1. Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation
- Author
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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, and Adrian J. Thrasher
- Subjects
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 - Abstract
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
- Published
- 2022