Function of Fc Receptor Related Intracellular Proteins

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We have identified FcRLA as a new member of the Fc receptor (FcR) and FcR-like (FcRL) gene families of humans and mice. Among hemopoietic cells, FcRLA is a B cell-specific gene. In humans FcRLA is preferentially expressed by germinal center B cells but the expression of FcRLA in the mouse has not yet been well defined. The FcRLA protein has a predicted endoplasmic reticulum (ER)-targeting signal sequence, but lacks N-linked glycosylation sites and a transmembrane region and is an intracellular protein. Our preliminary data suggest that FcRLA is a resident ER protein that associates with immunoglobulin in this organelle. In the Ramos IgM B cell line, which produces both the membrane (m) and secretory (s) forms of m heavy chain, FcRLA preferentially associates with ms. We hypothesize that FcRLA functions early in the biosynthesis of Ig molecules. Definition of the composition and function of the Ig-FcRLA complex is a major goal of our studies. In Aim 1, the specificity and features of the Ig-FcRLA interaction will be defined and other components of the FcRLA-lg complex will be identified. The effect of B cell differentiation stage on the composition of the complex will be determined. In Aim 2, depletion and overexpression of FcRLA in cell lines will be used as a means to identify its normal function. We will examine the expression of FcRLA by normal human B cells at different developmental stages and use ex vivo models to examine the regulation of FcRLA expression. We will also examine FcRLA expression in B cell chronic lymphocytic leukemia and correlate its expression with other markers of disease severity. There is limited information available about the expression of mouse FcRLA and none about its function. In Aim 3, monoclonal antibodies to mouse FcRLA will be produced and used in a comprehensive analysis. We have constructed an Fcrla gene targeted mouse. In Aim 4 we will analyze the effect of FcRLA deficiency on B cell development and function and will generate a transgenic mouse in which FcRLA is overexpressed throughout B cell differentiation to test the effect of ectopic expression. FcRLA may play an essential role in the intracellular quality control system that ensures the correct production of antibodies. Moreover, its expression in human germinal center B cells, where proliferation, antibody class switching and mutation of antibody genes occurs, suggest that defects in FcRLA expression may lead to autoimmunity or immunodeficiency diseases.