Induced Autoantigen Expression Exacerbates EAE

描述（由申请人提供）：长期以来，微生物病原体被认为是可能导致多发性硬化症（一种中枢神经系统疾病）发展和/或严重程度的环境损害。然而，对这一假设的担忧仍然存在。第一个问题是，没有明确的证据表明任何特定的微生物病原体可以直接导致患者患上这种疾病。这导致人们猜测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，以及暴露于环境因素如传染病。事实上，已经有人提出，病原体可能不会直接引起多发性硬化症，而是导致临床疾病恶化为多发性硬化症的各种形式之一。 第二个关于“病原体引起的恶化”假说的问题是，没有明确的机制来说明任何特定的病原体如何增加疾病的发展。病原体诱导致脑炎性CD 4 + T淋巴细胞活化的机制有多种，包括分子模拟、旁观者活化和表位扩散。有证据支持这些机制中的每一种，并且可能有不止一种参与临床疾病的恶化。显然，如果“病原体诱发的恶化”假设是正确的，这将是一个非常困难的证明单独使用人类受试者。 使用小鼠实验性自身免疫性脑脊髓炎模型，我们建议探索一种可能的机制，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。具体而言，我们将质疑感染后针对晶状体蛋白α-β的自身免疫反应是否可能导致多发性硬化症动物模型中临床疾病的恶化。为了进行这些研究，我们将依靠体外和体内测定来确定细胞如巨噬细胞、树突状细胞和B淋巴细胞是否可以作为自身抗原的专职抗原呈递细胞。还将在外周组织和中枢神经系统中确定自身反应性CD 4 + T淋巴细胞的存在。在这些研究的结论中，我们将清楚地证明在多发性硬化症的动物模型中疾病恶化的“病原体诱导的晶状体蛋白α-β”假说的可验证性。 公共卫生相关性：使用小鼠实验性自身免疫性脑脊髓炎模型，我们建议探索一种可能的机制，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。具体来说，我们将质疑感染后针对晶状体蛋白α-β的自身免疫反应是否可能导致多发性硬化症动物模型中临床疾病的恶化。

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.