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Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency
Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes, and poor antigen-specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is reg...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9582261/ https://www.ncbi.nlm.nih.gov/pubmed/36275744 http://dx.doi.org/10.3389/fimmu.2022.959002 |
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author | van Schouwenburg, Pauline Unger, Susanne Payne, Kathryn J. Kaiser, Fabian M. P. Pico-Knijnenburg, Ingrid Pfeiffer, Jens Hausmann, Oliver Friedmann, David Erbel, Michelle Seidl, Maximilian van Zessen, David Stubbs, Andrew P. van der Burg, Mirjam Warnatz, Klaus |
author_facet | van Schouwenburg, Pauline Unger, Susanne Payne, Kathryn J. Kaiser, Fabian M. P. Pico-Knijnenburg, Ingrid Pfeiffer, Jens Hausmann, Oliver Friedmann, David Erbel, Michelle Seidl, Maximilian van Zessen, David Stubbs, Andrew P. van der Burg, Mirjam Warnatz, Klaus |
author_sort | van Schouwenburg, Pauline |
collection | PubMed |
description | Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes, and poor antigen-specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is regularly associated with a severe decrease of germinal center (GC)-derived B-cell populations in peripheral blood. However, data from B-cell differentiation within GC is limited. We present a multiplex approach combining histology, flow cytometry, and B-cell receptor repertoire analysis of sorted GC B-cell populations allowing the modeling of distinct disturbances in GCs of three CVID patients. Our results reflect pathophysiological heterogeneity underlying the reduced circulating pool of post-GC memory B cells and plasmablasts in the three patients. In patient 1, quantitative and qualitative B-cell development in GCs is relatively normal. In patient 2, irregularly shaped GCs are associated with reduced somatic hypermutation (SHM), antigen selection, and class-switching, while in patient 3, high SHM, impaired antigen selection, and class-switching with large single clones imply increased re-cycling of cells within the irregularly shaped GCs. In the lymph nodes of patients 2 and 3, only limited numbers of memory B cells and plasma cells are formed. While reduced numbers of circulating post GC B cells are a general phenomenon in CVID, the integrated approach exemplified distinct defects during GC maturation ranging from near normal morphology and function to severe disturbances with different facets of impaired maturation of memory B cells and/or plasma cells. Integrated dissection of disturbed GC B-cell maturation by histology, flow cytometry, and BCR repertoire analysis contributes to unraveling defects in the essential steps during memory formation. |
format | Online Article Text |
id | pubmed-9582261 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95822612022-10-21 Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency van Schouwenburg, Pauline Unger, Susanne Payne, Kathryn J. Kaiser, Fabian M. P. Pico-Knijnenburg, Ingrid Pfeiffer, Jens Hausmann, Oliver Friedmann, David Erbel, Michelle Seidl, Maximilian van Zessen, David Stubbs, Andrew P. van der Burg, Mirjam Warnatz, Klaus Front Immunol Immunology Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes, and poor antigen-specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is regularly associated with a severe decrease of germinal center (GC)-derived B-cell populations in peripheral blood. However, data from B-cell differentiation within GC is limited. We present a multiplex approach combining histology, flow cytometry, and B-cell receptor repertoire analysis of sorted GC B-cell populations allowing the modeling of distinct disturbances in GCs of three CVID patients. Our results reflect pathophysiological heterogeneity underlying the reduced circulating pool of post-GC memory B cells and plasmablasts in the three patients. In patient 1, quantitative and qualitative B-cell development in GCs is relatively normal. In patient 2, irregularly shaped GCs are associated with reduced somatic hypermutation (SHM), antigen selection, and class-switching, while in patient 3, high SHM, impaired antigen selection, and class-switching with large single clones imply increased re-cycling of cells within the irregularly shaped GCs. In the lymph nodes of patients 2 and 3, only limited numbers of memory B cells and plasma cells are formed. While reduced numbers of circulating post GC B cells are a general phenomenon in CVID, the integrated approach exemplified distinct defects during GC maturation ranging from near normal morphology and function to severe disturbances with different facets of impaired maturation of memory B cells and/or plasma cells. Integrated dissection of disturbed GC B-cell maturation by histology, flow cytometry, and BCR repertoire analysis contributes to unraveling defects in the essential steps during memory formation. Frontiers Media S.A. 2022-10-06 /pmc/articles/PMC9582261/ /pubmed/36275744 http://dx.doi.org/10.3389/fimmu.2022.959002 Text en Copyright © 2022 van Schouwenburg, Unger, Payne, Kaiser, Pico-Knijnenburg, Pfeiffer, Hausmann, Friedmann, Erbel, Seidl, van Zessen, Stubbs, van der Burg and Warnatz https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology van Schouwenburg, Pauline Unger, Susanne Payne, Kathryn J. Kaiser, Fabian M. P. Pico-Knijnenburg, Ingrid Pfeiffer, Jens Hausmann, Oliver Friedmann, David Erbel, Michelle Seidl, Maximilian van Zessen, David Stubbs, Andrew P. van der Burg, Mirjam Warnatz, Klaus Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency |
title | Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency |
title_full | Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency |
title_fullStr | Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency |
title_full_unstemmed | Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency |
title_short | Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency |
title_sort | deciphering imprints of impaired memory b-cell maturation in germinal centers of three patients with common variable immunodeficiency |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9582261/ https://www.ncbi.nlm.nih.gov/pubmed/36275744 http://dx.doi.org/10.3389/fimmu.2022.959002 |
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