Department of Pediatrics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
J Immunol. 2012 May 15;188(10):4906-12. doi: 10.4049/jimmunol.1200493. Epub 2012 Apr 6.
Chronic inflammatory demyelinating polyneuropathy is a debilitating autoimmune disease characterized by peripheral nerve demyelination and dysfunction. How the autoimmune response is initiated, identity of provoking Ags, and pathogenic effector mechanisms are not well defined. The autoimmune regulator (Aire) plays a critical role in central tolerance by promoting thymic expression of self-Ags and deletion of self-reactive T cells. In this study, we used mice with hypomorphic Aire function and two patients with Aire mutations to define how Aire deficiency results in spontaneous autoimmune peripheral neuropathy. Autoimmunity against peripheral nerves in both mice and humans targets myelin protein zero, an Ag for which expression is Aire-regulated in the thymus. Consistent with a defect in thymic tolerance, CD4(+) T cells are sufficient to transfer disease in mice and produce IFN-γ in infiltrated peripheral nerves. Our findings suggest that defective Aire-mediated central tolerance to myelin protein zero initiates an autoimmune Th1 effector response toward peripheral nerves.
慢性炎症性脱髓鞘性多发性神经病是一种使人虚弱的自身免疫性疾病，其特征是周围神经脱髓鞘和功能障碍。自身免疫反应如何启动、引发自身抗原的身份以及致病效应机制尚不清楚。自身免疫调节因子 (Aire) 通过促进胸腺中自身抗原的表达和自身反应性 T 细胞的删除，在中枢耐受中发挥关键作用。在这项研究中，我们使用了 Aire 功能减弱的小鼠和两名 Aire 突变患者，以确定 Aire 缺乏如何导致自发性自身免疫性周围神经病。小鼠和人类的自身免疫针对髓鞘蛋白零，这是一种在胸腺中由 Aire 调节表达的抗原。与胸腺耐受缺陷一致，CD4(+) T 细胞足以在小鼠中传递疾病，并在浸润的周围神经中产生 IFN-γ。我们的研究结果表明，髓鞘蛋白零的 Aire 介导的中枢耐受缺陷引发了针对周围神经的自身免疫 Th1 效应反应。
