Induced Autoantigen Expression Exacerbates EAE

描述（由申请人提供）：微生物病原体长期以来被认为是一种环境损害，可能导致多发性硬化症（一种中枢神经系统疾病）的发展和/或严重程度。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，以及暴露于传染病等环境因素。事实上，已经有人提出，病原体可能不是直接引起多发性硬化症，而是导致临床疾病恶化为多种形式的多发性硬化症之一。关于“病原体引起的恶化”假说的第二个问题是，没有明确的机制说明任何特定病原体如何加剧正在发展的疾病。病原体诱导脑源性CD4+ T淋巴细胞活化的多种机制已被提出，包括分子模仿、旁观者活化和表位扩散。有证据支持这些机制，可能有不止一个参与临床疾病的恶化。显然，如果“病原体引起的恶化”假设是正确的，那么仅用人类受试者来证明这一假设将是极其困难的。利用实验性自身免疫性脑脊髓炎小鼠模型，我们提出探索一种可能的机制，可能有助于这种自身免疫性疾病的“病原体诱导恶化”假说。具体来说，我们将质疑感染后针对结晶蛋白α - β的自身免疫反应是否会导致多发性硬化症动物模型的临床疾病恶化。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淋巴细胞是否可以作为自身抗原的专业抗原提呈细胞。自身反应性CD4+ T淋巴细胞的存在也将在外周组织和中枢神经系统中确定。在这些研究的结论中，我们将清楚地证明在多发性硬化症动物模型中“病原体诱导的结晶蛋白α - β”加重疾病假说的合理性。

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.