Fc gamma Receptors: deregulation in autoimmune diseases

Receptors for antibodies and immune complexes form a central element in the inflammatory response. Fc gamma receptors are important determinants of susceptibility and severity in autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. Our laboratory is involved in the identification and characterization of acquired and genetic factors that alter the expression and function of Fc receptors in autoimmune diseases. The main goal of our research efforts is to verify these factors as disease markers, and as targets for therapeutic intervention.

Mutations in the regulatory regions of Fc receptors resulting in alterations in expression play a pivotal role in the development of autoimmunity in animal models. We have identified single nucleotide polymorphisms in the promoter of the human FcgRIIA and FcgRIIB genes. FcgRIIB promoter polymorphisms are associated with systemic lupus erythematosus.

Inhibitory FcgRIIB receptors function as suppressors of innate and adaptive immune responses. The functional deficiency of FcgRIIb is associated with increased susceptibility and severity to autoimmune diseases. Inflammatory cytokines downregulate the expression of FcgRIIB and reduce their inhibitory potential in mononuclear phagocytes, contributing to the pathogenesis of chronic inflammation.

The laboratory also studies the dynamics of expression of various Fc receptor isoforms in human dendritic cells. Our results suggest that the expression of activating and inhibitory Fc receptors isoforms varies with the stage of differentiation of dendritic cells. Changes in expression and function of Fc receptors in human dendritic cells can result in altered uptake and presentation of immune complexes and could contribute to the abnormal afferent response in autoimmune diseases. The scope of our research is to use genetic and immunologic approaches to verify and validate mechanisms underlying the role of Fc gamma receptors in autoimmune pathogenesis in the transition from animal models to human disease.