Post Translational Modifications and Autoimmunity

说明（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害的系统。与 考虑到目的，淋巴细胞已被编程以区分自身组织 来自外源抗原的抗原。然而，自身免疫性疾病的出现 以及正常人群中自身反应性淋巴细胞的存在 这表明，对免疫力的监管远非完美。系统性 自身免疫疾病是淋巴细胞复杂相互作用的产物， 可溶性大分子和导致疾病病理学的自身组织。 自身免疫反应通常靶向自身抗原内的多个决定簇。 例如，在系统性红斑狼疮（SLE）中，自身抗体被定向于 在小核核糖核蛋白（snRNP）和 核小体参与自发免疫的自身或外源蛋白质 这些自身免疫应答的起始是未知的。 我们最近发现了一种新的翻译后蛋白的能力， 修饰，称为异戊酰基，以赋予自身免疫力，否则 免疫惰性自身肽。例如，免疫接种 snRNP的异戊酰基形式可以引起人类典型的自身抗体应答， SLE。异戊酰肽修饰经常出现在老年人和应激 细胞这个应用程序将检查是否存在异戊酰形式的狼疮 静息、老化和活化淋巴细胞群中的自身抗原， 决定了它们规避免疫耐受的能力。第二，我们将研究 免疫异常、淋巴因子反应和细胞内 信号传导，在不能修复异戊酰修饰的鼠模型（PIMT）中 敲除小鼠）。最后，我们将研究自发性狼疮的进展 MRL Lpr/lpr-PIMT-/-小鼠中的自身免疫和病理学， SLE。 本申请将定义以下的生物学和免疫学含义： 翻译后蛋白质修饰。总的来说，我们的研究将解决 在自身免疫性疾病的诱导和延续中起重要作用的机制。一 更彻底地了解宇宙起源中最早的事件 自身免疫可能有助于确定利用的重要因素， 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.