ABSTRACT While Fc receptors (FcRs) for switched immunoglobulin isotypes have been extensively characterized, an FcR for IgM (FcμR) has defied genetic identification. By retroviral expression and functional cloning, we have recently identified a cDNA encoding a bona fide FcμR. The FCMR gene encodes a type I membrane protein with the following features: an extracellular region with a single V-set Ig-like domain that has homology to the polymeric Ig receptor (pIgR) and the FcR for IgA and IgM (Fcα/μR), a transmembrane segment, and a relatively long cytoplasmic tail containing conserved serine and tyrosine residues. FcμR is defined as an ~60 kDa transmembrane sialoglycoprotein with exclusive and high affinity binding specificity for the Fc portion of IgM. Unlike other FcRs, the major cell types expressing FcμR are adaptive immune cells, both B and T lymphocytes. Although this receptor was initially designated as Fas apoptotic inhibitory molecule 3 (FAIM3) or TOSO, our results clearly indicate that FcμR per se has no inhibitory activity in Fas-mediated apoptosis and that such inhibition is only achieved when anti-Fas antibody of IgM, but not IgG, isotype is used for inducing apoptosis. Based on these findings, together with FcμR-specific antibodies and Fcmr-deficient mice that we have developed, we will be able to define mechanisms by which the FcμR can regulate the immune system. We hypothesize that FcμR regulates immune responses by binding to IgM antibodies and IgM/antigen immune complexes. This hypothesis will be tested through the following Specific Aims: 1) Expand our recently published initial characterization of the FcμR to more precisely define: (a) its cellular distribution and how its surface expression is regulated, (b) the biochemical events that occur after ligand binding, and (c) its potential association with other membrane proteins; 2) Determine the functional potential of the FcμR in B cells; 3) Employ an Fcmr-deficient mouse model to explore the in vivo function of the FcμR. The data generated from these studies could provide insights into strategies for vaccine development, therapies for inflammatory, autoimmune and immunodeficient disorders, and the pathogenesis of hematological malignancies.

Project Narrative This application tests the hypotheses that the enhancement of immune responses by IgM antibody is mediated by its Fc receptor and that the dysfunction of this FcμR leads to immunological abnormalities.