Molecular regulation of immune complex disease

描述（由申请人提供）：自身免疫性疾病仅在美国就困扰着1400万至2200万人。免疫复合物（IC）是几种自身免疫性疾病（包括系统性红斑狼疮和类风湿性关节炎）发病机制的组成部分。IC激活补体系统，从而与免疫球蛋白G的Fc受体（Fc-γ R）和多种补体受体相互作用。Fc-γ R包含两类受体：激活性和抑制性受体，其平衡决定了受体连接后的效应子应答。可溶性IC疾病的原型实验模型是Arthus反应，其特征在于水肿、出血和中性粒细胞浸润。 激活Fc-γ R和补体裂解产物C5 a受体（C5 aR）对Arthus模型中的病理学至关重要。此外，有明确的证据表明Fc-γ R和C5 aR诱导的信号传导途径之间存在交叉调节。C5 ar信号传导改变激活和抑制Fc-γ R之间的平衡。反过来，Fc-γ R信号传导可以调节C5 aR驱动的效应子功能。激活Fc-γ R和C5 aR的结合诱导驻留的腹膜肥大细胞和巨噬细胞释放CXC趋化因子KC和MIP- 2，其在该模型中的中性粒细胞运输中起重要作用。值得注意的是，通过抑制性Fc-γ R的信号传导抑制中性粒细胞对KC和C5 a的趋化性，表明这些趋化因子的受体下游的保守信号传导途径的调节。本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。本文提出的研究的中心假设是IC介导的炎症在两个水平上通过化学引诱物受体和Fc-γ R之间的双向相互作用进行调节，包括：（1）通过化学引诱物受体的接合调节激活Fc-γ R的效应器功能;（2）通过抑制性Fc-γ R的接合调节化学引诱物受体效应器功能。我们的目标是：（1）确定化学引诱物受体和驻留细胞和浸润细胞的Fc-γ R信号传导在免疫复合物介导的炎症反应调节中的特定作用;（2）确定化学引诱物受体信号传导调节Fc-γ R功能的机制;（3）表征抑制性Fc-γ R信号传导调节化学引诱物受体功能的机制。

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.