaccharides is associated with expansion of ICOS+ circulating memory T follicular-helper cells which is impaired by HIV infection. PLoS One 2017; 12:e0176641. [PMID: 28463977 PMCID: PMC5413043 DOI: 10.1371/journal.pone.0176641] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 04/13/2017] [Indexed: 11/26/2022] Open
Abstract
Dysfunction of T follicular-helper (TFH) cells is a possible cause of impaired germinal centre (GC) and IgG antibody responses in individuals with human immunodeficiency virus-1 (HIV-1) infection and might contribute to decreased magnitude and isotype diversification of IgG antibodies to pneumococcal polysaccharides (PcPs). We examined the production of IgG1 and IgG2 antibodies to PcPs 4, 6B, 9V and 14 by enumerating antibody secreting cells (ASCs) at day (D) 7 and determining fold-increase in serum antibody levels at D28 after vaccination with unconjugated PcPs in HIV seronegative subjects (n = 20) and in HIV patients who were receiving antiretroviral therapy (ART) (n = 28) or who were ART-naive (n = 11) and determined their association with ICOS+ and ICOS- circulating memory TFH (cmTFH) cells (CD4+CD45RA-CD27+CXCR5+PD-1+) and short lived plasmablasts (SPBs) at D7, and with PcP-specific and total IgM+ and IgG+ memory B cells at D0. In HIV seronegative subjects, production of IgG1+ and IgG2+ ASCs was consistently associated with the frequency of ICOS+ cmTFH cells but not ICOS- cmTFH cells or memory B cells. In contrast, post-vaccination ASCs in HIV patients, regardless of ART status, were lower than in HIV seronegative subjects and not associated with ICOS+ cmTFH cells, the expansion of which was absent (ART-naive patients) or much lower than in HIV seronegative subjects (ART-treated patients). Production of SPBs was also lower in ART-naive patients. Fold-increase in IgG2 antibodies at D28 also correlated with ICOS+ cmTFH cells at D7 in HIV seronegative subjects but not in HIV patients. These novel findings provide evidence that ICOS+ cmTFH cells contribute to the regulation of PcP-specific IgG antibody responses, including isotype diversification, and that TFH cell dysfunction may be a cause of impaired PcP-specific IgG antibody responses and increased susceptibility to pneumococcal disease in HIV patients.
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19
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Tanko RF, Soares AP, Müller TL, Garrett NJ, Samsunder N, Abdool Karim Q, Abdool Karim SS, Riou C, Burgers WA. Effect of Antiretroviral Therapy on the Memory and Activation Profiles of B Cells in HIV-Infected African Women. THE JOURNAL OF IMMUNOLOGY 2016; 198:1220-1228. [PMID: 28039305 DOI: 10.4049/jimmunol.1601560] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 11/30/2016] [Indexed: 12/25/2022]
Abstract
Human immunodeficiency virus infection induces a wide range of effects in B cells, including skewed memory cell differentiation, compromised B cell function, and hypergammaglobulinemia. However, data on the extent to which these B cell abnormalities can be reversed by antiretroviral therapy (ART) are limited. To investigate the effect of ART on B cells, the activation (CD86) and differentiation (IgD, CD27, and CD38) profiles of B cells were measured longitudinally in 19 HIV-infected individuals before (median, 2 mo) and after ART initiation (median, 12 mo) and compared with 19 age-matched HIV-uninfected individuals using flow cytometry. Twelve months of ART restored the typical distribution of B cell subsets, increasing the proportion of naive B cells (CD27-IgD+CD38-) and concomitantly decreasing the immature transitional (CD27-IgD+CD38+), unswitched memory (CD27+IgD+CD38-), switched memory (CD27+IgD-CD38- or CD27-IgD-CD38-), and plasmablast (CD27+IgD-CD38high) subsets. However, B cell activation was only partially normalized post-ART, with the frequency of activated B cells (CD86+CD40+) reduced compared with pre-ART levels (p = 0.0001), but remaining significantly higher compared with HIV-uninfected individuals (p = 0.0001). Interestingly, unlike for T cell activation profiles, the extent of B cell activation prior to ART did not correlate with HIV plasma viral load, but positively associated with plasma sCD14 levels (p = 0.01, r = 0.58). Overall, ART partially normalizes the skewed B cell profiles induced by HIV, with some activation persisting. Understanding the effects of HIV on B cell dysfunction and restoration following ART may provide important insights into the mechanisms of HIV pathogenesis.
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Affiliation(s)
- Ramla F Tanko
- Department of Pathology, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Andreia P Soares
- Department of Pathology, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Tracey L Müller
- Department of Pathology, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Nigel J Garrett
- Centre for the AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban 4013, South Africa
| | - Natasha Samsunder
- Centre for the AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban 4013, South Africa
| | - Quarraisha Abdool Karim
- Centre for the AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban 4013, South Africa.,Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032; and
| | - Salim S Abdool Karim
- Centre for the AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban 4013, South Africa.,Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032; and
| | - Catherine Riou
- Department of Pathology, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa.,Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
| | - Wendy A Burgers
- Department of Pathology, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa; .,Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
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20
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Tsachouridou O, Skoura L, Zebekakis P, Margariti A, Georgiou A, Bougiouklis D, Pilalas D, Galanos A, Daniilidis M, Metallidis S. Antiretroviral naive and treated patients: Discrepancies of B cell subsets during the natural course of human immunodeficiency virus type 1 infection. World J Virol 2016; 5:155-160. [PMID: 27878102 PMCID: PMC5105048 DOI: 10.5501/wjv.v5.i4.155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 06/24/2016] [Accepted: 08/18/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate alterations of memory B cell subpopulations during a 48-wk period in human immunodeficiency virus type 1 (HIV-1) patients.
METHODS Forty-one antiretroviral naïve and 41 treated HIV-1 patients matched for age and duration of HIV infection were recruited. All clinical, epidemiological and laboratory data were recorded or measured. The different B cell subsets were characterized according to their surface markers: Total B cells (CD19+), memory B cells (CD19+CD27+, BMCs), resting BMCs (CD19+CD27+CD21high, RM), exhausted BMCs (CD19+CD21lowCD27-, EM), IgM memory B (CD19+CD27+IgMhigh), isotype-switched BMCs (CD19+CD27+IgM-, ITS) and activated BMCs (CD19+CD21low+CD27+, AM) at baseline on week 4 and week 48.
RESULTS Mean counts of BMCs were higher in treated patients. There was a marginal upward trend of IgM memory B cell proportions which differed significantly in the treated group (overall trend, P = 0.004). ITS BMC increased over time significantly in all patients. Naive patients had of lower levels of EM B cells compared to treated, with a downward trend, irrespectively of highly active antiretroviral therapy (HAART) intake. Severe impairment of EM B cells was recorded to both treated (P = 0.024) and naive (P = 0.023) and patients. Higher proportions of RM cells were noted in HAART group, which differed significantly on week 4th (P = 0.017) and 48th (P = 0.03). Higher levels of AM were preserved in HAART naive group during the whole study period (week 4: P = 0.018 and 48: P = 0.035). HIV-RNA viremia strongly correlated with AM B cells (r = 0.54, P = 0.01) and moderately with RM cells (r = -0.45, P = 0.026) at baseline.
CONCLUSION HIV disrupts memory B cell subpopulations leading to impaired immunologic memory over time. BMC, RM, EM and ITS BMC were higher in patients under HAART. Activated BMCs (AM) were higher in patients without HAART. Viremia correlated with AM and RM. Significant depletion was recorded in EM B cells irrespectively of HAART intake. Perturbations in BMC-populations are not fully restored by antiretrovirals.
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Yaseen MM, Yaseen MM, Alqudah MA. Broadly neutralizing antibodies: An approach to control HIV-1 infection. Int Rev Immunol 2016; 36:31-40. [PMID: 27739924 DOI: 10.1080/08830185.2016.1225301] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although available antiretroviral therapy (ART) has changed human immunodeficiency virus (HIV)-1 infection to a non-fatal chronic disease, the economic burden of lifelong therapy, severe adverse ART effects, daily ART adherence, and emergence of ART-resistant HIV-1 mutants require prospecting for alternative therapeutic modalities. Indeed, a growing body of evidence suggests that broadly neutralizing anti-HIV-1 antibodies (BNAbs) may offer one such feasible alternative. To evaluate their therapeutic potential in established HIV-1 infection, we sought to address recent advances in pre-clinical and clinical investigations in this area of HIV-1 research. In addition, we addressed the obstacles that may impede the success of such immunotherapeutic approach, suggested strategic solutions, and briefly compared this approach with the currently used ART to open new insights for potential future passive immunotherapy for HIV-1 infection.
