Department of Neurology, Clinic of Neurology and Institute for Translational Neurology, University of Münster, 48149 Münster, Germany.
Department of Neurology, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany.
Nat Commun. 2016 May 18;7:11626. doi: 10.1038/ncomms11626.
Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
异常的免疫反应是中枢神经系统（CNS）自身免疫的根本原因，包括多发性硬化症（MS）。最近的证据表明凝血和免疫之间的串扰与 CNS 自身免疫有关。在这里，我们确定凝血因子 XII（FXII），即内在凝血级联和激肽释放酶-激肽系统的启动子，是一种特定的免疫细胞调节剂。在复发期间，MS 患者的血浆中存在高水平的 FXII 活性。FXII 的缺乏或药理学阻断使小鼠对实验性自身免疫性脑脊髓炎（MS 的模型）的易感性降低，并且伴随着白细胞介素-17A 产生 T 细胞数量减少。FXII 通过树突状细胞以 CD87 依赖性方式进行免疫激活，涉及细胞内环磷酸腺苷形成的改变。我们的研究表明，血浆凝血级联的一个成员是自身免疫的关键介质。FXII 抑制可能为治疗 MS 和其他免疫相关疾病提供一种策略。
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