Induced Autoantigen Expression Exacerbates EAE

描述(申请人提供)：微生物病原体长期以来一直被认为是对环境的侮辱，可能导致多发性硬化症的发展和/或严重程度，多发性硬化症是一种中枢神经系统疾病。然而，对这一假设的担忧依然存在。第一个担忧是，目前还没有明确的证据表明，任何特定的微生物病原体都可以直接导致患者患上这种疾病。这导致了一种猜测，即多发性硬化症发展为临床疾病可能需要多种因素，包括遗传易感性，以及暴露在传染病等环境因素中。事实上，已经有人提出，病原体可能不会直接导致多发性硬化症，而是会导致临床疾病的恶化成为多发性硬化症的各种形式之一。对这一“病原体诱导的恶化”假说的第二个担忧是，对于任何特定的病原体如何可能加剧正在发展的疾病，没有明确的机制。病原体诱导脑源性CD4+T淋巴细胞活化的机制有多种，包括分子模拟、旁观者激活和表位扩散。有证据支持这些机制中的每一种，而且可能有不止一种机制参与了临床疾病的恶化。显然，如果“病原体诱导的恶化”假说是正确的，那么仅用人类受试者来证明这一点将是极其困难的。利用实验性自身免疫性脑脊髓炎的小鼠模型，我们提出了一种可能的机制，该机制可能有助于这种自身免疫性疾病的“病原体诱导加重”假说。具体地说，我们将质疑在多发性硬化症的动物模型中，感染后针对晶体蛋白α-β的自身免疫反应是否可能导致临床疾病的恶化。为了进行这些研究，我们将依靠体外和体内试验来确定巨噬细胞、树突状细胞和B淋巴细胞等细胞是否可能作为自身抗原的专业抗原呈递细胞。外周组织和中枢神经系统中是否存在具有自身反应性的CD4+T淋巴细胞也将被确定。在这些研究的结论中，我们将在多发性硬化症的动物模型中清楚地证明“病原体诱导的晶体蛋白α-β”假说在多发性硬化症的动物模型中加重疾病的合理性。 公共卫生相关性：利用实验性自身免疫性脑脊髓炎的小鼠模型，我们建议探索一种可能有助于这种自身免疫性疾病的“病原体诱导的恶化”假说的可能机制。具体地说，我们将质疑在多发性硬化症的动物模型中，感染后针对晶体蛋白α-β的自身免疫反应是否可能导致临床疾病的恶化。

DESCRIPTION (provided by applicant): Microbial pathogens have long been implicated as environmental insults which might contribute to the development and/or severity of Multiple Sclerosis, a disease of the central nervous system. However concerns with this hypothesis remain. The first concern is that there has not been a clear demonstration that any particular microbial pathogen can directly cause this disease in patients. This has lead to the speculation that the development of Multiple Sclerosis into a clinical disease might require multiple factors including genetic predisposition, as well as exposure to environmental factors like infectious diseases. In fact, it has been suggested that pathogens may not cause Multiple Sclerosis directly, but rather lead to the exacerbation of clinical disease into one of the various forms of Multiple Sclerosis. A second concern with this "pathogen-induced exacerbation" hypothesis is that there is no clear mechanism as to how any particular pathogen might augment developing disease. A variety of mechanisms have been suggested for pathogen-induced activation of encephalitogenic CD4+ T lymphocytes, including molecular mimicry, bystander activation, and epitope spreading. There is evidence to support each of these mechanisms, and there may be more than one involved in the exacerbation of clinical disease. Clearly, if the "pathogen-induced exacerbation" hypothesis is correct, this will be an extremely difficult one to prove using human subjects alone. Using a mouse model of Experimental Autoimmune Encephalomyelitis, we propose to explore one possible mechanism which might contribute to the "pathogen-induced exacerbation" hypothesis of this autoimmune disease. Specifically, we will question whether an autoimmune response against crystallin alpha-beta following an infection might contribute to the exacerbation of clinical disease in this animal model of multiple sclerosis. To perform these studies, we will rely on in vitro and in vivo assays to determine if cells such as macrophages, dendritic cells, and B lymphocytes might serve as professional antigen presenting cells for autoantigens. The presence of auto-reactive CD4+ T lymphocytes will also be determined in the peripheral tissues and in the central nervous system. At the conclusion of these studies, we will have clearly demonstrated the plausibility of the "pathogen-induced crystallin alpha-beta" hypothesis of exacerbated disease in an animal model of Multiple Sclerosis. PUBLIC HEALTH RELEVANCE: Using a mouse model of Experimental Autoimmune Encephalomyelitis, we propose to explore one possible mechanism which might contribute to the "pathogen-induced exacerbation" hypothesis of this autoimmune disease. Specifically, we will question whether an autoimmune response against crystallin alpha-beta following an infection might contribute to the exacerbation of clinical disease in this animal model of multiple sclerosis.