The Journal of allergy and clinical immunology · 2021
Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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He Minghui, Saeed Mezida B, Record Julien, Keszei Marton, Gonçalves Pinho Lia, Vasconcelos-Fontes Larissa, D'Aulerio Roberta, Vieira Rhaissa, Oliveira Mariana M S, Geyer Chiara, Bohaumilitzky Lena, Thiemann Meike, Deordieva Ekaterina, Buedts Lieselot, Matias Lopes Joao Pedro, Pershin Dmitry, Hammarström Lennart, Xia Yu, Zhao Xiaodong, Cunningham-Rundles Charlotte, Thrasher Adrian J, Burns Siobhan O, Cotta-de-Almeida Vinicius, Liu Chaohong, Shcherbina Anna, Vandenberghe Peter, Westerberg Lisa S
Аннотация
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.
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.