Role of autoantibodies for long-term outcome and cognitive function following ischemic stroke

自身抗体经常在缺血性脑卒中患者中检测到，然而，它们的（病理）生理作用仍然难以捉摸。在实验性脑卒中中，B细胞以延迟的方式浸润缺血脑组织并形成异位淋巴样结构（ELS）。脑卒中后认知能力下降与脑浸润性B细胞和CNS抗原特异性抗体的发生有关。在小鼠中风模型中，通过阻断ELS的形成可以防止认知能力下降，这强烈提示了中枢神经系统定向的体液免疫反应的病理生理作用。在这里，我们验证了这样一种假设，即这些自身抗体中有几种会导致小鼠和人类的长期中风结果和认知能力下降。为此，我们将利用在慈善基金会建立的几个前瞻性卒中队列，我们将系统地筛选针对中枢神经系统抗原的致病性自身抗体，建立与结果参数的临床相关性。此外，我们将从小鼠脑卒中后ELS来源的浆细胞以及脑卒中后认知能力下降的脑卒中患者脑脊液（CSF）中获得的浆细胞中克隆并产生重组抗体。克隆抗体的功能效应将在小鼠中风模型和细胞培养模型中与联盟的合作伙伴进行评估。

Autoantibodies are frequently detected in patients with ischemic stroke, however, their (patho)physiological role remains elusive. In experimental stroke B cells infiltrate the ischemic brain tissue in a delayed manner and form ectopic lymphoid structures (ELS). Post–stroke cognitive decline was associated with the occurrence of brain-infiltrating B cells and CNS antigen-specific antibodies in stroke patients. Cognitive decline was prevented by blocking ELS formation in a stroke model of mice, which strongly suggests a pathophysiological role of CNS -directed humoral immune responses. Here, we test the hypothesis that several of these autoantibodies contribute to long-term stroke outcome and to cognitive decline in mice and humans. To do so, we will exploit several established prospective stroke cohorts at the Charité, which we will systematically screen for pathogenic autoantibodies targeting CNS antigens, establishing clinical correlations with outcome parameters. In addition, we will clone and generate recombinant antibodies from ELS -derived plasma cells after murine stroke as well as from plasma cells obtained from cerebrospinal fluid (CSF) of stroke patients suffering from post-stroke cognitive decline. Functional effects of cloned antibodies will be assessed in mouse models of stroke and in cell culture models with partners of the consortium.