Katz-Levy Y, Neville K L, Girvin A M, Vanderlugt C L, Pope J G, Tan L J, Miller S D
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Clin Invest. 1999 Sep;104(5):599-610. doi: 10.1172/JCI7292.
The mechanisms underlying the initiation of virus-induced autoimmune disease are not well understood. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a mouse model of multiple sclerosis, is initiated by TMEV-specific CD4(+) T cells targeting virally infected central nervous system-resident (CNS-resident) antigen-presenting cells (APCs), leading to chronic activation of myelin epitope-specific CD4(+) T cells via epitope spreading. Here we show that F4/80(+), I-A(s+), CD45(+) macrophages/microglia isolated from the CNS of TMEV-infected SJL mice have the ability to endogenously process and present virus epitopes at both acute and chronic stages of the disease. Relevant to the initiation of virus-induced autoimmune disease, only CNS APCs isolated from TMEV-infected mice with preexisting myelin damage, not those isolated from naive mice or mice with acute disease, were able to endogenously present a variety of proteolipid protein epitopes to specific Th1 lines. These results offer a mechanism by which localized virus-induced, T cell-mediated inflammatory myelin destruction leads to the recruitment/activation of CNS-resident APCs that can process and present endogenous self epitopes to autoantigen-specific T cells, and thus provide a mechanistic basis by which epitope spreading occurs.
病毒诱导的自身免疫性疾病起始的潜在机制尚未完全明确。Theiler氏鼠脑脊髓炎病毒诱导的脱髓鞘疾病（TMEV-IDD）是一种多发性硬化症的小鼠模型，由靶向病毒感染的中枢神经系统驻留（CNS驻留）抗原呈递细胞（APC）的TMEV特异性CD4(+) T细胞引发，通过表位扩展导致髓鞘表位特异性CD4(+) T细胞的慢性激活。在此，我们表明，从感染TMEV的SJL小鼠中枢神经系统分离出的F4/80(+)、I-A(s+)、CD45(+)巨噬细胞/小胶质细胞在疾病的急性和慢性阶段均具有内源性加工和呈递病毒表位的能力。与病毒诱导的自身免疫性疾病的起始相关，只有从已存在髓鞘损伤的感染TMEV的小鼠中分离出的中枢神经系统APC，而不是从未感染小鼠或患有急性疾病的小鼠中分离出的APC，能够向内源性特异性Th1细胞系呈递多种蛋白脂蛋白表位。这些结果提供了一种机制，通过该机制局部病毒诱导的、T细胞介导的炎性髓鞘破坏导致CNS驻留APC的募集/激活，这些APC能够加工并将内源性自身表位呈递给自身抗原特异性T细胞，从而为表位扩展的发生提供了一个机制基础。
