Molecular regulation of immune complex disease

描述(申请人提供)：仅在美国就有1400万至2200万人患有自身免疫性疾病。免疫复合体(IC)是包括系统性红斑狼疮和类风湿性关节炎在内的多种自身免疫性疾病发病机制中不可或缺的一部分。IC激活补体系统，与免疫球蛋白G的Fc受体(Fc-Gammar)和多种补体受体相互作用。Fc-Gammar包括两类受体：激活受体和抑制受体，它们的平衡决定了受体连接后的效应反应。阿尔萨斯反应是可溶性IC病的典型实验模型，以水肿、出血和中性粒细胞浸润为特征。 激活Fc-Gammar和补体裂解产物C5a受体(C5aR)在ARTHUS模型的病理过程中是必不可少的。此外，有明确的证据表明，FC-Gammar和C5aR诱导的信号通路之间存在交叉调节。C5aR信号改变了激活和抑制Fc-Gammar之间的平衡。反过来，FC-Gammar信号可以调节C5aR驱动的效应器功能。激活Fc-Gammar和C5aR的结合诱导常驻的腹膜肥大细胞和巨噬细胞释放CXC趋化因子KC和MIP-2，这在该模型的中性粒细胞运输中起着重要作用。值得注意的是，通过抑制性Fc-Gammar发出的信号抑制了中性粒细胞对KC和C5a的趋化，这表明这些趋化物质受体下游保守的信号通路受到了调节。这项研究的长期目标是确定调节IC介导的自身免疫过程的分子机制。这些研究的中心假设是IC介导的炎症通过趋化受体和Fc-Gammar之间的双向相互作用在两个水平上进行调节，包括：(1)通过与趋化受体结合来调节激活Fc-Gammar的效应功能；(2)通过与抑制性Fc-Gammar结合来调节趋化受体效应功能。我们的目标是：(1)明确趋化受体和Fc-Gammar信号在免疫复合体介导的炎症反应调节中的具体作用；(2)确定趋化受体信号调节Fc-Gammar功能的机制；(3)表征抑制性Fc-Gammar信号调节趋化受体功能的机制。

DESCRIPTION (provided by applicant): Autoimmune diseases afflict 14-22 million people in the U.S. alone. Immune complexes (IC) are integral to the pathogenesis of several autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. IC activate the complement system and thus interact both with receptors for Fc of immunoglobulin G (Fc-gammaR) and a variety of complement receptors. Fc-gammaR comprise two classes of receptors: activating and inhibitory receptors, the balance of which defines the effector response after receptor ligation. The prototypic experimental model of soluble IC disease is the Arthus reaction, characterized by edema, hemorrhage and neutrophil infiltration. Activating Fc-gammaR and the complement cleavage product C5a receptor (C5aR) are essential to the pathology in the Arthus model. Further, there is clear evidence of cross-regulation between Fc-gammaR and C5aR induced signaling pathways. C5ar signaling alters the balance between activating and inhibitory Fc-gammaR. In turn, Fc-gammaR signaling can modulate C5aR-driven effector functions. Engagement of activating Fc-gammaR and C5aR induces the release of the CXC chemokines KC and MIP- 2 by resident peritoneal mast cells and macrophages, which play an important role in neutrophil trafficking in this model. Of note, signaling through inhibitory Fc-gammaR inhibits neutrophil chemotaxis towards KC and C5a, suggesting modulation of conserved signaling pathways downstream of the receptors for these chemoattractants. The long term goal of this research is to define the molecular mechanisms that regulate IC-mediated auto-immune processes. The central hypothesis of the studies proposed here is that IC mediated inflammation is regulated at two levels by bidirectional interactions between chemoattractant receptors and Fc-gammaR, including: (1) modulation of the effector functions of activating Fc-gammaR through engagement of chemoattractant receptors; (2) regulation of chemoattractant receptor effector functions through engagement of inhibitory Fc-gammaR. We aim to: (1) define the specific roles of chemoattractant receptors and Fc-gammaR signaling by resident and infiltrating cells in the regulation of immune complex-mediated inflammatory responses; (2) determine the mechanisms by which chemoattractant receptor signaling regulates Fc-gammaR function; and (3) characterize the mechanisms by which inhibitory Fc-gammaR signaling regulates chemoattractant receptor function.