The loss of tolerance to self-antigens with the resultant accumulation of autoantibodies and pathogenic immune complexes is a hallmark of many autoimmune diseases and contributes to their pathological sequelae with resulting morbidity and mortality. Genetic and biochemical studies have identified the inhibitory IgG Fc receptor, FcgRIIB, as a key regulatory molecule in the maintenance of tolerance;its dysregulation is associated with autoimmune diseases such as lupus. We have generated a series of novel mouse strains in which FcgRIIB has been deleted in selected cellular populations. These strains will be utilized to resolve the contributions of this pleiotropic inhibiory receptor in B cell development, autoantibody development and susceptibility to autoimmunity by determining how FcgRIIB expression at different stages of B cell development impacts their development and function in normal and autoimmune susceptible backgrounds, by characterizing the role of FcgRIIB-expression on DCs in the regulation of their maturation and T cell activation in vivo and by defining how FcgRIIB expression regulates the capacity of effector cells, such as regulatory macrophages, mast cells and basophils to modulate inflammation. While suggestive correlative evidence has been accumulated in human populations that inappropriate regulation of FcgRIIB is a likely contributor to disease susceptibility and progression, direct experimental evidence has been lacking. We have developed a mouse model in the last funding period in which human FcR gene expression has been achieved which fully recapitulates the human pattern of expression and functional reconstitution of the diverse functions of this receptor has been achieved. The regulation of the mouse and human FcgRIIB locus will be investigated in this novel mouse strain to determine the inputs that regulate expression of this inhibitory receptor. These strains will be investigated for their ability to regulate FcgRIIB expression and for their interaction with other autoimmune susceptibility factors linked to human diseases.
Novel mouse strains, including those conditionally deleted for FcgRIIB in selected cellular populations as well as those in which the normal and dysregulated FcgRIIB gene are functionally reconstituted has been developed to resolve its role in B cell development and regulation, tolerance and autoimmune disease.
|Ahmed, Alysia A; Giddens, John; Pincetic, Andrew et al. (2014) Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. J Mol Biol 426:3166-79|