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Affiliation(s)
- Mahmoud Mohammad Yaseen
- a Department of Medical Laboratory Sciences , College of Applied Medical Sciences, Jordan University of Science and Technology , Irbid , Jordan
| | - Mohammad Mahmoud Yaseen
- b Department of Public Health, College of Nursing , University of Benghazi , Benghazi , Libya
| | - Mohammad Ali Alqudah
- c Department of Clinical Pharmacy , College of Pharmacy, Jordan University of Science and Technology , Irbid , Jordan
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22
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Mohanram V, Demberg T, Musich T, Tuero I, Vargas-Inchaustegui DA, Miller-Novak L, Venzon D, Robert-Guroff M. B Cell Responses Associated with Vaccine-Induced Delayed SIVmac251 Acquisition in Female Rhesus Macaques. THE JOURNAL OF IMMUNOLOGY 2016; 197:2316-24. [PMID: 27534560 DOI: 10.4049/jimmunol.1600544] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 07/19/2016] [Indexed: 11/19/2022]
Abstract
An established sex bias in HIV pathogenesis is linked to immune responses. Recently we reported a vaccine-induced sex bias: vaccinated female but not male rhesus macaques exhibited delayed SIV acquisition. This outcome was correlated with SIV Env-specific rectal IgA, rectal memory B cells, and total rectal plasma cells. To uncover additional contributing factors, using samples from the same study, we investigated memory B cell population dynamics in blood, bone marrow, and rectal tissue during immunization and postchallenge; IgG subtypes and Ab avidity; and regulatory B (Breg) cell frequency and function. Few sex differences were seen in Env-specific memory B cell, plasmablast, or plasma cell frequencies in the three compartments. Males had higher IgG Ab titers and avidity indices than females. However, females had elevated levels of Env-specific IgG1, IgG2, and IgG3 Abs compared with males. gp140-specific IgG3 Abs of females but not males were correlated with Ab-dependent cell-mediated cytotoxicity activity against gp120 targets (p = 0.026) and with Ab-dependent phagocytic activity (p = 0.010). IgG3 Ab of females but not males also correlated with decreased peak viremia (p = 0.028). Peripheral blood CD19(+)CD25(+) Breg cells suppressed T cell proliferation compared with CD19(+)CD25(-) cells (p = 0.031) and exhibited increased IL-10 mRNA expression (p = 0.031). Male macaques postvaccination (p = 0.018) and postinfection (p = 0.0048) exhibited higher Breg frequencies than females. Moreover, male Breg frequencies correlated with peak viremia (p = 0.0071). Our data suggest that vaccinated females developed better Ab quality, contributing to better functionality. The elevated Breg frequencies in males may have facilitated SIV acquisition.
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Affiliation(s)
- Venkatramanan Mohanram
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Thorsten Demberg
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Thomas Musich
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Iskra Tuero
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Diego A Vargas-Inchaustegui
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Leia Miller-Novak
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - David Venzon
- Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD 20892
| | - Marjorie Robert-Guroff
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
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Abstract
OBJECTIVES Many children with HIV infection now survive into adulthood. This study explored the impact of vertically acquired HIV in the era of antiretroviral therapy on the development of humoral immunity. DESIGN Natural and vaccine-related immunity to pneumococcus and B-cell phenotype was characterized and compared in three groups of young adults: those with vertically-acquired infection, those with horizontally acquired infection and healthy controls. METHODS Serotype-specific pneumococcal (Pnc) immunoglobulin M and G concentrations before and up to 1 year post-Pnc polysaccharide (Pneumovax) immunization were determined, and opsonophagocytic activity was analysed. B-cell subpopulations and dynamic markers of B-cell signalling, turnover and susceptibility to apoptosis were evaluated by flow cytometry. RESULTS HIV-infected patients showed impaired natural Pnc immunity and reduced humoral responses to immunization with Pneumovax; this was greatest in those viraemic at time of the study. Early-life viral control before the age of 10 years diminished these changes. Expanded populations of abnormally activated and immature B-cells were seen in both HIV-infected cohorts. Vertically infected patients were particularly vulnerable to reductions in marginal zone and switched memory populations. These aberrations were reduced in patients with early-life viral control. CONCLUSION In children with HIV, damage to B-cell memory populations and impaired natural and vaccine immunity to pneumococcus is evident in early adult life. Sustained viral control from early childhood may help to limit this effect and optimize humoral immunity in adult life.
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Ohtola JA, Saul-McBeth JL, Iyer AS, Leggat DJ, Khuder SA, Khaskhely NM, Westerink MJ. Quantitative and Functional Antibody Responses to the 13-Valent Conjugate and/or 23-Valent Purified Polysaccharide Vaccine in Aging HIV-Infected Adults. ACTA ACUST UNITED AC 2016; 7. [PMID: 27158552 DOI: 10.4172/2155-6113.1000556] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND The number of aging human immunodeficiency virus-infected (HIV+) individuals living in the United States has substantially grown over the past two decades. Advanced age and HIV infection both increase susceptibility to Streptococcus pneumoniae infection due to B cell dysfunction. The combined impact of these factors on pneumococcal vaccine responses remains unknown. METHODS We assessed serum immunoglobulin (Ig) G and IgM levels and opsonophagocytic killing assay (OPA) titers to pneumococcal serotypes 14 and 23F in HIV+ subjects and HIV-uninfected (HIV-) controls 50-65 years old. HIV+ individuals with CD4+ T cells/μl (CD4) >200 and ≥1 year of antiretroviral therapy (ART) received either a dose of the 13-valent pneumococcal conjugate vaccine followed by the 23-valent pneumococcal polysaccharide vaccine 8 weeks later (PCV/PPV) as currently recommended (n=15) or a single dose of PPV only (n=22). HIV- controls received PCV/PPV (n=14). RESULTS HIV+ PCV/PPV and PPV groups exhibited similar increases in IgG levels and OPA titers for both serotypes after immunization. Postvaccination IgM levels for serotype 23F, but not 14, were significantly higher in HIV+ PCV/PPV compared to PPV groups. IgG and IgM levels for serotype 14 and OPA titers to serotype 23F were significantly reduced in HIV+ compared to HIV- PCV/PPV groups. Serotype-specific IgG levels correlated with OPA titers for all groups. CONCLUSIONS Our data suggest that the recommended PCV/PPV regimen may not significantly improve quantitative or functional antibody responses compared to PPV only in aging HIV+ subjects. Continued efforts aimed at improving vaccine responses in this high risk population are warranted.
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Affiliation(s)
- Jennifer A Ohtola
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio
| | - Jessica L Saul-McBeth
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio
| | - Anita S Iyer
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio
| | - David J Leggat
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio
| | - Sadik A Khuder
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio; Department of Public Health and Preventative Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio
| | - Noor M Khaskhely
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio
| | - Ma Julie Westerink
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio; Department of Pathology, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio; Department of Medical Microbiology and Immunology, University of Toledo College of Medicine & Life Sciences, Toledo, Ohio
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25
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Ohtola JA, Khaskhely NM, Saul-Mcbeth JL, Iyer AS, Leggat DJ, Khuder SA, Westerink MAJ. Alterations in serotype-specific B cell responses to the 13-valent pneumococcal conjugate vaccine in aging HIV-infected adults. Vaccine 2015; 34:451-457. [PMID: 26707220 DOI: 10.1016/j.vaccine.2015.12.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 11/18/2015] [Accepted: 12/07/2015] [Indexed: 01/22/2023]
Abstract
BACKGROUND Advanced age and human immunodeficiency virus (HIV) infection are associated with increased pneumococcal disease risk. The impact of these factors on cellular responses to vaccination is unknown. METHODS HIV-infected (HIV+) individuals 50-65 years old with CD4(+) Tcells/μl (CD4) >200 on antiretroviral therapy (ART) ≥1 year received either the 13-valent pneumococcal conjugate vaccine followed by the 23-valent pneumococcal polysaccharide vaccine (PCV/PPV) or PPV only. HIV-uninfected (HIV-) controls received PCV/PPV. Phenotype distribution and surface expression of complement receptor CD21 and tumor necrosis factor superfamily receptors (TNFRs) were compared on serotype-specific B cells postvaccination. RESULTS Postvaccination serotype-specific B cell percentages were significantly lower in HIV+ PCV/PPV compared to PPV groups, but similar between HIV+ or HIV- PCV/PPV groups. Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI)(+) serotype-specific B cell percentages were significantly decreased in HIV+ PCV/PPV compared to PPV groups. CD21(+) serotype-specific B cells were significantly higher in HIV- compared to HIV+ PCV/PPV groups. CONCLUSIONS An initial dose of PCV reduced the frequency, but not phenotype distribution, of serotype-specific B cells and also lowered TACI expression in aging HIV+ subjects postvaccination with PPV. These findings suggest that PCV does not enhance cellular responses to revaccination with PPV.
