Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
J Autoimmun. 2013 Jun;43:32-43. doi: 10.1016/j.jaut.2013.02.005. Epub 2013 Mar 17.
Multiple sclerosis (MS) is an autoimmune, demyelinating disease and as such, the gold standard of treatment is to selectively suppress the pathogenic autoimmune response without compromising the entire arm of the adaptive immune response. One target of this strategy lying upstream of the pathologic adaptive immune response is the local, innate immune signaling that initiates and drives autoimmunity and sterile injury. High-mobility group box 1 protein (HMGB1) is a ubiquitous nuclear protein that when released from necrotic cells, such as damaged oligodendrocytes in MS lesions, drives pro-inflammatory responses. Here we demonstrate that HMGB1 drives neuroinflammatory responses in experimental autoimmune encephalomyelitis (EAE), a murine model for MS, and that inhibition of HMGB1 signaling ameliorates disease. Specifically i.v. injection of an HMGB1 neutralizing antibody in the C57BL/6 model of chronic EAE or SJL/J model of relapsing-remitting EAE ameliorated clinical disease prophylactically or during ongoing disease, blocked T cell infiltration of the central nervous system, and inhibited systemic CD4(+) T cell responses to myelin epitopes. Additionally, lymphocytes from EAE mice restimulated in vitro in the presence of recombinant HMGB1 exhibited increased proliferation and pro-inflammatory cytokine production, an effect that was blocked by anti-HMGB1 antibody. Similarly recombinant HMGB1 promoted proliferation and pro-inflammatory cytokine production of human peripheral blood mononuclear cells stimulated in vitro, and anti-HMGB1 antibody blocked this effect. These findings indicate that HMGB1 contributes to neuroinflammatory responses that drive EAE pathogenesis and that HMGB1 blockade may be a novel means to selectively disrupt the pro-inflammatory loop that drives MS autoimmunity.
多发性硬化症（MS）是一种自身免疫性脱髓鞘疾病，因此，治疗的金标准是选择性抑制致病性自身免疫反应，而不损害适应性免疫反应的整个分支。这种策略的一个靶点位于病理性适应性免疫反应的上游，即启动和驱动自身免疫和无菌性损伤的局部固有免疫信号。高迁移率族蛋白 B1（HMGB1）是一种广泛存在的核蛋白，当从坏死细胞（如 MS 病变中的受损少突胶质细胞）中释放时，它会驱动促炎反应。在这里，我们证明 HMGB1 在实验性自身免疫性脑脊髓炎（EAE）中驱动神经炎症反应，EAE 是 MS 的一种小鼠模型，并且抑制 HMGB1 信号转导可改善疾病。具体来说，在慢性 EAE 的 C57BL/6 模型或复发缓解型 EAE 的 SJL/J 模型中，静脉注射 HMGB1 中和抗体可预防或在疾病进展期间改善临床疾病，阻断 T 细胞浸润中枢神经系统，并抑制对髓鞘表位的系统性 CD4+T 细胞反应。此外，在存在重组 HMGB1 的情况下，体外重新刺激 EAE 小鼠的淋巴细胞表现出增加的增殖和促炎细胞因子产生，抗 HMGB1 抗体阻断了这种作用。同样，重组 HMGB1 促进体外刺激的人外周血单核细胞的增殖和促炎细胞因子产生，抗 HMGB1 抗体阻断了这种作用。这些发现表明 HMGB1 有助于驱动 EAE 发病机制的神经炎症反应，并且 HMGB1 阻断可能是选择性破坏驱动 MS 自身免疫的促炎循环的新方法。
