Immunoglobulin M (IgM) is the first immunoglobulin to appear after immunization, the first to occur in ontogeny and in phylogeny, and the first to be expressed at the surface of B cells during their differentiation. Most of these properties are a result of the fact that the genes encoding their CH regions are the closest to the VH locus. IgM is built on the classical H2L2 model as either m2k2 or m2^ monomers (see Immunoglobulin Structure). As such, these monomers are expressed at the B- cell surface, where they represent, associated with the Iga-Igb heterodimer signaling module, the B-cell receptor that interacts with the immunogen upon primary immunization. In the serum, most of the circulating IgM is a pentamer, (m2k2)5 or (m2l2)5, in which monomers are covalently disulfide- bonded, a linkage that involves the addition of theJ chain, similar to that present in the IgA dimer. The constant region of the m chain does not contain a hinge region, but instead has an additional C domain, as compared with IgG. IgM has a high content of carbohydrate (10% to 12% by weight) which is bound at N-glycosylation sites of the first three Cm domains.
The basic monomer has a molecular weight of 180 kDa, and the pentamer has a molecular weight of about 970 kDa. Because of their size, circulating IgM subclasses were originally designated as macroglobulins. They are found in a lymphoproliferative disease, the Waldenstrom macroglobulinemia, where they are overexpressed as the result of the malignant amplification of an IgM-producing B-cell clone. In normal serum, IgM accounts for 10% to 15% of the total circulating immunoglobulins. IgM behaves as expected as decavalent antibodies for binding to epitopes, provided that they are located on a small antigen, such as a hapten. On larger antigens, as a result of steric hindrance, IgM pentamers will interact with at most five molecules of antigen. Individual antibody-combining sites are most often of low affinity but the pentamerization potentiates the binding efficiency, demonstrated by the "avidity" of the antibody, a typical immunologist parameter not really defined in mathematical terms. IgM is very efficient in complement binding and thus is highly lytic for cellular targets, which may be bacteria or eukaryotic cells like red blood cells; in this case one uses the term hemolysins, rather than hemagglutinins, when the complement component is not participating in the final reaction.
The so-called natural antibodies are most often of the IgM type. This is the case of natural anti-A and anti-B hemagglutinins, described as the classical alloantibodies responsible for major transfusion incompatibilities. More generally speaking, natural antibodies are frequently endowed with autoimmune recognition properties and thus may bind a large variety of molecules, such as tubulin, actin, double-stranded DNA, and so on. These natural antibodies are harmless and most likely represent the basic repertoire of germline-encoded immunoglobulins, which therefore have nearly no somatic mutations. As a result, their specificity is very low, which makes them bind many antigens, although usually only weakly. Why these antibodies are not aggressive to the organism is still subject to debate, although the combination of two parameters, low affinity and low concentration, is possibly the answer.
As already mentioned, IgM is the first group of isotypes to be produced upon primary immunization. Whenever the antigen is T-dependent, which is the most frequent situation, IgM is rapidly replaced by IgG, which will warrant a better affinity because of the acquisition and selection of somatic hypermutations. Immunization with polysaccharides, which are essentially T-independent antigens, will thus be limited to the production of IgM antibodies. In phylogeny, IgM is also the first group of immunoglobulin classes that have been identified in primitive fishes. It should be mentioned that the classical immune response, with the existence of circulating antibodies, seems to have occurred with the lower vertebrates. Invertebrates have, however, other types of responses to fight very efficiently against pathogens.