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Affiliation(s)
- Jennifer A Ohtola
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States
| | - Noor M Khaskhely
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States
| | - Jessica L Saul-Mcbeth
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States
| | - Anita S Iyer
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States
| | - David J Leggat
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States
| | - Sadik A Khuder
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States; Department of Public Health and Preventative Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States
| | - M A Julie Westerink
- Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States; Department of Pathology, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States; Department of Medical Microbiology and Immunology, University of Toledo College of Medicine & Life Sciences, Toledo, OH, United States.
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26
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Persistent subclinical immune defects in HIV-1-infected children treated with antiretroviral therapy. AIDS 2015; 29:1745-56. [PMID: 26372381 DOI: 10.1097/qad.0000000000000765] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVES With the introduction of combined antiretroviral therapy (cART), HIV-infected children can reach adulthood with minimal clinical complications. However, long-term HIV and cART in adults are associated with immunosenescence and end-organ damage. Long-term consequences of HIV and cART in children are currently unknown. DESIGN AND METHOD We studied 69 HIV-infected children and adolescents under cART (0-23 years) for the occurrence of subclinical immunological aberrations in blood B and T cells, using detailed flow cytometric immunophenotyping and molecular analyses. RESULTS Children with undetectable plasma HIV viral loads for more than 1 year showed near-normal to normal CD4 T-cell numbers and near-normal numbers of most class-switched memory B cells. Furthermore, expansions of aberrant CD21 B cells contracted in patients with virus suppression. In contrast, CD8 effector T cells were increased, and CD4 memory T cells, Vγ9Vδ2 T cells and CD27IgA memory B cells were decreased and did not normalize under ART. Moreover, Vγ9Vδ2 T cells showed defects in their T-cell receptor repertoire selection. CONCLUSION Our results show the effectiveness of current cART to enable the build-up of phenotypically diverse B-cell and T-cell memory in HIV-infected children. However, several subclinical immune abnormalities were detected, which were partially caused by defective immune maturation. These persistent abnormalities were most severe in adolescents and therefore warrant long-term follow-up of HIV-infected children. Early identification of such immune defects might provide targets for monitoring future treatment optimization.
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27
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Demberg T, Mohanram V, Musich T, Brocca-Cofano E, McKinnon KM, Venzon D, Robert-Guroff M. Loss of marginal zone B-cells in SHIVSF162P4 challenged rhesus macaques despite control of viremia to low or undetectable levels in chronic infection. Virology 2015; 484:323-333. [PMID: 26151223 DOI: 10.1016/j.virol.2015.06.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 06/16/2015] [Accepted: 06/17/2015] [Indexed: 10/23/2022]
Abstract
Marginal zone (MZ) B cells generate T-independent antibody responses to pathogens before T-dependent antibodies arise in germinal centers. They have been identified in cynomolgus monkeys and monitored during acute SIV infection, yet have not been well-studied in rhesus macaques. Here we characterized rhesus macaque MZ B cells, present in secondary lymphoid tissue but not peripheral blood, as CD19(+), CD20(+), CD21(hi), IgM(+), CD22(+), CD38(+), BTLA(+), CD40(+), CCR6(+) and BCL-2(+). Compared to healthy macaques, SHIVSF162P4-infected animals showed decreased total B cells and MZ B cells and increased MZ B cell Ki-67 expression early in chronic infection. These changes persisted in late chronic infection, despite viremia reductions to low or undetectable levels. Expression levels of additional phenotypic markers and RNA PCR array analyses were in concert with continued low-level activation and diminished function of MZ B cells. We conclude that MZ B-cell dysregulation and dysfunction associated with SIV/HIV infection are not readily reversible.
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Affiliation(s)
- Thorsten Demberg
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, Bethesda, MD 20892, United States
| | - Venkatramanan Mohanram
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, Bethesda, MD 20892, United States
| | - Thomas Musich
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, Bethesda, MD 20892, United States
| | - Egidio Brocca-Cofano
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, Bethesda, MD 20892, United States
| | - Katherine M McKinnon
- FACS Core, Vaccine Branch, National Cancer Institute, Bethesda, MD 20892, United States
| | - David Venzon
- Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD 20892, United States
| | - Marjorie Robert-Guroff
- Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, Bethesda, MD 20892, United States.
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28
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Zhang L, Li Z, Wan Z, Kilby A, Kilby JM, Jiang W. Humoral immune responses to Streptococcus pneumoniae in the setting of HIV-1 infection. Vaccine 2015; 33:4430-6. [PMID: 26141012 DOI: 10.1016/j.vaccine.2015.06.077] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 06/07/2015] [Accepted: 06/19/2015] [Indexed: 02/06/2023]
Abstract
Streptococcus pneumoniae (pneumococcus) remains one of the most commonly identified causes of bacterial infection in the general population, and the risk is 30-100 fold higher in HIV-infected individuals. Both innate and adaptive host immune responses to pneumococcal infection are important against pathogen invasion. Pneumococcal-specific IgA antibody (Ab) is key to control infection at the mucosal sites. Ab responses against pneumococcal infection by B cells can be generated through T cell-dependent or T cell-independent pathways. Depletion of CD4+ T cells is a hallmark of immunodeficiency in HIV infection and this defect also contributes to B cell dysfunction, which predisposes to infections such as the pneumococcus. Two pneumococcal vaccines have been demonstrated to have potential benefits for HIV-infected patients. One is a T cell dependent 13-valent pneumococcal conjugate vaccine (PCV13); the other is a T cell independent 23-valent pneumococcal polysaccharide vaccine (PPV23). However, many questions remain unknown regarding these two vaccines in the clinical setting in HIV disease. Here we review the latest research regarding B cell immune responses against pneumococcal antigens, whether derived from potentially invading pathogens or vaccinations, in the setting of HIV-1 infection.
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Affiliation(s)
- Lumin Zhang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Zihai Li
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Zhuang Wan
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Andrew Kilby
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
| | - J Michael Kilby
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, United States; Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Wei Jiang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, United States; Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States.
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Hu Z, Luo Z, Wan Z, Wu H, Li W, Zhang T, Jiang W. HIV-associated memory B cell perturbations. Vaccine 2015; 33:2524-9. [PMID: 25887082 PMCID: PMC4420662 DOI: 10.1016/j.vaccine.2015.04.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 04/01/2015] [Accepted: 04/02/2015] [Indexed: 12/15/2022]
Abstract
Memory B-cell depletion, hyperimmunoglobulinemia, and impaired vaccine responses are the hallmark of B cell perturbations inhuman immunodeficiency virus (HIV) disease. Although B cells are not the targets for HIV infection, there is evidence for B cell, especially memory B cell dysfunction in HIV disease mediated by other cells or HIV itself. This review will focus on HIV-associated phenotypic and functional alterations in memory B cells. Additionally, we will discuss the mechanism underlying these perturbations and the effect of anti-retroviral therapy (ART) on these perturbations.
