Article
Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation
Registro en:
Minghui, He et al. Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation. J. Allergy Clin. Immunol., v. 149, n. 3, p. 1 - 16, Mar. 2022.
0091-6749
10.1016/j.jaci.2021.07.033
Autor
Minghui, He
Saeed, Mezida B.
Record, Julien
Keszei, Marton
Pinho, Lia Gonc¸alves
Fontes, Larissa Vasconcelos
D`Aurelio, Roberta
Vieira, Raissa
Oliveira, Mariana M. S.
Geyer, Chiara
Bohaumilitzky, Lena
Thiemann, Meike
Deordieva, Ekaterina
Buedts, Lieselot
Lopes, Joao Pedro Matias
Pershin, Dmitry
Hammarström, Lennart
Xia, Yu
Zhao, Xiaodong
Cunningham-Rundles, Charlotte
Thrasher, Adrian J.
Burns, Siobhan O.
Almeida, Vinicius Cotta de
Liu, Chaohong
Shcherbina, Anna
Vandenberghe, Peter
Westerberg, Lisa S.
Resumen
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 IgA1 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. (