(Taken from the application): In chronic autoimmune diseases the production of autoantibodies and the formation of immune complexes leads to the induction of the inflammatory cascade. Binding of immune complexes to receptors for IgG (Fc-gammaR) on monocytes and neutrophils can contribute to tissue injury through a variety of mechanisms, including. release of inflammatory cytokines. Human Fc-gammaR consist of three families Fc-gammaRI, Fc-gammaRII and Fc-gammaRIII. Within the Fc-gammaRII family several members are differentially regulated and subserve different functions. Fc-gammaRIIa mediates internalization of immune complexes and initiates an inflammatory response. This pathway can be inhibited by coligation with an inhibitory Fc-gammaR (Fc-gammaRIIb). The coordinate expression of stimulatory and inhibitory Fc-gammaR on effector cells likely determines the threshold of immune complex-triggered activation. Alterations in the ratio of stimulatory and inhibitory Fc-gammaR created by gene deletion either accelerate or prevent murine models of autoimmune diseases like rheumatoid arthritis and lupus. Although extensively studied in mouse models, the expression of inhibitory Fc-gammaR and their function in human myeloid cells is unknown. The recent detection by our group of an inhibitory Fc-gammaR, Fc-gammaRIIb2, on human monocytes and neutrophils provides evidence for the presence of a negative regulator of IgG-mediated responses, and suggests that regulation of differential Fc-gammaR expression may influence the extent of immune-complex mediated inflammation and organ damage. Accordingly, the goals of this project are (1) to assess the relative expression of positive and negative signaling FcTR in monocytes and neutrophils and to investigate their modulation by cytokines and (2) to define the functional capacity of Fc-gammaRIIb2 as a negative regulator of cellular activation and immune-complex handling by human phagocytes and the molecular mechanisms that underlie inhibition.
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| Pricop, Luminita; Salmon, Jane E (2002) Redox regulation of Fcgamma receptor-mediated phagocytosis: implications for host defense and tissue injury. Antioxid Redox Signal 4:85-95 |