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Affiliation(s)
- Zhiliang Hu
- Department of Infectious Disease, the Second Affiliated Hospital of the Southeast University, Nanjing 210003, China; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Zhenwu Luo
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Zhuang Wan
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Hao Wu
- Beijing You'an Hospital, Capital Medical University, No. 8 Xitoutiao, You'an men wai, Fengtai District, Beijing 100069, China
| | - Wei Li
- Beijing You'an Hospital, Capital Medical University, No. 8 Xitoutiao, You'an men wai, Fengtai District, Beijing 100069, China
| | - Tong Zhang
- Beijing You'an Hospital, Capital Medical University, No. 8 Xitoutiao, You'an men wai, Fengtai District, Beijing 100069, China.
| | - Wei Jiang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
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Kantsø B, Green N, Goldblatt D, Benfield T. Antibody Response is More Likely to Pneumococcal Proteins Than to Polysaccharide After HIV-associated Invasive Pneumococcal Disease. J Infect Dis 2015; 212:1093-9. [PMID: 25762789 DOI: 10.1093/infdis/jiv158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Accepted: 03/06/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Human immunodeficiency virus (HIV)-infected individuals are at increased risk of invasive pneumococcal disease (IPD). In order to assess the immunogenicity of pneumococcal proteins and polysaccharide, we investigated protein and serotype-specific antibody responses after HIV-associated IPD. METHODS Specific antipneumococcal immunoglobulin G to 27 pneumococcal protein antigens and 30 serotype polysaccharides was measured in plasma before and after IPD in HIV-infected individuals and compared to HIV-infected individuals without IPD. RESULTS Over time, 81% of IPD cases responded to at least 1 protein compared to 51% of non-IPD controls. HIV IPD cases responded to more proteins than non-IPD controls (8.6 ± 8.4 vs 4.2 ± 7.6 proteins; P = .01), and had a significantly higher probability of yielding an antibody response to the proteins PiaA, PsaA, and PcpA. Twenty-two percent of HIV-infected individuals with IPD had a serotype-specific antibody response. Younger age at the time of IPD was the only predictor of a serotype-specific pneumococcal antibody response, whereas we did not identify predictors of a protein-specific antibody response. CONCLUSIONS Antibody responses occurred more frequently to pneumococcal proteins than to polysaccharide, and protein antibodies persisted for longer than polysaccharide-specific antibodies. PcpA, PiaA, and PsaA were the most immunogenic proteins.
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Affiliation(s)
- Bjørn Kantsø
- Department of Microbiological Diagnostics and Virology, Statens Serum Institut, Copenhagen, Denmark
| | - Nicola Green
- Immunobiology Unit, Institute of Child Health, University College London, United Kingdom
| | - David Goldblatt
- Immunobiology Unit, Institute of Child Health, University College London, United Kingdom
| | - Thomas Benfield
- Department of Infectious Diseases Clinical Research Centre, Hvidovre Hospital Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
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Tsachouridou O, Skoura L, Zebekakis P, Margariti A, Galanos A, Pilalas D, Daniilidis M, Malisiovas N, Metallidis S. Alterations in memory B cell subsets upon immunization against Streptococcus pneumoniae in HIV-1 infected adults. HIV & AIDS REVIEW 2015. [DOI: 10.1016/j.hivar.2015.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Leggat DJ, Iyer AS, Ohtola JA, Kommoori S, Duggan JM, Georgescu CA, Khuder SA, Khaskhely NM, Westerink MJ. Response to Pneumococcal Polysaccharide Vaccination in Newly Diagnosed HIV-Positive Individuals. ACTA ACUST UNITED AC 2015; 6. [PMID: 25908995 PMCID: PMC4405239 DOI: 10.4172/2155-6113.1000419] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Newly diagnosed HIV-positive individuals are 35 to 100-fold more susceptible to Streptococcus pneumoniae infection compared to non-infected individuals. Therefore, the 23-valent pneumococcal polysaccharide vaccine (PPV23) has previously been recommended, though efficacy and effectiveness of vaccination remains controversial. Early severe B cell dysfunction is a central feature of HIV infection. The specific nature of the immune cells involved in the production of protective antigen-specific antibodies in HIV-positive individuals remains to be elucidated. OBJECTIVES Evaluate the antibody and antigen-specific B cell response to the 23-valent pneumococcal polysaccharide vaccine in newly diagnosed HIV-positive patients. Moreover, determine if newly diagnosed patients with CD4<200 cells/μl benefit from 6-12 months of HAART, allowing partial viral suppression and immune reconstitution, prior to immunization. METHODS Newly diagnosed HIV-positive patients with CD4>200 cells/μl and CD4<200 cells/μl were immunized with PPV23. Patients with CD4<200 cells/μl received either immediate or delayed immunization following 6-12 months of HAART. Antibody responses, opsonophagocytic activity and phenotypic analysis of pneumococcal polysaccharide-specific B cells were studied. RESULTS Newly diagnosed HIV-positive patients demonstrated CD4-dependent increases in antibody and opsonophagocytic titers thought to be commensurate with protection. Functional opsonophagocytic titers of patients with CD4<200 cells/μl immunized immediately compared to patients with CD4<200 cells/μl receiving HAART for 6-12 months were not significantly different. Pneumococcal polysaccharide-specific B cells were distributed evenly between IgM memory and switched memory B cells for all groups, but IgM memory B cells were significantly lower than in HIV-negative individuals. CONCLUSIONS Despite CD4-dependent pneumococcal polysaccharide-specific deficiencies in newly diagnosed HIV-positive patients, vaccination was beneficial based on opsonophagocytic titers for all newly diagnosed HIV-positive groups. In HIV-positive patients with CD4<200 cells/μl, 6-12 months of HAART did not improve opsonophagocytic titers or antibody concentrations. Based on these findings, immunization with the 23-valent pneumococcal polysaccharide vaccine should not be delayed in newly diagnosed HIV-positive patients with CD4<200 cells/μl.
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Affiliation(s)
| | - Anita S Iyer
- Department of Medicine, University of Toledo, USA
| | | | | | - Joan M Duggan
- Department of Medicine, University of Toledo, USA ; Department of Medical Microbiology and Immunology, University of Toledo, USA ; Department of Internal Medicine, University of Toledo, USA ; Department of Pathology, University of Toledo, USA ; Department of Physiology, University of Toledo, USA ; Department of Pharmacology, University of Toledo, USA ; Department of Metabolism & Cardiovascular Science, University of Toledo, USA
| | | | - Sadik A Khuder
- Department of Medicine, University of Toledo, USA ; Department of Public Health, University of Toledo, USA
| | | | - Ma Julie Westerink
- Department of Medicine, University of Toledo, USA ; Department of Medical Microbiology and Immunology, University of Toledo, USA ; Department of Internal Medicine, University of Toledo, USA ; Department of Pathology, University of Toledo, USA
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Iyer AS, Leggat DJ, Ohtola JA, Duggan JM, Georgescu CA, Al Rizaiza AA, Khuder SA, Khaskhely NM, Westerink J. Response to Pneumococcal Polysaccharide Vaccination in HIV-Positive Individuals on Long Term Highly Active Antiretroviral Therapy. ACTA ACUST UNITED AC 2015; 6. [PMID: 25908996 PMCID: PMC4405245 DOI: 10.4172/2155-6113.1000421] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Background and objectives Streptococcus pneumoniae continues to cause serious infections in HIV-positive individuals in the era of highly active anti-retroviral therapy. This led to the recommendation to revaccinate HIV-positive individuals with PPV23 five years after primary vaccination. The benefits of revaccination and the impact of long term highly active anti-retroviral therapy (HAART) on antigen-specific B cell reconstitution have remained unclear thus far and were investigated. Design and methods We assessed antibody levels, opsonophagocytic activity and phenotype of pneumococcal polysaccharide (PPS) specific-B cells post-revaccination in long term HAART cohorts stratified according to CD4 count as group A (CD4>200) and group B (CD4<200). Anti-PPS IgG, IgM and functional antibody response against vaccine serotypes 14 and 23F were measured by ELISA and opsonophagocytic assay followed by phenotypic analysis of PPS14 and 23F-specific B cells using fluorescently labeled PPS. Results Significant increases in total and functional antibody titers were noted in groups A and B post-vaccination concomitant with significant rise in PPS-specific IgM memory B cells, a critical B cell subset required for protection against PPS although the overall response remained significantly diminished compared to HIV-negative volunteers. Conclusion Comparable increases in opsonophagocytic titers between study groups A and B concomitant with a comparable rise in PPS-specific IgM memory B cells indicate revaccination to be beneficial regardless of the degree of CD4 T cell reconstitution. These findings emphasize the importance of defining effective vaccination practices amongst high-risk individuals.
