Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Allergy, Immunology, B cells, X-linked neutropenia, actin, WASp, IgA, germinal center, plasma cells, primary immunodeficiency, WISKOTT-ALDRICH-SYNDROME, SYNDROME PROTEIN-DEFICIENCY, MEDIATED GENE-THERAPY, GERMINAL-CENTER, N-WASP, ACTIN POLYMERIZATION, DIFFERENTIATION, MUTATIONS, ANTIGEN, COMPARTMENT, Animals, B-Lymphocytes, Cell Division, Genetic Diseases, X-Linked, Humans, Immunoglobulin A, Mice, Neutropenia, Plasma Cells, Wiskott-Aldrich Syndrome Protein, 1107 Immunology, 3204 Immunology

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.