J Allergy Clin Immunol. 2021 Aug 9:S0091-6749(21)01207-0. doi: 10.1016/j.jaci.2021.07.033. Online ahead of print.
ABSTRACT
BACKGROUND: B cell affinity maturation in germinal center (GC) 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: To investigate the role of B cells in XLN pathogenesis.
METHODS: We examined B cells from six XLN patients of which two have 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 naïve B cells and plasmablasts, but reduced IgA+ B cells and memory B cells, and poor B cell proliferation. Upon immunization, XLN mice had a 2-fold reduction in germinal center B cells in spleen, however, increased generation of plasmablasts and plasma cells. In vitro, XLN B cells showed reduced Ig class switching and aberrant cell division, and increased production of Ig switched plasma cells.
CONCLUSION: These results show that overactive WASp predisposes B cells for pre-mature differentiation into plasma cells at the expense of cell proliferation and Ig class switching.
PMID:34384840 | DOI:10.1016/j.jaci.2021.07.033
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