Molecular requirements for forming polymeric IgM

Initially expected to be important for the formation of polymeric immunoglobulins, the J chain is in fact strongly (but not exclusively) dependent on the J chain for polymerization of IgA.In contrast, aggregated IgM is formed efficiently in the absence of the J chain.The major form of human and mouse IgM is a pentamer. In contrast,IgM from frogs (Xenopus laevis) is predominantly hexameric in structure,IgM from bony fishes is predominantly tetrameric and IgM from cartilaginous fishes (mainly sharks) is predominantly Pentamer.Although the pentameric form predominates in mice and humans, a hexameric form has also been observed.Subsequent studies using recombinant DNA expression systems showed that hexamers are the predominant form of mouse IgM when IgM is produced under conditions in which J-chain incorporation is prevented, by Produce IgM or by producing IgM with a µ heavy chain that lacks a cysteine at the tail.In conclusion, hexameric IgMs never contain the J chain; pentameric IgMs can be formed to include or exclude the J chain.

An important difference between µ and γ heavy chains is that cysteines are available to form disulfide bonds between the heavy chains.In the case of gamma heavy chains, the only inter-gamma bonds are formed by cysteines in the hinges, so each gamma chain binds to only one other gamma chain.In contrast, the Cµ2 and Cµ3 domains and tails each contain a cysteine that forms a disulfide bond with the other µ chain.Cysteine in the Cµ2 domain mediates the formation of monomeric IgM (µL)2.The tail, together with the cysteine it contains, is necessary and sufficient for the formation of polymerized immunoglobulins.That is, deletion of the tail from the µ heavy chain prevents the formation of aggregated IgM.In contrast, cells expressing the γ heavy chain that has been modified to include the tail piece produce aggregated IgG.The role of cysteines in the Cµ3 domain is more subtle. Figure 1C and 1D represent possible models for pentameric IgM.In these models, each µ chain is envisioned to bind two other µ chains.However, neither model alone can explain the structure of aggregated IgM.For example, the model in predicts that disulfide bonds between Cµ2 domains are critical for making disulfide-bonded aggregated IgM.The model in1D predicts that disulfide bonds between Cµ3 domains are essential.If any of the three cysteines are absent, disulfide bonds, polymers, IgM can still be made.In the context of a model in which each µ chain interacts with only two other µ chains, these results suggest that some molecules behave as shown in 1C and some as shown in 1D. However, the availability of three cysteines for μ interchain bonding suggests that each μ chain may bind three other μ chains.In the same spirit,presents a model of a pentamer containing J chains reflecting evidence of J chains joined to µ chains that are not linked to other µ chains via cysteines in the Cµ3 domain.These and other models, both regular and irregular, are discussed elsewhere. Pentameric IgM is often expressed as containing one J chain per polymer, but in practice J chain stoichiometry is measured from one J molecule per polymer to three J molecules per polymer.The wide range may be due to technical issues such as incomplete radiolabeling or imprecise quantification of Ouchterlony lines.However, this variation may also be due to the heterogeneity of IgM preparations, i.e., various preparations may differ significantly in terms of J-containing and J-lacking polymer content.

Function

IgM interacts with several other physiological molecules:

1.IgM can bind complement component C1 and activate the classical pathway, leading to opsonization of antigen and cytolysis.

2.IgM binds to the multiple immunoglobulin receptor (pIgR) during the process of carrying IgM to mucosal surfaces such as the intestinal lumen and into breast milk.This binding depends on the J chain.

3.Two other IgM-binding Fc receptors have been detected - Fcα/μ-R and Fcμ-R. Fcα/µ-R, like pIgR, binds aggregated IgM and IgA. Fcα/μ-R mediates endocytosis, and its expression in the gut suggests a role in mucosal immunity. Fcµ-R (formerly known as Toso/Faim3) specifically binds IgM and can mediate cellular uptake of IgM-conjugated antigens.Inactivation of the corresponding genes in knockout mice produces phenotypes,but the physiological function of these receptors remains uncertain.