Although Fc receptors (FcRs) for switched immunoglobulin (Ig) isotypes have been extensively characterized, FcR for IgM (FcμR) has defied identification. By retroviral expression and functional cloning, we have identified a complementary DNA (cDNA) encoding a bona fide FcμR in human B-lineage cDNA libraries. FcμR is defined as a transmembrane sialoglycoprotein of ∼60 kD, which contains an extracellular Ig-like domain homologous to two other IgM-binding receptors (polymeric Ig receptor and Fcα/μR) but exhibits an exclusive Fcμ-binding specificity. The cytoplasmic tail of FcμR contains conserved Ser and Tyr residues, but none of the Tyr residues match the immunoreceptor tyrosine-based activation, inhibitory, or switch motifs. Unlike other FcRs, the major cell types expressing FcμR are adaptive immune cells, including B and T lymphocytes. After antigen-receptor ligation or phorbol myristate acetate stimulation, FcμR expression was up-regulated on B cells but was down-modulated on T cells, suggesting differential regulation of FcμR expression during B and T cell activation. Although this receptor was initially designated as Fas apoptotic inhibitory molecule 3, or TOSO, our results 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 an IgM but not IgG isotype is used for inducing apoptosis.
Cell surface Fc receptor for IgM antibody (FcμR) is the most recently identified member among FcRs. We determined the cellular distribution of mouse FcμR and the functional consequences of Fcmr disruption. Surface FcμR expression was restricted to B-lineage cells, from immature B to plasma cells, except for a transient downmodulation during germinal center reactions. Fcmr ablation had no significant effect on overall B-and T-cell development, but led to a reduction of marginal zone B cells and an increase in splenic B1 B cells. Preimmune serum IgM in mutant mice was significantly elevated as were natural autoantibodies. When immunized with live attenuated pneumococci, mutant mice mounted robust antibody responses against phosphorylcholine, but not protein, determinants compared with wild-type mice. By contrast, upon immunization with a hapten-carrier conjugate, nitrophenyl-coupled chicken γ-globulin (NP-CGG), the mutant mice had a diminished primary IgG1 response to both NP and CGG. These findings suggest that FcμR has an important role in IgM homeostasis and regulation of humoral immune responses.natural antibody | B-cell tolerance | B-cell subset | autoimmunity
The association of an IgM-Fc receptor (FcR) with chronic lymphocytic leukemia (CLL) was suggested more than 30 years ago, but its authenticity has never been formally addressed. We exam IntroductionChronic lymphocytic leukemia (CLL) is the most common leukemia of adults in Western countries and accounts for ϳ 30% of all cases of leukemia in the United States. It is a heterogeneous leukemia that is thought to originate from antigen-stimulated B cells that escape from normal cell death mechanisms. 1,2 Survival of CLL patients ranges from a few years to several decades. The most reliable marker thus far for predicting the prognosis of CLL is the mutation status in the immunoglobulin heavy chain variable region (IGHV). Unmutated (UM)-CLL is aggressive and mutated (MT)-CLL is more indolent. [3][4][5] Because DNA sequencing is not practical for most clinical laboratories, various cell surface and intracellular proteins have been explored as potential surrogate markers. ZAP-70, a Syk family tyrosine kinase normally expressed in T cells, has proved to be a very good indicator for UM-CLL, but the required intracellular staining is technically challenging and results in diagnostic inconsistency among clinical laboratories. [6][7][8][9][10][11] Other markers, including membrane proteins (eg, CD38, Fc receptor-like protein 2) and serum proteins (eg, thymidine kinase, soluble CD23, and 2-microglobulin), also have been studied as surrogate prognostic indicators. 3,4,[12][13][14][15][16][17] The association of the IgM Fc receptor (FcR) with CLL has long been suggested based on the ability of CLL cells to form rosettes with IgM-coated erythrocytes. [18][19][20][21][22] Unfortunately, this early intriguing suggestion was not pursued thereafter, probably because of uncertainties with such a crude detection procedure. During the course of analysis of B-cell activation antigens with the BAC-1 mouse IgM monoclonal antibody (mAb), we serendipitously found an IgM-binding protein of ϳ 60 kDa that was expressed on CLL B cells and activated normal B cells by immunofluorescence and biochemical analyses using various IgM ligands. 23,24 The gene encoding an authentic FcR has defied identification until our recent discovery of a bona fide FcR cDNA in the B-lineage libraries, including one library derived from CLL B cells. 25 Surprisingly, the corresponding FCMR gene had been already reported as TOSO or Fas apoptosis inhibitory molecule 3 (FAIM3). 26 Notably, the reported inhibition of apoptosis was based on an assay in which apoptosis was induced by ligation of Fas on the Jurkat T-cell line with a mouse IgM mAb (CH11). Our results indicated that FcR per se had no inhibitory activity in Fas-mediated apoptosis and that such inhibition was only achieved when anti-Fas mAb of an IgM but not IgG isotype was used for inducing apoptosis. 25 This incorrect designation has led to the misconception that enhanced FAIM3/TOSO expression by CLL cells may be linked to their resistance to cell death mechanisms. [27][28][29] Here, we examined the expression...
IgM exists as both a monomer on the surface of B cells and a pentamer secreted by plasma cells. Both preimmune “natural” and antigen-induced “immune” IgM antibodies are important for protective immunity and for immune regulation of autoimmune processes by recognizing pathogens and self-antigens. Effector proteins interacting with the Fc portion of IgM, such as complement and complement receptors, have thus far been proposed but fail to fully account for the IgM-mediated protection and regulation. A major reason for this deficit in our understanding of IgM function seems to be lack of data on a long elusive Fc receptor for IgM (FcμR). We have recently identified a bona fide FcμR in both humans and mice. In this article we briefly review what we have learned so far about FcμR.
The IgM-Fc receptor (FcμR) is involved in IgM homeostasis as evidenced by increased pre-immune serum IgM and natural auto-antibodies of both IgM and IgG isotypes in Fcmr-deficient C57BL/6 (B6) mice. To determine the impact of Fcmr-ablation on autoimmunity, we introduced the Fcmr null mutation onto the Fas-deficient autoimmune-prone B6.MRL Fas (lpr/lpr) mouse background (B6/lpr). Both IgM and IgG auto-antibodies against dsDNA or chromatin appeared earlier in FcμR(-) B6/lpr than FcμR(+) B6/lpr mice, but this difference became less pronounced with age. Splenic B2 cells, which were 2-fold elevated in FcμR(+) B6/lpr mice, were reduced to normal B6 levels in FcμR(-) B6/lpr mice, whereas splenic B1 cells were comparable in both groups of B6/lpr mice. By contrast, marginal zone (MZ) B cells were markedly reduced in FcμR(-) B6/lpr mice compared with either FcμR(+) B6/lpr or wild type (WT) B6 mice. This reduction appeared to result from rapid differentiation of MZ B cells into plasma cells in the absence of FcμR, as IgM antibody to a Smith (Sm) antigen, to which MZ B cells are known to preferentially respond, was greatly increased in both groups (B6/lpr and B6) of FcμR(-) mice compared with FcμR(+) B6/lpr or B6 mice. Mott cells, aberrant plasma cells with intra-cytoplasmic inclusions, were also increased in the absence of FcμR. Despite these abnormalities, the severity of renal pathology and function and survival were all indistinguishable between FcμR(-) and FcμR(+) B6/lpr mice. Collectively, these findings suggest that FcμR plays important roles in the regulation of auto-antibody production, Mott cell formation and the differentiation of MZ B cells into plasma cells in B6.MRL Fas (lpr/lpr) mice.
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