ROLE OF SELF PEPTIDES IN TOLERANCE AND AUTOIMMUNITY

系统性自身免疫性疾病是以下因素复杂相互作用的产物： 淋巴细胞、可溶性大分子和自身组织， 疾病的病理学自身免疫反应通常针对多个 自身抗原内的决定簇， 蔓延例如，在系统性红斑狼疮（SLE）中， 自身抗体直接作用于细胞核上的许多决定簇， 核糖核蛋白（snRNP）和核小体。在小鼠模型中， 人多发性硬化症、实验性自身免疫性脑脊髓炎（EAE）， 由髓鞘碱性蛋白的单个自身肽引起的疾病 很快就会在蛋白质上的多个位点上扩散， 疾病表位扩散的概念是一个至关重要的 免疫系统的一种机制，可以增强清除重要或 细菌感染或抵抗肿瘤挑战。比如最 有效的手段，通过它清除感染剂是直接 免疫攻击，因为他们的网站上的目标尽可能。一 本提案的目的是研究B淋巴细胞的作用， 自身抗原呈递细胞，在自身免疫的传播中。是B 对短的自身肽特异的细胞能够呈现多样的 自身抗原决定簇引发多种T细胞自身免疫 回应？ 在MHC分子背景下呈递的自身抗原的类型是 在免疫反应的许多方面至关重要，从积极和消极的 选择在胸腺中的自身免疫T细胞的激活， 外围我们最近发现了一种新的翻译后蛋白 赋予免疫原性的修饰， 惰性自身肽。本建议的第二个目标将审查 这些翻译后修饰在淋巴细胞中的表达 以及修饰肽在SLE和EAE自身免疫中的作用。 总的来说，我们的研究将解决在诱导中重要的机制， 和自身免疫性疾病的延续。的更透彻理解 自身免疫性疾病发生的早期事件可能有助于识别 重要的因素，利用这些免疫干预， 疾病

Systematic autoimmune disease are the product of a complex interaction of lymphocytes, soluble macromolecules, and self tissues leading to the pathology of disease. Autoimmune responses often target multiple determinants within an autoantigen in a phenomenon known as epitope spreading. For example, in systemic lupus erythematosus (SLE), autoantibodies are direct at a number of determinants on small nuclear ribonucleoproteins (snRNPs) and on nucleosomes. In the murine model of human multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), disease that is induced with a single self peptide of myelin basic protein soon diversities to multiple sites on the protein during the course of disease. The concept of epitope spreading is a fundamentally important mechanism of the immune system that enhances the ability to clear vital or bacterial infection or to resist tumor challenges. For example, the most efficient means by which to clear an infectious agent is to direct an immune attack against as they sites on the target as possible. One objective of this proposal is to examine the role of B lymphocytes, as autoantigen presenting cells, in the spreading of autoimmunity. Are B cells specific for a short self peptides able to present diverse autoantigenic determinants in eliciting a diverse T cell autoimmune response? The types of self antigens presented in the context of MHC molecules are critical in many aspects of immune responses, from positive and negative selection in the thymus to the activation of autoimmune T cells in the periphery. We have recently identified a novel post translational protein modification that confers immunogenicity to otherwise immunologically inert self peptides. The second objective of this proposal will examine the expression of these post translational modifications in lymphocytes and the role od modified peptides in the autoimmunity of SLE and EAE. Overall, our studies will address mechanisms important in the induction and perpetuation of autoimmune disease. A more thorough understanding of the earlier events in the genesis of autoimmune disease may help identify important elements to exploit for the immunologic intervention of these diseases.