Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation
| Autor: | E.A. Deordieva, Lieselot Buedts, Lisa S. Westerberg, Chaohong Liu, Roberta D’Aulerio, Julien Record, Mezida B. Saeed, Peter Vandenberghe, Siobhan O. Burns, Lennart Hammarström, Marton Keszei, Larissa Vasconcelos-Fontes, Yu Xia, Chiara Geyer, Mariana M.S. Oliveira, Charlotte Cunningham-Rundles, Anna Shcherbina, Minghui He, Vinicius Cotta-de-Almeida, Lia Gonçalves Pinho, Lena Bohaumilitzky, Meike Thiemann, Dmitry Pershin, Rhaissa Vieira, Joao Pedro Lopes, Xiaodong Zhao, Adrian J. Thrasher |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Neutropenia
Wiskott–Aldrich syndrome Plasma Cells Immunology Naive B cell macromolecular substances Plasma cell Biology primary immunodeficiency plasma cells Affinity maturation Mice X-linked neutropenia medicine Animals Humans Immunology and Allergy B cell B-Lymphocytes B cells Cell growth Germinal center Genetic Diseases X-Linked WASp medicine.disease Molecular biology Immunoglobulin A medicine.anatomical_structure Immunoglobulin class switching germinal center actin Cell Division Wiskott-Aldrich Syndrome Protein IgA |
| Popis: | BACKGROUND: B-cell affinity maturation in germinal center relies on regulated actin dynamics for cell migration and cell-to-cell communication. Activating mutations in the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASp) cause X-linked neutropenia (XLN) with reduced serum level of IgA. OBJECTIVE: We investigated the role of B cells in XLN pathogenesis. METHODS: We examined B cells from 6 XLN patients, 2 of whom had novel R268W and S271F mutations in WASp. By using immunized XLN mouse models that carry the corresponding patient mutations, WASp L272P or WASp I296T, we examined the B-cell response. RESULTS: XLN patients had normal naive B cells and plasmablasts, but reduced IgA+ B cells and memory B cells, and poor B-cell proliferation. On immunization, XLN mice had a 2-fold reduction in germinal center B cells in spleen, but with increased generation of plasmablasts and plasma cells. In vitro, XLN B cells showed reduced immunoglobulin class switching and aberrant cell division as well as increased production of immunoglobulin-switched plasma cells. CONCLUSIONS: Overactive WASp predisposes B cells for premature differentiation into plasma cells at the expense of cell proliferation and immunoglobulin class switching. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:149 issue:3 pages:1069-1084 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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