IgM, previously known as y-macroglobulin, exists as a variable size polymer of identical subunits. Each subunit (monomer) displays a molecular weight of 180 kDa and a sedimentation rate of 7.8 S. The IgM molecule possesses a double heterodimeric structure, consisting of two identical p heavy (H) (jjl2) and two identical k or \ light (L2) chains. In healthy humans, the predominant polymer is the pentamer (|x2, I.2)5, with a molecular weight of 970 kDa and a sedimentation rate of approximately 19 S. The IgM pentamer contains one joining (J) chain of about 15 kDa molecular weight. The J chain is produced by the same B cell that makes the IgM. It contains at least six cysteins (Cys), but it does not share any amino acid sequence, nor does it display any antigenic cross-reactivity with any Ig H or L chains. Other human IgM polymers include the tetramer (p2, L2)4 and the hexamer (|jl2, L2)6, with the hexamer being the most frequent polymer after the pentamer. IgM are present as pentamers throughout the vertebrate evolutionary ladder, from the less evolved bony fishes (Osteich-thyes) to mammalians. Remarkable exceptions are most present-day bony fishes (Actinoperygii) and the amphibian Xenopus laevis which display IgM only as tetramers and hexamers, respectively. At the low end of the evolutionary ladder, cartilaginous fishes (Chondrichthyes) display IgM in the monomeric form only. Monomeric IgM (|j.2, I.,) occur at a low concentration in the circulation of healthy humans, and are synthesized as such, rather than resulting from the degradation of polymers. Monomeric IgM are common in patients with Waldenstrom's macro-globulinemia, systemic lupus erythematosus, rheumatoid arthritis and ataxia telangiectasia. Many of these patients also display relatively high levels of circulating tetrameric and hexameric IgM.
Polymeric IgM can be split into (p.,, I.2) monomers by mild reduction at neutral pH. Each of the two identical H chains of a monomer consists of five domains, i.e. one variable (V) and four constant, C.l, 0^2, CV3 and C^, H chain domains or regions, encoded by five different exons. The C^ domains range in length from 105 (CM1) to 111 (C^4) amino acids (Figure 1). In contrast to IgG, IgA and IgD, IgM lacks a hinge region, which is substituted by a full C^ domain. The lack of a hinge region confers on IgM a more rigid structure than that of other Ig. Comparison of the IgM H chain primary structure to that of the other Ig classes entails the alignment of C^l, C^.3 and CM4 with the other Ig CM1, C,,2 and CH3 domains, except for IgE that also lacks a hinge region and possesses a four-domain CL. H chain. Overall comparison of the amino acid sequence of human C^ to that of the human CJ, C,2, Cy3, Cy4, CQ1 and Q.H chains yields identity values of 31, 31, 31, 34 and 28%, respectively. An extra 'tail' of 19 amino acids, including one Cys, is attached to the C-terminal end of the C(i4 domain (amino acid residue 557). This is not considered a domain and its primary structure is unrelated to that of any of the four C^ domains (Figure 1). Studies of the mouse IgM have shown that the entire tail plus the amino acid at position 557, a glycine (Gly), are missing in the mature transcript of the membrane-anchored form of IgM (mlgM), and are substituted by a sequence of 41 amino acid residues that contains a highly hydrophobic (cell membrane anchoring) C-terminal stretch. Elements critical to the structure of the human IgM monomer are the Cys 140 (C^l) and the Cys337 (CH2), which allow for the formation of the intrasubunit disulfide bonds to the L and H chain, respectively. Elements critical to IgM polymerization are the Cys414 (CM3) and the Cys575 (tail). These Cys provide anchoring points
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