Deletion of WASp and N-WASp in B cells cripples the germinal center response and results in production of IgM autoantibodies.
Deletion of WASp and N-WASp in B cells cripples the germinal center response and results in production of IgM autoantibodies.
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DOI：
10.1016/j.jaut.2015.06.003
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发表时间：
2015-08
影响因子：
12.8
通讯作者：
Westerberg LS
中科院分区：
文献类型：
--
作者：
Dahlberg CI;Torres ML;Petersen SH;Baptista MA;Keszei M;Volpi S;Grasset EK;Karlsson MC;Walter JE;Snapper SB;Notarangelo LD;Westerberg LS
由Wiskott-Aldrich综合征蛋白（WASp）突变引起的体液免疫缺陷与对常见病原体的应答失败和高频率的自身免疫相关。在这里，我们解决了WASp和同源蛋白N-WASp的缺陷如何使免疫应答偏向自身反应性的问题。在B细胞中缺乏WASp或WASp和N-WASp的小鼠形成生殖中心，以增加作为自身抗原来源的凋亡细胞的负荷。但生发中心极性消失，B细胞在生发中心滞留时间延长，增殖减少。WASp缺陷小鼠具有高滴度的自身反应性IgG，而缺乏WASp和N-WASp的B细胞主要产生对自身抗原具有广泛反应性的IgM自身抗体。此外，缺乏WASp和N-WASp的B细胞以降低的频率诱导体细胞超突变。尽管如此，缺乏WASp和N-WASp的表达IgG 1的B细胞获得了特定的高亲和力突变，这意味着在生殖中心选择的BCR信号阈值增加。我们的数据为N-WASp表达单独驱动WASp缺陷型B细胞朝向自身免疫提供了证据。
Humoral immunodeficiency caused by mutations in the Wiskott-Aldrich syndrome protein (WASp) is associated with failure to respond to common pathogens and high frequency of autoimmunity. Here we addressed the question how deficiency in WASp and the homologous protein N-WASp skews the immune response towards autoreactivity. Mice devoid of WASp or both WASp and N-WASp in B cells formed germinal center to increased load of apoptotic cells as a source of autoantigens. However, the germinal centers showed abolished polarity and B cells retained longer and proliferated less in the germinal centers. While WASp-deficient mice had high titers of autoreactive IgG, B cells devoid of both WASp and N-WASp produced mainly IgM autoantibodies with broad reactivity to autoantigens. Moreover, B cells lacking both WASp and N-WASp induced somatic hypermutation at reduced frequency. Despite this, IgG1-expressing B cells devoid of WASp and N-WASp acquired a specific high affinity mutation, implying an increased BCR signaling threshold for selection in germinal centers. Our data provides evidence for that N-WASp expression alone drives WASp-deficient B cells towards autoimmunity.
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影响因子：
56.9
作者：
Allen, Christopher D. C.;Okada, Takaharu;Cyster, Jason G.
通讯作者：
Cyster, Jason G.
影响因子：
14.2
作者：
Bosticardo, Marita;Draghici, Elena;Villa, Anna
通讯作者：
Villa, Anna
影响因子：
8.6
作者：
Adriani, Marsilio;Aoki, Joseph;Schwartzberg, Pamela L.
通讯作者：
Schwartzberg, Pamela L.
影响因子：
20.3
作者：
Meyer-Bahlburg A;Becker-Herman S;Humblet-Baron S;Khim S;Weber M;Bouma G;Thrasher AJ;Batista FD;Rawlings DJ
通讯作者：
Rawlings DJ
影响因子：
7.3
作者：
Catucci M;Castiello MC;Pala F;Bosticardo M;Villa A
通讯作者：
Villa A