PHAGOCYTOSIS AND MERTK FAMILY OF THE RECEPTOR TYROSINE KINASE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 受体酪氨酸激酶的TAM家族参与先天性和适应性免疫应答。缺乏所有三种受体的小鼠表现出专职或非专职吞噬细胞对凋亡细胞或耗尽的细胞器的清除缺陷。凋亡细胞是自身抗原的主要来源，清除受损导致自身免疫的发展。此外，TAM家族的两个成员Axl和Mertk由巨噬细胞和树突状细胞（DC）表达，并在抗原呈递细胞（APC）活化过程中起负调节作用。自身抗原在突变型APC中的过度呈递导致自身免疫性疾病。我们以前已经表明，TAM三重（以及AM双）突变体产生循环自身抗体，过度反应性眼抗原特异性同基因T细胞群水平升高。在这一阶段的研究中，我们进一步证明了AM双（也三）突变小鼠通过压倒性的Th 1亚型T细胞的超活化发展成眼部自身免疫性疾病。这项研究使我们更接近了解人类葡萄膜炎的分子病因。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The TAM family of receptor tyrosine kinases participates in both innate and adaptive immune response. Mice lacking all three receptors exhibit defective clearance of apoptotic cells or spent cellular organelles by the professional or non-professional phagocytes. Apoptotic cells are a major source of autoantigens and impaired clearance leads to the development of autoimmunity. Furthermore, Axl and Mertk, two members of TAM family, are expressed by macrophage and dendritic cells (DC), and play a negatively regulatory role during the antigen-presenting cell (APC) activation. Overpresentation of autoantigens in the mutant APCs causes autoimmune disorders. We have previously shown that TAM triple (as well as AM double) mutants produce elevated levels of circulating autoantibodies, overreactive ocular antigen-specific syngeneic T-cell population. In this period of study, we further demonstrated that AM double (also triple) mutant mice developed ocular autoimmune disorder through overwhelmingly hyperactivation of Th1 subtype of T cells. This study brings us even closer to understanding of the molecular etiology for human uveitis.