Emerging Functions of Natural IgM and Its Fc Receptor FCMR in Immune Homeostasis

Abstract

Most natural IgM antibodies are encoded by germline Ig sequences and are produced in large quantities by both mice and humans in the absence of intentional immunization. Natural IgM are reactive with many conserved epitopes, including those shared by microorganisms and autoantigens. As a result, these antibodies play important roles in clearing intruding pathogens, as well as apoptotic/necrotic cells and otherwise damaged tissues. While natural IgM binds to target structures with low affinity due to a lack of significant selection by somatic hypermutation, its pentameric structure with 10 antigen-binding sites enables these antibodies to bind multivalent target antigens with high avidity. Opsonization of antigen complexed with IgM is mediated by cell surface Fc receptors. While the existence of Fc alpha/mu receptor has been known for some time, only recently has the Fc receptor specific for IgM (FCMR) been identified. In this review, we focus on our current understandings of how natural IgM and FCMR regulate the immune system and maintain homeostasis under physiological and pathological conditions.

Secreted IgM: New tricks for an old molecule

“…In addition, low expression has also been observed on granulocytes, macrophages, and dendritic cells in mice. In humans, the receptor was shown to be expressed on T and NK cells, but not on myeloid cells . Expression on human T cells was higher on α/β T cells than γ/δ T cells, and higher on CD4+ than on CD8+ T cells .…”

“…All jawed vertebrates express IgM, including amphibians, reptiles, shark, fish, and mammals, whereas jawless vertebrates, such as hagfish and lamprey, lack IgM . IgM production can be detected very early, in humans as early as week 20 of gestation .…”

“…A possible mechanistic explanation for its polyreactivity is that natural IgM is encoded by V regions containing higher frequencies of tyrosine and serine residues, which contain hydroxylated side chains that enable IgM greater binding flexibility (reviewed in Ref. ). With regard to the specificity of IgM, in addition to the antigens mentioned above, natural IgM also binds to various epitopes on phosphorylcholine and other phospholipids, carbohydrates such as phosphatidylcholine, ssDNA and dsDNA, oxidized LDL, and certain PAMPS .…”

Position of human blood group O(H) and phenotype‐determining enzymes in growth and infectious disease

“…Finally, the human blood group A–specific α1‐3‐ N ‐acetylgalactosaminyltransferase and blood group B‐specific α1‐3‐galactosyltransferase, expressed by plasma proteins might, together with serine/threonine kinases produced by P. falciparum , provide the essential metabolic condition for trans‐species synthesis of mucin‐type adhesion proteins and GalNAc‐1‐ O ‐Ser/Thr or Tn glycosylation in blood group A, and Gal‐1‐3GalNAc‐1‐ O ‐Ser/Thr or T 24 glycosylation in the blood group B. This proposed glycosidic accommodation of plasma proteins is not a lock‐and‐key event but a dynamic process, dominated by continuous synthesis of α2‐macroglobulin and its functional synergism with the structurally related nonimmune IgM; with this molecule being engaged in the adhesion process via its Fc region and O ‐glycosylation of germ‐line serine residues, it obviously cannot induce rosetting on its own, whereas α2‐macroglobulin crosslinks multiple PfEMP1 molecules and, thus, is an integral component of rosette formation. The differences in the life cycle of the parasite during uncomplicated malaria in blood group O(H) individuals and life‐threatening disease in blood group A and B individuals remain unknown.…”

Natural IgM and the Development of B Cell-Mediated Autoimmune Diseases

“…106 Three independent lines of FcμR deficient mice have been generated to study the functions of the FcμR. 103,107–110 FcμR was reported to be expressed relatively early in development, the pre-B cell stage. Together with the increased serum IgG autoantibody titers in FcμR −/− mice, the data suggest that natural IgM - FcμR interactions may regulate B-cell homeostasis and development.…”