Essential role of TOSO/FAIM3 in intestinal IgM reverse transcytosis

Immunoglobulin M perception by FcμR

“…Besides these lymphocyte-related functions, FcµR has also been implicated in the activation of myeloid cells and their responses to cancer [23][24][25] , although this functional aspect is under debate 26,27 . In addition, FcμR has a role in mucosal immunity, as it can convey the retro-transport of SIgM-antigen complexes back from the mucosa to elicit immune responses 4 . Finally, FcμR is highly expressed on chronic lymphocytic leukemia (CLL) B-cells 2,[28][29][30][31] ; and targeting FcμR using either an IgMtoxin conjugate 32 or the engineered chimeric antigen receptor T cells 33 could provide new CLL treatment strategies.…”

“…IgM can exist in several distinct forms, including monomeric, membrane-bound IgM (mIgM) within the B-cell receptor (BCR) complex, pentameric and hexameric IgM in serum, and secretory IgM on mucosal surface. FcμR/Toso/Faim3, the only IgM-specific receptor in mammals, recognizes different forms of IgM to regulate diverse immune responses [2][3][4] . However, the underlying molecular mechanisms remain unknown.…”

Structural basis for Fc receptor recognition of immunoglobulin M

“…We showed the structural basis for multiple FcμR binding sites on IgM. Multivalent engagement of IgM facilitates capture of soluble IgM or IgM immune complexes by FcμR anchored on cell surfaces, leading to clustering, signalling 16 , and transport 17 through FcμR. Clustering has been found to be essential to induce phosphorylation at the serine and tyrosine residues in the immunoglobulin tail tyrosine (ITT) motif within the cytoplasmic region of FcμR 1 .…”

Physiological and Pathophysiological Roles of IgM Fc Receptor (FcµR) Isoforms

“…In addition to sampling of these heterogenous materials by M cells, immune complexes of secretory IgA (SIgA) and antigens in intestinal lumens have been shown to be reversely transcytosed through the mucosal epithelium by selective binding to receptors, Dectin-1 (C-type lectin) and Siglec-5 (sialic acid binding Ig-like lectin 5), expressed on the apical surface of M cells [ 26 ]. Recently, the same group of authors extended this receptor-mediated, reverse transcytosis to secretory IgM (SIgM) and found that FcµR was expressed on the apical surface of M cells and was involved in the M cell-mediated reverse transcytosis of SIgM/antigen complexes, suggesting a regulatory role of FcµR in mucosal immunity [ 27 ] (see Figure 1 B). However, IgM can bind various proteins other than FcµR (e.g., CD22/siglec-2, tripartite motif-containing protein 21 (TRIM21)/E3 ubiquitin ligase, apoptosis inhibitor of macrophages (AIM)/soluble protein α/CD5L, Fcα/µR, polymeric Ig receptor (pIgR), mannan binding protein, binding Ig protein (Bip)/heat shock protein A5 (HSPA5)/78 kDa glucose-regulated protein (GRP78)).…”

“…From studies of Fcmr -deficient mice, FcµR has a regulatory function in B cell tolerance, as evidenced by their propensity to produce autoantibodies of both IgM and IgG isotypes (see the review in [ 13 ]). In this article, we have introduced our comments or frank opinions about two recent articles describing conflicting views—the regulation of anti-tumor activity by FcµR-bearing phagocytes infiltrating around tumors [ 19 ] and the reverse transcytosis of secretory IgM by FcµR expressed on the apical surface of M cells in Peyer’s patches [ 27 ]. The signal function of the Ig-tail tyrosine (ITT)-like motif seen in the FcµR cytoplasmic tail is now formally demonstrated by substitution of the IgG2a ITT.…”