Anti-chromatin antibodies drive in vivo antigen-specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites
Anti-chromatin antibodies drive in vivo antigen-specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites
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DOI：
10.1002/eji.200737752
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发表时间：
2007-12-01
影响因子：
5.4
通讯作者：
Shlomchik, Mark J.
中科院分区：
文献类型：
--
作者：
Herlands, Robin A.;William, Jacqueline;Shlomchik, Mark J.
在狼疮鼠中自发性自身反应性B细胞活化的一种主要类型是浆母细胞的滤泡外生成。由于反应的随机性和慢性性质，控制这种激活的因素一直难以确定。因此，在体内用已知的自身抗原诱导类似的自身反应性B细胞应答的能力将是解释自身免疫应答如何启动的有力工具。我们在这里报告的建立和表征的系统，启动自身反应性滤泡外B细胞的反应，使用IgG抗染色质抗体，密切反映了自发性反应。我们证明，外源性给予抗染色质抗体，大概是通过与释放的核物质形成免疫复合物，驱动激活类风湿因子B细胞在AM 14 Tg小鼠。抗染色质在T区/红髓边界处激发自身反应性B细胞活化并发育成抗体形成细胞。在BALB/c、MRL/+和MRL/lpr小鼠中同样发生浆母细胞生成，表明诱导的应答不需要自身免疫倾向的遗传背景。重要的是，输注的IgG抗染色质在没有GC反应的情况下诱导体细胞超突变，从而证明了滤泡外体细胞超突变途径。该系统提供了一个窗口的自身抗体反应的启动，并揭示了它的真实发起人。
A dominant type of spontaneous autoreactive B cell activation in murine lupus is the extrafollicular generation of plasmablasts. The factors governing such activation have been difficult to identify due to the stochastic onset and chronic nature of the response. Thus, the ability to induce a similar autoreactive B cell response with a known autoantigen in vivo would be a powerful tool in deciphering how autoimmune responses are initiated. We report here the establishment and characterization of a system to initiate autoreactive extrafollicular B cell responses, using IgG anti-chromatin antibodies, that closely mirrors the spontaneous response. We demonstrate that exogenously administered anti-chromatin antibody, presumably by forming immune complexes with released nuclear material, drives activation of rheumatoid factor B cells in AM14 Tg mice. Anti-chromatin elicits autoreactive B cell activation and development into antibody-forming cells at the T zone/red pulp border. Plasmablast generation occurs equally in BALB/c, MRL/+ and MRL/lpr mice, indicating that an autoimmuneprone genetic background is not required for the induced response. Importantly, infused IgG anti-chromatin induces somatic hypermutation in the absence of a GC response, thus proving the extrafollicular somatic hypermutation pathway. This system provides a window on the initiation of an autoantibody response and reveals authentic initiators of it.