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Affiliation(s)
- Anita S Iyer
- Department of Medicine, University of Toledo, USA
| | | | | | - Joan M Duggan
- Department of Medicine, University of Toledo, USA ; Department of Medical Microbiology and Immunology, University of Toledo, USA ; Department of Internal Medicine, University of Toledo, USA ; Department of Pathology, University of Toledo, USA ; Department of Physiology, University of Toledo, USA ; Department of Pharmacology, University of Toledo, USA ; Department of Metabolism and Cardiovascular Science, University of Toledo, USA
| | | | | | - Sadik A Khuder
- Department of Medicine, University of Toledo, USA ; Department of Public Health, University of Toledo, USA
| | | | - Julie Westerink
- Department of Medicine, University of Toledo, USA ; Department of Medical Microbiology and Immunology, University of Toledo, USA ; Department of Internal Medicine, University of Toledo, USA ; Department of Pathology, University of Toledo, USA
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Serological response to 13-valent pneumococcal conjugate vaccine in children and adolescents with perinatally acquired HIV infection. AIDS 2014; 28:2033-43. [PMID: 25222526 PMCID: PMC4166014 DOI: 10.1097/qad.0000000000000385] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Background: Children with perinatally acquired HIV (paHIV) remain at an increased risk of pneumococcal infection despite highly active antiretroviral therapy (HAART). Beyond infancy, responses to pneumococcal conjugate vaccine (PCV) remain under-investigated. There are currently no published data on serological response to 13-valent PCV (PCV13) in the HIV-infected populations. Methods: We measured pneumococcal serotype-specific IgG in 48 paHIV-infected child patients (CP), 27 young adult healthy controls (AHC) and 30 child healthy controls (CHC). Opsonophagocytic assay (OPA) titres for three PCV13-exclusive serotypes were measured in a subset of children. Serotype-specific IgG was repeated 1 and 6 months following PCV13 vaccination of CP and AHC groups. OPA titres for four serotypes were measured at the 1-month time-point. Results: The majority of CP, CHC and AHC had serotype-specific IgG above 0.35 μg/ml at baseline, although OPA activity was undetectable for two of the three serotypes studied. Baseline IgG concentrations were significantly lower in CP than AHC for a proportion of serotypes and were strongly predictive of responses to vaccine. After adjusting for baseline, postvaccination IgG concentrations were comparable, although responses to some serotypes were impaired for CP. OPA correlated well with IgG after vaccination. Detectable HIV viral load was associated with significantly lower IgG concentration and OPA titre. Conclusion: Children with paHIV mount a robust serological response to PCV13 for most but not all vaccine serotypes. Viral load suppression with HAART and higher baseline IgG concentration are associated with higher postvaccination antibody levels. This has implications for HAART treatment and vaccination practices.
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Antiretroviral therapy restores age-dependent loss of resting memory B cells in young HIV-infected Zambian children. J Acquir Immune Defic Syndr 2014; 65:505-9. [PMID: 24326598 DOI: 10.1097/qai.0000000000000074] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Antiretroviral therapy (ART) is associated with incomplete restoration of resting memory B (RMB) cell percentages in adults infected with HIV, but the effects on RMB cells in children are less well defined, in part because changes in RMB cell percentages are confounded by the development and maturation of the RMB cell pool. The objective of this study was to assess the effect of age at ART initiation on RMB cell percentages over time in HIV-infected Zambian children. METHODS RMB cell percentages (CD19CD21CD27) were measured by flow cytometry in 146 HIV-infected Zambian children (9-120 months old) at baseline and at 3-month intervals after ART initiation and in 34 control children at a single study visit. RESULTS RMB cell percentages among untreated HIV-infected children younger than 24 months did not differ from those of control children (P = 0.97). Among HIV-infected children older than 24 months of age, however, each 12-month increase in age at ART initiation was associated with a 1.8% decrease in RMB cell percentage. In contrast, RMB cell percentages in control children up to 48 months increased 4.4% with each 12-month increase in age. After 12 months of ART, children aged 24-60 months had a significant increase in RMB cell percentages that no longer differed from those of control children. CONCLUSIONS Initiation of ART in 2- to 5-year-old HIV-infected children resulted in reconstitution of RMB cell percentages to levels similar to control children and may help restore normal development and maintenance of B-cell immunity.
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Yilmaz A, Jennbacken K, Fogelstrand L. Reduced IgM levels and elevated IgG levels against oxidized low-density lipoproteins in HIV-1 infection. BMC Infect Dis 2014; 14:143. [PMID: 24636004 PMCID: PMC3995360 DOI: 10.1186/1471-2334-14-143] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 03/12/2014] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Chronic HIV infection is associated with increased risk of cardiovascular disease caused by atherosclerosis. Oxidized forms of low-density lipoprotein (LDL) are present in atherosclerotic lesions and constitute major epitopes for natural antibodies. IgM has been shown to be protective against atherosclerosis, whereas the role of corresponding IgG is less clear. The objective of this study was to determine if HIV + individuals have disturbed levels of IgM and IgG directed against oxidized forms of LDL as compared to HIV- individuals. METHODS Ninety-one HIV + patients and 92 HIV- controls were included in this retrospective study. Circulating levels of IgG and IgM directed against two forms of oxidized LDL; copper oxidized (OxLDL) and malondialdehyde modified (MDA-LDL), total IgM and IgG, C-reactive protein (CRP), soluble CD14, and apolipoproteins A1 and B were determined. RESULTS HIV + individuals had slightly lower levels of IgM against MDA-LDL and higher levels of IgG against MDA-LDL, OxLDL, and total IgG, than HIV- controls. Anti-MDA-LDL and Anti-OxLDL IgG displayed a positive correlation with viral load and a negative correlation with the CD4+ T-cell count. HIV + individuals also displayed elevated CRP and soluble CD14 levels compared to HIV- individuals, but there were no correlations between CRP or soluble CD14 and specific antibodies. CONCLUSIONS HIV infection is associated with higher levels of IgG including specific IgG against oxidized forms of LDL, and lower IgM against the same epitope. In addition to dyslipidemia, immune activation, HIV-replication and an accumulation of risk factors for atherosclerosis, this adverse antibody profile may be of major importance for the increased risk of cardiovascular disease in HIV + individuals.
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Affiliation(s)
- Aylin Yilmaz
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Karin Jennbacken
- Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Linda Fogelstrand
- Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, all at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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cART Reverses Hyposplenism in HIV-1 Infection. J Acquir Immune Defic Syndr 2014; 65:e88-90. [DOI: 10.1097/qai.0b013e3182a2d0b3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
A variety of B-cell dysfunctions are manifested during HIV-1 infection, as reported early during the HIV-1 epidemic. It is not unusual that the pathogenic mechanisms presented to elucidate impairment of B-cell responses during HIV-1 infection focus on the impact of reduced T-cell numbers and functions, and lack of germinal center formation in lymphoid tissues. To our understanding, however, perturbation of B-cell phenotype and function during HIV-1 infection may begin at several different B-cell developmental stages. These impairments can be mediated by intrinsic B-cell defects as well as by the lack of proper T-cell help. In this review, we will highlight some of the pathways and molecular interactions leading to B-cell impairment prior to germinal center formation and B-cell activation mediated through the B-cell receptor in response to HIV-1 antigens. Recent studies indicate a regulatory role for B cells on T-cell biology and immune responses. We will discuss some of these novel findings and how these regulatory mechanisms could potentially be affected by the intrinsic defects of B cells taking place during HIV-1 infection.
