Post Translational Modifications and Autoimmunity

描述(申请人提供)：这是免疫的主要目的 保护宿主免受传染性病原微生物侵袭的系统。有了这些， 目的记住，淋巴细胞已经被编程为分化自身组织 来自外来抗原的抗原。然而，自身免疫性疾病的出现 正常人群中自身反应性淋巴细胞的存在 说明对豁免权的监管还很不完善。系统性 自身免疫性疾病是淋巴细胞复杂相互作用的产物， 可溶的大分子和自身组织导致疾病的病理。 自身免疫反应通常针对自身抗原中的多个决定因素。 例如，在系统性红斑狼疮(SLE)中，自身抗体是 在小核核糖核蛋白的一些决定因素上 核小体。参与自发性的自身或外源蛋白质 这些自身免疫反应的启动尚不清楚。 我们最近发现了一种新的翻译后蛋白质的能力 修饰，称为异天冬氨酸，赋予自身免疫力 免疫惰性自体多肽。例如，使用 异天冬氨酸形式的SNRNPs可激发典型的人类自身抗体反应 SLE。异天冬氨酸修饰在老年人和应激状态下频繁出现 细胞。这个应用程序将检查狼疮的异天冬氨酸形式的存在。 静息、老化和激活的淋巴细胞群体中的自身抗原和 确定它们规避免疫耐受的能力。第二，我们将审查 免疫异常、淋巴因子反应和细胞内 在不能修复异天冬氨酸修饰(PIMT)的小鼠模型中的信号转导 基因敲除小鼠)。最后，我们将研究自发性狼疮的进展。 人类模型MRL-LPR/LPR-PIMT-/-小鼠的自身免疫和病理学 SLE。 这项申请将定义病毒的生物学和免疫学意义 翻译后蛋白质修饰。总体而言，我们的研究将解决 在自身免疫性疾病的诱发和永久存在中起重要作用的机制。一个 更透彻地了解地球起源中的最早事件 自身免疫可能有助于识别要利用的重要元素 这些疾病的免疫干预。

DESCRIPTION (provided by applicant): It is the principle purpose of the immune system to protect the host from infectious pathogenic microorganisms. With that purpose in mind, lymphocytes have been programmed to differentiate self tissue antigens from foreign antigen. However, the appearance of autoimmune diseases and the presence of autoreactive lymphocytes in the normal population illustrates that the regulation of immunity is far from perfect. Systemic autoimmune diseases 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. For example, in systemic lupus erythematosus (SLE), autoantibodies are directed at a number of determinants on small nuclear ribonucleoproteins (snRNPs) and on nucleosomes. The self or foreign proteins involved in the spontaneous initiation of these autoimmune responses is not known. We have recently identified the ability of a novel post-translational protein modification, termed isoaspartyl, to confer autoimmunity to otherwise immunologically inert self peptides. For example, the immunization with isoaspartyl forms of snRNPs can provoke autoantibody responses typical of human SLE. Isoaspartyl peptide modifications arise frequently in aged and stressed cells. This application will examine the presence of isoaspartyl forms of lupus autoantigens in resting, aged, and activated lymphocyte populations and determine their ability to circumvent immune tolerance. Second, we will examine the immunologic abnormalities, lymphokine responses and intracellular signalling, in murine models unable to repair isoaspartyl modifications (PIMT knockout mice). Finally, we will study the progression of spontaneous lupus autoimmunity and pathology in MRL Lpr/lpr-PIMT-/- mice, a murine model of human SLE. This application will define the biological and immunological implications of post-translational protein modifications. Overall, our studies will address mechanisms important in the induction and perpetuation of autoimmune disease. A more thorough understanding of the earliest events in the genesis of autoimmunity may help identify important elements to exploit for the immunologic intervention of these diseases.