The Function of Human AIM in Rheumatic Disease

描述（由申请人提供）： 风湿性关节炎（伊拉）是一种慢性炎症性疾病，影响近1%的成年人。尽管有有效的治疗方法，但它会导致巨大的身体残疾和经济损失。虽然自身免疫T和B淋巴细胞是RA发病机制的一部分，但先天免疫系统已成为强烈关注的焦点，部分原因是靶向滑膜巨噬细胞和成纤维细胞的细胞因子产物的治疗的成功。然而，这种疗法并不是对所有患者都有效。巨噬细胞表达的凋亡抑制剂（AIM）是清道夫受体富含半胱氨酸超家族的成员，最近已被证明是小鼠巨噬细胞和树突状细胞中炎性细胞因子的有效诱导剂，除了其阻断单核细胞和淋巴细胞凋亡的能力之外。人类AIM与小鼠AIM约80%相同，但具有不同的结构特征。该探索性/开发项目的目的是确定人类AIM是否也是人类细胞的有效刺激物，并可抑制其凋亡。两个具体目标将进行调查：1。检测组织和外周血来源的单核细胞表达人AIM蛋白2.确定人AIM诱导细胞因子和炎症介质从人细胞释放以及抑制细胞凋亡的能力。将在患者和对照的血清以及滑液中定量AIM。将表征RA滑膜组织中的AIM表达细胞。将检测重组人AIM刺激血液和滑膜组织单核细胞释放炎性介质以及阻断Fas连接或生长因子退出引起的细胞凋亡的能力。如果成功，这些研究将确定AIM作为治疗自身免疫性和炎症性疾病的新靶点。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (IRA) is a chronic, inflammatory disorder affecting nearly 1% of the adult population. Despite effective therapies, it causes enormous physical disability and financial cost. Although autoimmune T and B lymphocytes are clearly part of the pathogenesis of RA, the innate immune system has become a focus of intense interest, in part due to the success of treatments that target cytokine products of Synovial macrophages and fibroblasts. Such therapies are not effective in all patients, however. Apoptosis Inhibitor expressed in Macrophages (AIM), a member of the Scavenger Receptor Cysteine Rich superfamily, has recently been shown to be a potent inducer of inflammatory cytokines in mouse macrophages and dendritic cells, in addition to its ability to block apoptosis in monocytic and lymphocytic cells. Human AIM is about 80% identical to mouse AIM, yet has distinct structural features. The objective of this exploratory/developmental project is to determine whether human AIM is also a potent stimulator of human cells, and can inhibit their apoptosis. Two specific aims will be investigated: 1. Determine the expression of human AIM protein by monocytic cells derived from tissue and peripheral blood 2. Determine the ability of human AIM to induce cytokine and inflammatory mediator release from human cells, and to inhibit apoptosis AIM will be quantified in serum from patients and controls, as well as in synovial fluid. AIM-expressing cells in RA synovial tissue will be characterized. Recombinant human AIM will be tested for its ability to stimulate moncytic cells from blood and synovial tissue to release inflammatory mediators, and to block apoptosis caused by Fas ligation or growth factor withdrawal. If successful, these studies will identify AIM as a novel target for therapies in autoimmune and inflammatory disease.