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Antibody persistence and immunologic memory after sequential pneumococcal conjugate and polysaccharide vaccination in HIV-infected children on highly active antiretroviral therapy. Vaccine 2013; 31:4782-90. [PMID: 23954381 DOI: 10.1016/j.vaccine.2013.08.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 07/02/2013] [Accepted: 08/01/2013] [Indexed: 11/24/2022]
Abstract
BACKGROUND The capacity of pneumococcal vaccination to confer memory in HIV-infected children is critical for durable protection. METHODS HIV-infected children 2-<19 years administered two doses of pneumococcal conjugate vaccine (PCV7) and one dose of polysaccharide vaccine (PPV) on HAART were randomized 4-5 years later to receive a PCV7 or PPV booster. Total and high avidity antibodies to serotypes 1 (PPV) and 6B and 14 (PCV7 and PPV) were determined by ELISA. Memory was defined as persistence of ≥ 0.5 mcg/mL of serotype-specific antibody on day 0 or change from <0.5 mcg/mL to ≥ 0.5 mcg/mL between day 0 and week 1, or, ≥ 4-fold antibody rise between day 0 and week 1. RESULTS Prior to boosting, 4-5 years after the previous PCV7-PCV7-PPV series, geometric mean concentrations (GMCs) were 0.46 mcg/mL (serotype 1), 1.31 mcg/mL (serotype 6B), and 1.47 mcg/mL (serotype 14), with concentrations ≥ 0.5 mcg/mL in 41% (serotype 1) to 82% (serotypes 6B and 14). Memory based on antibody concentration ≥ 0.5 mcg/mL before or 1 week after boosting with PCV7 or PPV was demonstrated in 42-61% for serotype 1 and 87-94% for serotypes 6B and 14, with lower rates based on day 0 to week 1 ≥ 4-fold antibody rise (serotype 1, 3-13%; serotype 6B, 13-31%; serotype 14, 29-53%). Antibody concentrations post-boosting were greater following PCV7 than PPV for serotypes 6B and 14. Ratios of highly avid to total antibody pre- and post-boosting were 0.5-0.8. Predictors of memory included higher CD4% (nadir before HAART and at P1024 and P1061s entry), CD19% (at P1024 and P1061s entry), and antibody response after the PCV7-PCV7-PPV primary series and lower viral load (at P1024 and P1061s entry) and age. CONCLUSIONS Protective antibody concentrations, high avidity, and booster responses to PCV7 or PPV indicative of memory were present 4-5 years after PCV7-PCV7-PPV in HIV-infected children on HAART.
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Leggat DJ, Thompson RS, Khaskhely NM, Iyer AS, Westerink MAJ. The immune response to pneumococcal polysaccharides 14 and 23F among elderly individuals consists predominantly of switched memory B cells. J Infect Dis 2013; 208:101-8. [PMID: 23547142 PMCID: PMC3666141 DOI: 10.1093/infdis/jit139] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Accepted: 01/11/2013] [Indexed: 01/23/2023] Open
Abstract
The phenotype of B cells that respond to vaccination with the purified pneumococcal polysaccharide (PPS) has been a topic of debate. We have recently identified the phenotype of cells from healthy young volunteers as CD27(+)IgM(+) B cells. However, the PPS-responding B-cell population has not yet been identified in high-risk populations, such as elderly individuals. Previous studies have shown that elderly individuals have a lower percentage of immunoglobulin M memory B cells than healthy young adults. In this study, we directly characterized the phenotype of PPS-specific B cells before and after vaccination with PPS vaccine (PPV) in elderly adults, using fluorescently labeled PPS14 and PPS23F. In contrast to our observations in healthy young volunteers, the PPS-responding B-cell population consisted primarily of switched memory (CD27(+)IgM(-)) B cells. In concurrence with these findings, postvaccination immunoglobulin M concentrations were not significantly increased in this population, and the opsonophagocytic response was decreased, compared with that in young adults. These findings identify a significant shift in the phenotype of the B-cell population in response to PPV among elderly individuals.
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Affiliation(s)
- David J Leggat
- Department of Medicine, University of Toledo, Ohio 43614, USA
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Moussa S, Jenabian MA, Gody JC, Léal J, Grésenguet G, Le Faou A, Bélec L. Adaptive HIV-specific B cell-derived humoral immune defenses of the intestinal mucosa in children exposed to HIV via breast-feeding. PLoS One 2013; 8:e63408. [PMID: 23704905 PMCID: PMC3660449 DOI: 10.1371/journal.pone.0063408] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 04/01/2013] [Indexed: 11/30/2022] Open
Abstract
Background We evaluated whether B cell-derived immune defenses of the gastro-intestinal tract are activated to produce HIV-specific antibodies in children continuously exposed to HIV via breast-feeding. Methods Couples of HIV-1-infected mothers (n = 14) and their breastfed non HIV-infected (n = 8) and HIV-infected (n = 6) babies, and healthy HIV-negative mothers and breastfed babies (n = 10) as controls, were prospectively included at the Complexe Pédiatrique of Bangui, Central African Republic. Immunoglobulins (IgA, IgG and IgM) and anti-gp160 antibodies from mother’s milk and stools of breastfed children were quantified by ELISA. Immunoaffinity purified anti-gp160 antibodies were characterized functionally regarding their capacity to reduce attachment and/or infection of R5- and X4- tropic HIV-1 strains on human colorectal epithelial HT29 cells line or monocyte-derived-macrophages (MDM). Results The levels of total IgA and IgG were increased in milk of HIV-infected mothers and stools of HIV-exposed children, indicating the activation of B cell-derived mucosal immunity. Breast milk samples as well as stool samples from HIV-negative and HIV-infected babies exposed to HIV by breast-feeding, contained high levels of HIV-specific antibodies, mainly IgG antibodies, less frequently IgA antibodies, and rarely IgM antibodies. Relative ratios of excretion by reference to lactoferrin calculated for HIV-specific IgA, IgG and IgM in stools of HIV-exposed children were largely superior to 1, indicating active production of HIV-specific antibodies by the intestinal mucosa. Antibodies to gp160 purified from pooled stools of HIV-exposed breastfed children inhibited the attachment of HIV-1NDK on HT29 cells by 63% and on MDM by 77%, and the attachment of HIV-1JRCSF on MDM by 40%; and the infection of MDM by HIV-1JRCSF by 93%. Conclusions The intestinal mucosa of children exposed to HIV by breast-feeding produces HIV-specific antibodies harbouring in vitro major functional properties against HIV. These observations lay the conceptual basis for the design of a prophylactic vaccine against HIV in exposed children.
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Affiliation(s)
- Sandrine Moussa
- Institut Pasteur de Bangui, Laboratoire des Rétrovirus-VIH, Bangui, Central African Republic.
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Abstract
OBJECTIVES During HIV-1 infection, the development, phenotype, and functionality of B cells are impaired. Transitional B cells and aberrant B-cell populations arise in blood, whereas a declined percentage of resting memory B cells is detected. Our study aimed at pinpointing the demographic, immunological, and viral factors driving these pathological findings, and the role of antiretroviral therapy in reverting these alterations. DESIGN B-cell phenotype and correlating factors were evaluated. METHODS Variations in B-cell subsets were evaluated by flow cytometry in HIV-1-infected individuals naive to therapy, elite controllers, and patients treated with antiretroviral drugs (virological control or failure). Multivariable analysis was performed to identify variables independently associated with the B-cell alterations. RESULTS Significant differences were observed among patients' groups in relation to all B-cell subsets. Resting memory B cells were preserved in patients naive to therapy and elite controllers, but reduced in treated patients. Individuals naive to therapy and experiencing multidrug failure, as well as elite controllers, had significantly higher levels of activated memory B cells compared to healthy controls. In the multivariate analysis, plasma viral load and nadir CD4 T cells independently correlated with major B-cell alterations. Coinfection with hepatitis C but not hepatitis B virus also showed an impact on specific B-cell subsets. Successful protracted antiretroviral treatment led to normalization of all B-cell subsets with exception of resting memory B cells. CONCLUSION Our results indicate that viremia and nadir CD4 T cells are important prognostic markers of B-cell perturbations and provide evidence that resting memory B-cell depletion during chronic infection is not reverted upon successful antiretroviral therapy.
