Up to 30% of stroke patients experience cognitive decline within one year of their stroke. There are currently no FDA-approved drugs that can prevent post-stroke cognitive decline, in part due to a poor understanding of the mechanisms involved. We have previously demonstrated that a B-lymphocyte response to stroke, marked by IgA+ cells, can cause delayed cognitive dysfunction in mice and that a similar adaptive immune response occurs in the brains of some human stroke patients that suffer from vascular dementia. The stimuli which trigger B-lymphocyte activation following stroke, and their target antigens, are still unknown. Therefore, to learn more about the mechanisms by which B-lymphocytes become activated following stroke we first characterized the temporal kinetics of the B-lymphocyte, T-lymphocyte, and plasma cell (PC) response to stroke in the brain by immunohistochemistry (IHC). We discovered that B-lymphocyte, T-lymphocyte, and plasma cell infiltration within the infarct progressively increases between 2 and 7 weeks after stroke. We then compared the B-lymphocyte response to stroke in WT, MHCII-/-, CD4-/-, and MyD88-/- mice to determine if B-lymphocytes mature into IgA+ PCs through a T-lymphocyte and MyD88 dependent mechanism. Our data from a combination of IHC and flow cytometry indicate that following stroke, a population of IgA+ PCs develops independently of CD4+ helper T-lymphocytes and MyD88 signaling. Finally, sequencing of immunoglobulin genes of individual IgA+ PCs present within the infarct identified a novel population of natural antibodies with few somatic mutations in complementarity-determining regions. These findings indicate that a population of IgA+ PCs develops in the infarct following stroke by B-lymphocytes interacting with one or more thymus independent type 2 (TI-2) antigens, and that they produce IgA natural antibodies.

中文翻译：

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IgA 天然抗体是在中风后 T 细胞非依赖性 B 细胞激活后产生的

多达 30% 的中风患者在中风后一年内会出现认知能力下降。目前没有 FDA 批准的药物可以预防中风后认知能力下降，部分原因是对所涉及的机制了解不足。我们之前已经证明，以 IgA+ 细胞为标志的 B 淋巴细胞对中风的反应会导致小鼠的延迟认知功能障碍，并且在一些患有血管性痴呆的人类中风患者的大脑中也会发生类似的适应性免疫反应。中风后触发 B 淋巴细胞活化的刺激及其靶抗原仍然未知。因此，为了更多地了解中风后 B 淋巴细胞被激活的机制，我们首先对 B 淋巴细胞、T 淋巴细胞的时间动力学进行了表征，和浆细胞 (PC) 通过免疫组织化学 (IHC) 对大脑中风的反应。我们发现梗塞内的 B 淋巴细胞、T 淋巴细胞和浆细胞浸润在中风后 2 至 7 周之间逐渐增加。然后，我们比较了 WT、MHCII-/-、CD4-/- 和 MyD88-/- 小鼠中 B 淋巴细胞对中风的反应，以确定 B 淋巴细胞是否通过 T 淋巴细胞和 MyD88 依赖性机制成熟为 IgA+ PC。我们结合 IHC 和流式细胞术的数据表明，在中风后，IgA+ PC 群的发育独立于 CD4+ 辅助 T 淋巴细胞和 MyD88 信号传导。最后，对梗塞中存在的单个 IgA+ PC 的免疫球蛋白基因进行测序，确定了一个新的天然抗体群，在互补决定区几乎没有体细胞突变。