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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.959002/full |
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| author | Pauline van Schouwenburg Pauline van Schouwenburg Susanne Unger Susanne Unger Susanne Unger Kathryn J. Payne Kathryn J. Payne Kathryn J. Payne Fabian M. P. Kaiser Fabian M. P. Kaiser Ingrid Pico-Knijnenburg Jens Pfeiffer Oliver Hausmann David Friedmann David Friedmann David Friedmann Michelle Erbel Maximilian Seidl Maximilian Seidl David van Zessen Andrew P. Stubbs Mirjam van der Burg Klaus Warnatz Klaus Warnatz |
| author_facet | Pauline van Schouwenburg Pauline van Schouwenburg Susanne Unger Susanne Unger Susanne Unger Kathryn J. Payne Kathryn J. Payne Kathryn J. Payne Fabian M. P. Kaiser Fabian M. P. Kaiser Ingrid Pico-Knijnenburg Jens Pfeiffer Oliver Hausmann David Friedmann David Friedmann David Friedmann Michelle Erbel Maximilian Seidl Maximilian Seidl David van Zessen Andrew P. Stubbs Mirjam van der Burg Klaus Warnatz Klaus Warnatz |
| author_sort | Pauline van Schouwenburg |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T10:11:47Z |
| format | Article |
| id | doaj.art-003fd5f0403547f692216d98a57c9ffd |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T10:11:47Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-003fd5f0403547f692216d98a57c9ffd2022-12-22T03:37:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.959002959002Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiencyPauline van Schouwenburg0Pauline van Schouwenburg1Susanne Unger2Susanne Unger3Susanne Unger4Kathryn J. Payne5Kathryn J. Payne6Kathryn J. Payne7Fabian M. P. Kaiser8Fabian M. P. Kaiser9Ingrid Pico-Knijnenburg10Jens Pfeiffer11Oliver Hausmann12David Friedmann13David Friedmann14David Friedmann15Michelle Erbel16Maximilian Seidl17Maximilian Seidl18David van Zessen19Andrew P. Stubbs20Mirjam van der Burg21Klaus Warnatz22Klaus Warnatz23Laboratory for Pediatric Immunology, Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center (LUMC), Leiden, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyCenter for Chronic Immunodeficiency (CCI), Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyFaculty of Biology, University of Freiburg, Freiburg, GermanyDepartment of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyCenter for Chronic Immunodeficiency (CCI), Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyFaculty of Biology, University of Freiburg, Freiburg, GermanyDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Pediatrics, Erasmus University Medical Center, Rotterdam, NetherlandsLaboratory for Pediatric Immunology, Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center (LUMC), Leiden, NetherlandsDepartment of Otorhinolaryngology- Head and Neck Surgery, University of Freiburg, Freiburg, GermanyLöwenpraxis and Klinik St. Anna, Luzern, SwitzerlandDepartment of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyCenter for Chronic Immunodeficiency (CCI), Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyFaculty of Biology, University of Freiburg, Freiburg, GermanyInstitute of Surgical Pathology, Department of Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyInstitute of Surgical Pathology, Department of Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany0Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany1Clinical Bioinformatics Unit, Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands1Clinical Bioinformatics Unit, Department of Pathology, Erasmus University Medical Center, Rotterdam, NetherlandsLaboratory for Pediatric Immunology, Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center (LUMC), Leiden, NetherlandsDepartment of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyCenter for Chronic Immunodeficiency (CCI), Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyCommon 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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.959002/fullgerminal centercommon variable immunodeficiency (CVID)B-cell differentiationBCR repertoire analysissecondary lymphoid organs (SLO)plasma cell differentiation |
| spellingShingle | Pauline van Schouwenburg Pauline van Schouwenburg Susanne Unger Susanne Unger Susanne Unger Kathryn J. Payne Kathryn J. Payne Kathryn J. Payne Fabian M. P. Kaiser Fabian M. P. Kaiser Ingrid Pico-Knijnenburg Jens Pfeiffer Oliver Hausmann David Friedmann David Friedmann David Friedmann Michelle Erbel Maximilian Seidl Maximilian Seidl David van Zessen Andrew P. Stubbs Mirjam van der Burg Klaus Warnatz Klaus Warnatz Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency Frontiers in Immunology germinal center common variable immunodeficiency (CVID) B-cell differentiation BCR repertoire analysis secondary lymphoid organs (SLO) plasma cell differentiation |
| 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 | germinal center common variable immunodeficiency (CVID) B-cell differentiation BCR repertoire analysis secondary lymphoid organs (SLO) plasma cell differentiation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.959002/full |
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