Molecular regulation of immune complex disease

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

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.