Abstract
Both non-immune “natural” and antigen-induced “immune” IgM are important for protection against pathogens and for regulation of immune responses to self-antigens. Since the bona fide IgM Fc receptor (FcµR) was identified in humans by a functional cloning strategy in 2009, the roles of FcµR in these IgM effector functions have begun to be explored. In this short essay, we describe the differences between human and mouse FcµRs in terms of their identification processes, cellular distributions and ligand binding activities with emphasis on our recent findings from the mutational analysis of human FcµR. We have identified at least three sites of human FcµR, i.e., Asn66 in the CDR2, Lys79 to Arg83 in the DE loop and Asn109 in the CDR3, responsible for its constitutive IgM-ligand binding. Results of computational structural modeling analysis are consistent with these mutational data and a model of the ligand binding, Ig-like domain of human FcµR is proposed. Serendipitously, substitution of Glu41 and Met42 in the CDR1 of human FcµR with mouse equivalents Gln and Leu, either single or more prominently in combination, enhances both the receptor expression and IgM binding. These findings would help in the future development of preventive and therapeutic interventions targeting FcµR.
Highlights
Two separate lineages of lymphocytes are generated in their distinctive tissue sites and involved in adaptive immunity
As several review articles on FcμR have already been published elsewhere [10,11,12,13,14,15], in this short essay we focus on our recent findings on the mutational analysis of FcμR to explore the molecular basis for differences in IgM binding observed in human and mouse FcμRs
Similar weak IgM binding results were obtained with murine B cell lines (A20 and CH31) expressing endogenous FcμR. Treatment of these B cell lines with phorbol myristate acetate (PMA) or pre-incubation with stalk region-specific divalent monoclonal antibody (mAb) enhanced their IgM binding, whereas lipopolysaccharide (LPS) stimulation did not. This suggested an involvement of protein kinase C (PKC), a family of serine/threonine protein kinases, or receptor configuration in the ligand binding, but not of myeloid differentiation primary response 88 (MYD88)
Summary
Two separate lineages of lymphocytes are generated in their distinctive tissue sites and involved in adaptive immunity. At day 3 post-transfer, transferred CD19+IgDb B cells from Fcmr-deleted mice exhibited significantly reduced host-derived IgMa binding in vivo as compared with those from control mice [29] These findings suggest different modes of the ligand binding of FcμR in humans and mice, possibly due to unique post-translational modifications for mouse receptor. Treatment of these B cell lines with PMA or pre-incubation with stalk region-specific divalent mAbs enhanced their IgM binding, whereas lipopolysaccharide (LPS) stimulation did not This suggested an involvement of protein kinase C (PKC), a family of serine/threonine protein kinases, or receptor configuration in the ligand binding, but not of myeloid differentiation primary response 88 (MYD88). GFP+ cells are circled with red dotted lines and a black line corresponds with mean fluorescence intensity of PE of FcμR+/GFP+ cells at 0 h for comparison
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