Germinal center-independent, IgM-mediated autoimmunity in sanroque mice lacking Obf1
Germinal center-independent, IgM-mediated autoimmunity in sanroque mice lacking Obf1
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DOI：
10.1038/icb.2013.71
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发表时间：
2014-01-01
影响因子：
4
通讯作者：
Corcoran, Lynn M.
中科院分区：
文献类型：
--
作者：
Chevrier, Stephane;Kratina, Tobias;Corcoran, Lynn M.
编码Roquin 1的Rc 3 h1基因中的点突变的纯合子小鼠，称为sanroque小鼠，发展为严重的抗体介导的自身免疫性疾病。这种疾病是T细胞内在的，由巨噬细胞内在缺陷加剧，并由过度的T滤泡辅助细胞生成和自发性生发中心（GC）形成驱动。这最终导致异常高数量的浆细胞分泌高亲和力自身反应性免疫球蛋白G（IgG）。Obf 1是正常T细胞依赖性抗体应答所需的转录共激活因子，并且在迄今为止测试的所有情况下，它对GC形成都是必不可少的。我们将sanroque小鼠与Obf 1缺失小鼠杂交，以确定sanroque T细胞的过度活跃是否可以驱动Obf 1（-/-）B细胞分化为GC B细胞，或者相反，如果Obf 1缺失可以预防sanroque介导的自身免疫性疾病。令人惊讶的是，虽然sanroque/Obf 1（-/-）小鼠没有形成GC，但它们仍然发展出自身免疫性疾病，并且比sanroque小鼠更快地死亡。该疾病是由自身反应性IgM介导的，其可能来源于Obf 1（-/-）小鼠中预先存在的自身反应性B细胞群，这些细胞对Sanroque CD 4细胞的过度旺盛活性作出反应。
Mice homozygous for a point mutation in the Rc3h1 gene encoding Roquin1, designated sanroque mice, develop a severe antibody-mediated autoimmune condition. The disease is T-cell intrinsic, exacerbated by macrophage-intrinsic defects and driven by excessive T follicular helper cell generation and spontaneous germinal centre (GC) formation. This culminates in abnormally high numbers of plasma cells secreting high-affinity autoreactive immunoglobulin G (IgG). Obf1 is a transcriptional co-activator required for normal T-cell-dependent antibody responses, and it is essential for GC formation under all circumstances so far tested. We crossed sanroque mice with Obf1-null mice to determine whether the hyperactivity of sanroque T cells could drive Obf1(-/-) B cells to differentiate to GC B cells, or conversely, if Obf1 loss would prevent sanroque-mediated autoimmune disease. Surprisingly, while sanroque/Obf1(-/-) mice did not form GC, they still developed autoimmune disease and succumbed even more rapidly than did sanroque mice. The disease was mediated by autoreactive IgM, which may have been derived from a pre-existing population of autoreactive B cells in the Obf1(-/-) mice responding to the over-exuberant activity of sanroque CD4 cells.