The IgG Fc receptor Fc3RIIB (RIIB) is an inhibitory FcR that plays a central role in regulation of the activity of many hematopoietic cell types in mice and humans. Several signaling pathways emanating from RIIB are involved in its negative regulatory function. In mice, deficiency or altered expression of RIIB contributes to development of autoimmunity. In humans, a variety of RIIB gene polymorphisms resulting in altered expression levels or membrane distribution of this receptor are strongly associated with susceptibility to the development of several autoimmune diseases. It has also been proposed that RIIB plays a key regulatory role in the immune response to infectious pathogens in humans, a notion supported by a variety of studies on the immune responses of RIIB deficient mice. The mechanistic bases for these effects are incompletely understood. In the previous funding period we gained several new mechanistic insights into how RIIB on B cells regulates immunity and autoimmunity using novel mouse model systems created for this purpose. We found that a B cell RIIB deficiency or expression of an RIIB allele associated with development of autoimmunity resulted in quantitatively enhanced antibody forming cell (AFC), but not germinal center (GC) responses. We also found that expression of RIIB was up regulated on GC B cells from normal mice but not on B cells from autoimmune- prone strains. These and other data have led to the publication of several hypotheses suggesting a central role for RIIB in the regulation of the development of B cell tolerance and memory in the GC and beyond. In the next funding period we propose to test these hypotheses using our established as well as new mouse model systems. The resolution of our findings will be enhanced by the use of experimental readouts of individual B cell activity and antigen receptor structure and specificity.
Autoimmune and infectious diseases remain major health problems in the USA. Improving this situation will require a more detailed understanding of the workings of the immune system. The proposed studies utilize novel mouse models to characterize the mechanism of action of an immune receptor that plays a key role in the prevention of autoimmunity and the regulation of normal immune responses in humans.