Molecular regulation of immune complex disease

免疫复合物疾病的分子调控

• 批准号: 7533994
• 负责人: JOERG KOEHL
• 金额: $ 34.65万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533994
• 关键词: Address; Affinity; Alternative Complement Pathway; Antigen-Antibody Complex; Arthus Reaction; Autoimmune Diseases; Autoimmune Process; Binding; C5a anaphylatoxin receptor; CXC Chemokines; Cells; Chemotactic Factors; Chemotaxis; Complement; Complement 5a; Complement Activation; Complement Receptor; Complex; Data; Dendritic Cells; Deposition; Edema; Equilibrium; Experimental Models; Fc Immunoglobulins; Fc Receptor; G-Protein-Coupled Receptors; Generations; Glomerulonephritis; Goals; Hemorrhage; IL8RB gene; ITAM; ITIM; Immune; Immune Complex Diseases; Immunoglobulin G; Inflammation; Inflammatory; Inflammatory Response; Lead; Ligand Binding; Ligation; Macrophage-1 Antigen; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Myeloid Cell Activation; Myeloid Cells; Natural Killer Cells; Neutrophil Infiltration; Pathogenesis; Pathology; Pattern; Peritoneal; Peritoneal Macrophages; Play; Population; Process; Production; Receptor Signaling; Regulation; Research; Research Personnel; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Site; System; Systemic Lupus Erythematosus; Tissues; Vasculitis; chemokine; experimental analysis; fMet-Leu-Phe receptor; insight; macrophage; macrophage inflammatory protein 2; mast cell; neutrophil; programs; receptor; receptor function; response; trafficking

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 activates the complement system and thus interacts both with receptors for Fc of immunoglobulin G (Fc(R) and a variety of complement receptors. FcgammaR 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 FcgammaR 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 FcgammaR and C5aR induced signaling pathways. C5aR signaling alters the balance between activating and inhibitory FcgammaR. In turn, FcgammaR signaling can modulate C5aR-driven effector functions. Engagement of activating FcgammaR 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 FcgammaR 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 autoimmune 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(R, including: (1) modulation of the effector functions of activating Fc(R through engagement of chemoattractant receptors; (2) regulation of chemoattractant receptor effector functions through engagement of inhibitory Fc(R. We aim to: (1) define the specific roles of chemoattractant receptors and Fc(R 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(R function; and (3) characterize the mechanisms by which inhibitory FcgammaR signaling regulates chemoattractant receptor function.

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(R))和多种补体受体相互作用。FcGammaR包括两类受体：激活受体和抑制受体，受体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FcGammaR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，FcGammaR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FcGammaR之间的平衡。反过来，FcGammaR信号可以调节C5aR驱动的效应器功能。激活FcGammaR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FcGammaR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(R)之间的双向相互作用在两个水平上进行调节，包括：(1)通过参与趋化受体来调节激活Fc(R)的效应功能；(2)通过参与抑制性Fc(R)来调节趋化受体效应功能。我们的目的是：(1)明确趋化受体和Fc(R)信号在调节免疫复合体介导的炎症反应中的具体作用；(2)确定趋化受体信号调节Fc(R)功能的机制；以及(3)研究抑制性FcGammaR信号调节趋化受体功能的机制。