Post Translational Modifications in Tolerance and Autoimmunity

描述(申请人提供)：免疫系统的一个主要功能是区分自我和非自我的组织、细胞和蛋白质。我们的实验室专注于了解蛋白质翻译后修饰(PTM)的生物化学及其对免疫功能的影响，这是本提案的主题。已知人体内50%至90%的蛋白质获得翻译后修饰(PTMS)。PTMS改变了蛋白质化学的许多方面，包括一级和三级结构，生物学(和/或酶)功能，以及蛋白降解，这可能是产生免疫原性或耐受性自肽的关键。来自Mamula实验室的研究表明，PTMS可以通过改变免疫过程和呈现方式来产生新的自身抗原。虽然存在许多蛋白质修饰，但目前的工作将集中在那些被创建、放大或改变的蛋白质 系统性红斑狼疮模型中炎症的背景。这些观察结果与最近的研究相叠加，这些研究表明，天然免疫受体在狼疮自身免疫的发展中起着关键作用。例如，外来病原体成分(PAMP)和修饰的自身蛋白(损伤相关分子模式；DAMPS)都将激活Toll样受体(TLR)和Nod样受体(NLR)途径。此外，狼疮的发病机制创造了一种炎性环境，有利于翻译后修饰的产生，这些修饰可能会成为抑制因素。该提案的目标是识别和理解新的蛋白质修饰与NLRs的相互作用，以及在小鼠模型和人类疾病中SLE的炎症途径中的相互作用。总体而言，我们将识别和检查炎症介导的PTMS对免疫原性、细胞内信号通路和狼疮自身免疫发展的影响。目前工作的一个明确目标是不仅识别独特的炎症标志物，而且还识别潜在的治疗途径，包括可能改变疾病进程的PTM修复途径。

DESCRIPTION (provided by applicant): One major function of the immune system is to discriminate between self and non-self tissues, cells, and proteins. Our laboratory has focused on understanding the biochemistry of posttranslational modifications (PTMs) of proteins and their effect on immune function, the topic of the present proposal. It is known that between 50 and 90% of the proteins in the human body acquire posttranslational modification (PTMs). PTMs alter many aspects of protein chemistry, including primary and tertiary structure, biological (and/or enzymatic) functions, and proteolytic degradation that may be critical in generating immunogenic or tolerogenic self-peptides. Studies from the Mamula lab illustrate that PTMs can create new self-antigens by altering immunologic processing and presentation. While many protein modifications exist, the present work will focus on those created, amplified, or altered in the context of inflammation in models of SLE. These observations are superimposed on recent studies showing that innate immune receptors are critical in the development of lupus autoimmunity. For example, both foreign pathogen components (PAMPS) as well as modified self-proteins (Damage Associated Molecular Patterns; DAMPS) will activate both Toll Like Receptor (TLR) and NOD Like Receptor (NLR) pathways. Moreover, the pathogenesis in lupus creates an inflammatory milieu that favors the generation of posttranslational modifications that may become DAMPS. The goal of the proposal is to both identify and understand the interactions of novel protein modifications with NLRs and in inflammatory pathways of SLE in both murine models and in human disease. Overall, we will identify and examine the effects of inflammation-mediated PTMs on immunogenicity, intracellular signaling pathways, and the development of lupus autoimmunity. A clear goal of the present work is to not only identify unique markers of inflammation, but also to identify potential therapeutic pathways, including PTM repair pathways, that may alter the course of disease.