The Rac Activator DOCK2 Mediates Plasma Cell Differentiation and IgG Antibody Production.
The Rac Activator DOCK2 Mediates Plasma Cell Differentiation and IgG Antibody Production.
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DOI：
10.3389/fimmu.2018.00243
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发表时间：
2018
影响因子：
7.3
通讯作者：
Fukui Y
中科院分区：
文献类型：
--
作者：
Ushijima M;Uruno T;Nishikimi A;Sanematsu F;Kamikaseda Y;Kunimura K;Sakata D;Okada T;Fukui Y
体液免疫反应的一个标志是抗体的产生。该过程涉及分子和细胞相互作用的复杂级联，包括B细胞受体（BCR）对特异性抗原的识别，其触发B细胞的活化和向浆细胞（PC）的分化。尽管小GT3 Rac的激活与BCR介导的抗原识别有关，但其在体液免疫和上游调节因子中的确切作用仍然难以捉摸。DOCK 2是一种主要在造血细胞中表达的Rac特异性鸟嘌呤核苷酸交换因子。我们发现BCR介导的Rac活化在DOCK 2缺陷的B细胞中几乎完全丧失，导致B细胞中的缺陷在靶细胞膜上扩散，并在界面处维持BCR微簇的生长。当野生型B细胞在IL-4和IL-5存在下用抗IgM F（ab′）2抗体体外刺激时，它们有效地分化为PC。然而，BCR介导的PC分化在DOCK 2缺陷型B细胞中严重受损。当表达确定的BCR特异性的DOCK 2缺陷型B细胞过继转移到小鼠中并用同源抗原攻击时，在体内获得了类似的结果。此外，通过产生条件性基因敲除小鼠，我们发现DOCK 2在B细胞谱系中的表达是安装抗原特异性IgG抗体所必需的。这些结果突出了DOCK 2-Rac轴在PC分化和IgG抗体应答中的重要作用。
A hallmark of humoral immune responses is the production of antibodies. This process involves a complex cascade of molecular and cellular interactions, including recognition of specific antigen by the B cell receptor (BCR), which triggers activation of B cells and differentiation into plasma cells (PCs). Although activation of the small GTPase Rac has been implicated in BCR-mediated antigen recognition, its precise role in humoral immunity and the upstream regulator remain elusive. DOCK2 is a Rac-specific guanine nucleotide exchange factor predominantly expressed in hematopoietic cells. We found that BCR-mediated Rac activation was almost completely lost in DOCK2-deficient B cells, resulting in defects in B cell spreading over the target cell-membrane and sustained growth of BCR microclusters at the interface. When wild-type B cells were stimulated in vitro with anti-IgM F(ab′)2 antibody in the presence of IL-4 and IL-5, they differentiated efficiently into PCs. However, BCR-mediated PC differentiation was severely impaired in the case of DOCK2-deficient B cells. Similar results were obtained in vivo when DOCK2-deficient B cells expressing a defined BCR specificity were adoptively transferred into mice and challenged with the cognate antigen. In addition, by generating the conditional knockout mice, we found that DOCK2 expression in B-cell lineage is required to mount antigen-specific IgG antibody. These results highlight important role of the DOCK2–Rac axis in PC differentiation and IgG antibody responses.
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早发作感染患者的遗传DOCK2缺乏。
DOI：
10.1056/nejmoa1413462
发表时间：
2015-06-18
期刊：
The New England journal of medicine
影响因子：
--
作者：
Dobbs K;Domínguez Conde C;Zhang SY;Parolini S;Audry M;Chou J;Haapaniemi E;Keles S;Bilic I;Okada S;Massaad MJ;Rounioja S;Alwahadneh AM;Serwas NK;Capuder K;Çiftçi E;Felgentreff K;Ohsumi TK;Pedergnana V;Boisson B;Haskoloğlu Ş;Ensari A;Schuster M;Moretta A;Itan Y;Patrizi O;Rozenberg F;Lebon P;Saarela J;Knip M;Petrovski S;Goldstein DB;Parrott RE;Savas B;Schambach A;Tabellini G;Bock C;Chatila TA;Comeau AM;Geha RS;Abel L;Buckley RH;İkincioğulları A;Al-Herz W;Helminen M;Doğu F;Casanova JL;Boztuğ K;Notarangelo LD
通讯作者：
Notarangelo LD
脾脏中的B细胞发育发生在离散的步骤中，并取决于B细胞受体衍生的信号的质量。
影响因子：
15.3
作者：
Loder, F;Mutschler, B;Ray, R J;Paige, C J;Sideras, P;Torres, R;Lamers, M C;Carsetti, R
通讯作者：
Carsetti, R
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：
10.5
作者：
Laurin M;Côté JF
通讯作者：
Côté JF
影响因子：
4.8
作者：
Kulkarni, Kiran;Yang, Jing;Barford, David
通讯作者：
Barford, David