Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation

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.

Keywords: B cells; IgA; WASp; X-linked neutropenia; actin; germinal center; plasma cells; primary immunodeficiency.