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Buckner CM, Moir S, Ho J, Wang W, Posada JG, Kardava L, Funk EK, Nelson AK, Li Y, Chun TW, Fauci AS. Characterization of plasmablasts in the blood of HIV-infected viremic individuals: evidence for nonspecific immune activation. J Virol 2013; 87:5800-11. [PMID: 23487459 PMCID: PMC3648153 DOI: 10.1128/jvi.00094-13] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 03/05/2013] [Indexed: 01/08/2023] Open
Abstract
Terminal differentiation of B cells and hypergammaglobulinemia are hallmarks of B-cell hyperactivity in HIV disease. Plasmablasts are terminally differentiating B cells that circulate transiently in the blood following infection or vaccination; however, in HIV infection, they arise early and are maintained at abnormally high levels in viremic individuals. Here we show that only a small fraction of plasmablasts in the blood of viremic individuals is HIV specific. Assessment of plasmablast immunoglobulin isotype distribution revealed increased IgG(+) plasmablasts in early and most prominently during chronic HIV viremia, contrasting with a predominantly IgA(+) plasmablast profile in HIV-negative individuals or in aviremic HIV-infected individuals on treatment. Of note, IgG is the predominant immunoglobulin isotype of plasmablasts that arise transiently in the blood following parenteral immunization. Serum immunoglobulin levels were also elevated in HIV-infected viremic individuals, especially IgG, and correlated with levels of IgG(+) plasmablasts. Several soluble factors associated with immune activation were also increased in the sera of HIV-infected individuals, especially in viremic individuals, and correlated with serum immunoglobulin levels, particularly IgG. Thus, our data suggest that while plasmablasts in the blood may contribute to the HIV-specific immune response, the majority of these cells are not HIV specific and arise early, likely from indirect immune-activating effects of HIV replication, and reflect over time the effects of chronic antigenic stimulation. Such B-cell dysregulation may help explain why the antibody response is inadequate in HIV-infected individuals, even during early infection.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yuxing Li
- Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA
- IAVI Center for Neutralizing Antibodies at TSRI
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA
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Siebert JN, L'huillier AG, Grillet S, Delhumeau C, Siegrist CA, Posfay-Barbe KM. Memory B cell compartment constitution and susceptibility to recurrent lower respiratory tract infections in young children. J Leukoc Biol 2013; 93:951-62. [PMID: 23530161 DOI: 10.1189/jlb.0312117] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
A proportion of children have recurrent LRTIs, mostly as a result of Spn, which persist after 2 years of age. Here, we investigate, by flow cytofluorometry, the constitution of the memory B cell compartment in 90 healthy children and 49 children with recurrent LRTIs to determine if an increased susceptibility to recurrent LRTIs results from a delayed or abnormal ontogeny with poor antibody-mediated protection. Total IgA, IgM, IgG, and IgG subclasses were measured by nephelometry, as well as antipneumococcal antibodies by ELISA. Pneumococcal vaccination status was obtained. We show that the memory B cells increase between birth and 2 years of age (1.6% vs. 21.1%, P<0.001) without further significant increase noted per additional years (3-4 years old: 23.3%; 4-5 years old: 22.2%, P>0.40) to reach adult-like values (31.8±11.8%, P=0.08). Proportions of switched and IgM memory B cells were similar in children and adults. Comparatively, LRTI children had no delay in the constitution of their memory B cell compartment (2-3 years old: 26.9%; 3-4 years old: 18.2%; 4-5 years old: 26.8%, P>0.05). Their switched and IgM memory B cells were similar among age categories, and the distribution was overall similar to that of healthy controls. LRTI children had normal total and pneumococcal serotype-specific antibody values but showed a rapid waning of antipneumococcal antibody levels after vaccination. In summary, our results show that the memory B cell compartment is already similarly constituted at 2 years of age in healthy and LRTI children and thus, cannot explain the increased susceptibility to bacterial pneumonia. However, the waning of antibodies might predispose children to recurrent infections in the absence of revaccination.
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Affiliation(s)
- Johan N Siebert
- Department of Pediatrics, University Hospitals of Geneva and Medical School, University of Geneva, Geneva, Switzerland
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Demberg T, Brocca-Cofano E, Xiao P, Venzon D, Vargas-Inchaustegui D, Lee EM, Kalisz I, Kalyanaraman VS, DiPasquale J, McKinnon K, Robert-Guroff M. Dynamics of memory B-cell populations in blood, lymph nodes, and bone marrow during antiretroviral therapy and envelope boosting in simian immunodeficiency virus SIVmac251-infected rhesus macaques. J Virol 2012; 86:12591-604. [PMID: 22973034 PMCID: PMC3497654 DOI: 10.1128/jvi.00298-12] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 08/31/2012] [Indexed: 11/20/2022] Open
Abstract
Human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection causes B-cell dysregulation and the loss of memory B cells in peripheral blood mononuclear cells (PBMC). These effects are not completely reversed by antiretroviral treatment (ART). To further elucidate B-cell changes during chronic SIV infection and treatment, we investigated memory B-cell subpopulations and plasma cells/plasmablasts (PC/PB) in blood, bone marrow, and lymph nodes of rhesus macaques during ART and upon release from ART. Macaques previously immunized with SIV recombinants and the gp120 protein were included to assess the effects of prior vaccination. ART was administered for 11 weeks, with or without gp120 boosting at week 9. Naïve and resting, activated, and tissue-like memory B cells and PC/PB were evaluated by flow cytometry. Antibody-secreting cells (ASC) and serum antibody titers were assessed. No lasting changes in B-cell memory subpopulations occurred in bone marrow and lymph nodes, but significant decreases in numbers of activated memory B cells and increases in numbers of tissue-like memory B cells persisted in PBMC. Macaque PC/PB were found to be either CD27(+) or CD27(-) and therefore were defined as CD19(+) CD38(hi) CD138(+). The numbers of these PC/PB were transiently increased in both PBMC and bone marrow following gp120 boosting of the unvaccinated and vaccinated macaque groups. Similarly, ASC numbers in PBMC and bone marrow of the two macaque groups also transiently increased following envelope boosting. Nevertheless, serum binding titers against SIVgp120 remained unchanged. Thus, even during chronic SIV infection, B cells respond to antigen, but long-term memory does not develop, perhaps due to germinal center destruction. Earlier and/or prolonged treatment to allow the generation of virus-specific long-term memory B cells should benefit ART/therapeutic vaccination regimens.
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Affiliation(s)
- Thorsten Demberg
- Vaccine Branch, National Cancer Institute, Bethesda, Maryland, USA
| | | | - Peng Xiao
- Vaccine Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - David Venzon
- Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland, USA
| | | | - Eun Mi Lee
- Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA
| | - Irene Kalisz
- Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA
| | | | - Janet DiPasquale
- Vaccine Branch, National Cancer Institute, Bethesda, Maryland, USA
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Khaskhely N, Mosakowski J, Thompson RS, Khuder S, Smithson SL, Westerink MAJ. Phenotypic analysis of pneumococcal polysaccharide-specific B cells. THE JOURNAL OF IMMUNOLOGY 2012; 188:2455-63. [PMID: 22271652 DOI: 10.4049/jimmunol.1102809] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The phenotype of B cells responsible for the production of anti-pneumococcal polysaccharide Ab has been unclear. Although individuals that respond poorly to the 23-valent pneumococcal polysaccharide (PPS) vaccine, Pneumovax, such as children <2 y, the asplenic, and a subset of common variable immunodeficiency patients, are profoundly deficient or lack IgM memory cells (CD27(+)IgM(+)), they are also deficient in the switched memory (CD27(+)IgM(-)) compartment. Direct characterization of PPS-specific B cells has not been performed. In this study, we labeled PPS14 and PPS23F with fluorescent markers. Fluorescently labeled PPS were used in FACSAria flow cytometry to characterize the phenotype of PPS-specific B cells obtained from 18 young adults pre- and postimmunization with Pneumovax. The labeled PPS were capable of inhibiting binding of Ab to the native PPS. Similarly, the native PPS were able to inhibit binding of PPS-specific B cells in a flow cytometric assay demonstrating specificity and functionality. Phenotypic analysis of unselected B cells, pre- and postimmunization, demonstrated a predominance of naive CD27(-)IgM(+) cells accounting for 61.5% of B cells. Likewise, the PPS-specific B cells obtained preimmunization consisted primarily of naive, CD27(-) B cells, 55.4-63.8%. In contrast, the PPS-specific B cells obtained postimmunization were predominantly IgM memory cells displaying the CD27(+)IgM(+), 54.2% for PPS14 and 66% for PPS23F, significantly higher than both unselected B cells and PPS-specific B cells. There was no significant difference in switched memory B cell populations (CD27(+)IgM(-)) between groups. These results suggest a dominant role of IgM memory cells in the immune response to pneumococcal polysaccharides.
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Affiliation(s)
- Noor Khaskhely
- Department of Medicine, University of Toledo, Toledo, OH 43614, USA
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Oballah P, Flach B, Eller LA, Eller MA, Ouma B, de Souza M, Kibuuka HN, Wabwire-Mangen F, Brown BK, Michael NL, Robb ML, Montefiori D, Polonis VR. B cell depletion in HIV-1 subtype A infected Ugandan adults: relationship to CD4 T cell count, viral load and humoral immune responses. PLoS One 2011; 6:e22653. [PMID: 21886768 PMCID: PMC3160298 DOI: 10.1371/journal.pone.0022653] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Accepted: 06/27/2011] [Indexed: 11/19/2022] Open
Abstract
To better understand the nature of B cell dysfunctions in subjects infected with HIV-1 subtype A, a rural cohort of 50 treatment-naïve Ugandan patients chronically infected with HIV-1 subtype A was studied, and the relationship between B cell depletion and HIV disease was assessed. B cell absolute counts were found to be significantly lower in HIV-1+ patients, when compared to community matched negative controls (p<0.0001). HIV-1-infected patients displayed variable functional and binding antibody titers that showed no correlation with viral load or CD4+ T cell count. However, B cell absolute counts were found to correlate inversely with neutralizing antibody (NAb) titers against subtype A (p = 0.05) and subtype CRF02_AG (p = 0.02) viruses. A positive correlation was observed between subtype A gp120 binding antibody titers and NAb breadth (p = 0.02) and mean titer against the 10 viruses (p = 0.0002). In addition, HIV-1 subtype A sera showed preferential neutralization of the 5 subtype A or CRF02_AG pseudoviruses, as compared with 5 pseudoviruses from subtypes B, C or D (p<0.001). These data demonstrate that in patients with chronic HIV-1 subtype A infection, significant B cell depletion can be observed, the degree of which does not appear to be associated with a decrease in functional antibodies. These findings also highlight the potential importance of subtype in the specificity of cross-clade neutralization in HIV-1 infection.
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Affiliation(s)
- Peter Oballah
- Makerere University Walter Reed Project, Kampala, Uganda
| | - Britta Flach
- Makerere University Walter Reed Project, Kampala, Uganda
- Military HIV Research Program, Rockville, Maryland, United States of America
- The Henry M Jackson Foundation, Rockville, Maryland, United States of America
| | - Leigh A. Eller
- Military HIV Research Program, Rockville, Maryland, United States of America
- The Henry M Jackson Foundation, Rockville, Maryland, United States of America
| | - Michael A. Eller
- Military HIV Research Program, Rockville, Maryland, United States of America
- The Henry M Jackson Foundation, Rockville, Maryland, United States of America
| | - Benson Ouma
- Makerere University Walter Reed Project, Kampala, Uganda
| | - Mark de Souza
- Military HIV Research Program, Rockville, Maryland, United States of America
- The Henry M Jackson Foundation, Rockville, Maryland, United States of America
- Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
| | | | - Fred Wabwire-Mangen
- Makerere University Walter Reed Project, Kampala, Uganda
- Makerere University School of Public Health, Kampala, Uganda
| | - Bruce K. Brown
- Military HIV Research Program, Rockville, Maryland, United States of America
- The Henry M Jackson Foundation, Rockville, Maryland, United States of America
| | - Nelson L. Michael
- Military HIV Research Program, Rockville, Maryland, United States of America
- Walter Reed Army Institute of Research, Rockville, Maryland, United States of America
| | - Merlin L. Robb
- Military HIV Research Program, Rockville, Maryland, United States of America
- The Henry M Jackson Foundation, Rockville, Maryland, United States of America
| | - David Montefiori
- Duke University, Durham, North Carolina, United States of America
| | - Victoria R. Polonis
- Military HIV Research Program, Rockville, Maryland, United States of America
- Walter Reed Army Institute of Research, Rockville, Maryland, United States of America
- * E-mail:
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Cameron PU, Jones P, Gorniak M, Dunster K, Paul E, Lewin S, Woolley I, Spelman D. Splenectomy associated changes in IgM memory B cells in an adult spleen registry cohort. PLoS One 2011; 6:e23164. [PMID: 21829713 PMCID: PMC3150402 DOI: 10.1371/journal.pone.0023164] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Accepted: 07/13/2011] [Indexed: 12/12/2022] Open
Abstract
Asplenic patients have a lifelong risk of overwhelming post-splenectomy infection and have been reported to have low numbers of peripheral blood IgM memory B cells. The clinical value of quantitation of memory B cells as an indicator of splenic abnormality or risk of infection has been unclear. To assess changes in B cell sub-populations after splenectomy we studied patients recruited to a spleen registry (n = 591). A subset of 209 adult asplenic or hyposplenic subjects, and normal controls (n = 140) were tested for IgM memory B cells. We also determined a) changes in IgM memory B cells with time after splenectomy using the cross-sectional data from patients on the registry and b) the kinetics of changes in haematological markers associated with splenectomy(n = 45). Total B cells in splenectomy patients did not differ from controls, but memory B cells, IgM memory B cells and switched B cells were significantly (p<0.001) reduced. The reduction was similar for different indications for splenectomy. Changes of asplenia in routine blood films including presence of Howell-Jolly bodies (HJB), occurred early (median 25 days) and splenectomy associated thrombocytosis and lymphocytosis peaked by 50 days. There was a more gradual decrease in IgM memory B cells reaching a stable level within 6 months after splenectomy. IgM memory B cells as proportion of B cells was the best discriminator between splenectomized patients and normal controls and at the optimal cut-off of 4.53, showed a true positive rate of 95% and false positive rate of 20%. In a survey of 152 registry patients stratified by IgM memory B cells around this cut-off there was no association with minor infections and no registry patients experienced OPSI during the study. Despite significant changes after splenectomy, conventional measures of IgM memory cells have limited clinical utility in this population.
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Affiliation(s)
- Paul U Cameron
- Pathology Services, The Alfred Hospital, Melbourne, Victoria, Australia.
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Antibody and B-cell responses may control circulating lipopolysaccharide in patients with HIV infection. AIDS 2011; 25:1379-83. [PMID: 21572302 DOI: 10.1097/qad.0b013e328348a789] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES To examine the relationship between plasma markers of microbial translocation and antibodies to lipopolysaccharide (LPS) and circulating memory B cells in patients with HIV infection. DESIGN Cross-sectional study in antiretroviral therapy (ART)-naive (n = 23) and ART-treated (n = 27) HIV patients. METHODS Antibodies to LPS and immunoglobulins, assayed in stored serum, and matched memory B-cell counts were correlated with levels of LPS and bacterial 16S ribosome DNA (16S rDNA), assayed in stored plasma. RESULTS In ART-naive patients, plasma LPS levels correlated inversely with serum levels of IgG and IgA antibodies to LPS (P = 0.03 and 0.006, respectively), serum levels of IgA anti-LPS correlated with total IgA (P < 0.0001) and levels of IgG anti-LPS correlated with IgM(+) memory B-cell counts (P = 0.025). In ART-treated patients, plasma LPS levels were not related to levels of LPS antibodies, but were related to CD4(+) T-cell and switched memory B-cell counts. There were no correlations with plasma levels of 16S rDNA. CONCLUSION Plasma LPS levels were associated with antibody and possibly B-cell responses to LPS in ART-naive HIV patients, whereas they were associated with the degree of immune reconstitution in ART-treated patients.
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Abstract
The spleen is crucial in regulating immune homoeostasis through its ability to link innate and adaptive immunity and in protecting against infections. The impairment of splenic function is defined as hyposplenism, an acquired disorder caused by several haematological and immunological diseases. The term asplenia refers to the absence of the spleen, a condition that is rarely congenital and mostly post-surgical. Although hyposplenism and asplenia might predispose individuals to thromboembolic events, in this Review we focus on infectious complications, which are the most widely recognised consequences of these states. Because of the high mortality, the fulminant course, and the refractoriness to common treatment of overwhelming infections caused by encapsulated bacteria, prevention through vaccination and antibiotic prophylaxis is the basis of the management of patients who have had splenectomy or have hyposplenism. In this Review, we critically assess clinical and diagnostic aspects of splenic dysfunction and highlight new perspectives in the prevention of overwhelming post-splenectomy infections.
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Affiliation(s)
- Antonio Di Sabatino
- First Department of Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S Matteo, University of Pavia, Italy
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