may involve the regulation of RNA polymerase activity as the polymerase transcribes through the IgM locus. One factor that regulates the polyadenylation of RNA transcripts is a cleavage stimulation factor subunit, CstF-64, which favors production of the transcript for secreted IgM. The transcription elongation factor ELL2, which is induced in plasma cells, also promotes polyadenylation at the pAs site and favors the secreted form. CstF-64 and ELL2 co-associate with RNA polymerase within the immunoglobulin locus. This differential RNA processing is illustrated for Cμ in Fig. 5.22, but it occurs in the same way for all isotypes. In activated B cells that differentiate to become antibody-secreting plasma cells, most of the transcripts are spliced to yield the secreted rather than the transmembrane form of whichever heavy-chain isotype the B cell is expressing.
5-16 IgM and IgA can form polymers by interacting with the J chain.
Although all immunoglobulin molecules are constructed from a basic unit of two heavy and two light chains, both IgM and IgA can form multimers of these basic units (Fig. 5.23). C regions of IgM and IgA can include a ‘tailpiece’ of 18 amino acids that contains a cysteine residue essential for polymerization. A separate 15-kDa polypeptide chain called the J chain promotes polymerization by linking to the cysteine of this tailpiece, which is found only in the secreted forms of the μand α chains. (This J chain should not be confused with the immunoglobulin J region encoded by a J gene segment; see Section 5-2.) In the case of IgA, dimerization is required for transport through epithelia, as we will discuss in Chapter 10. IgM molecules are found as pentamers, and occasionally hexamers (without J chain), in plasma, whereas IgA is found mainly as a dimer in mucous secretions but as a monomer in plasma.
Immunoglobulin polymerization is also thought to be important in the binding of antibody to repetitive epitopes. An antibody molecule has at least two identical antigen-binding sites, each of which has a given affinity, or binding strength, for antigen. If the antibody attaches to multiple identical epitopes on a target antigen, it will dissociate only when all binding sites dissociate. The dissociation rate of the whole antibody will therefore be much slower than the dissociation rate for a single binding site; multiple binding sites thus give the antibody a greater total binding strength, or avidity. This consideration is particularly relevant for pentameric IgM, which has 10 antigen-binding sites.
Fig. 5.23 The IgM and IgA molecules can form multimers. IgM and IgA are usually synthesized as multimers in association with an additional polypeptide chain, the J chain. In dimeric IgA (left panel), the monomers have disulfide bonds to the J chain as well as to each other. In pentameric IgM (right panel), the monomers are cross-linked by disulfide bonds to each other and to the J chain. IgM can also form hexamers that lack a J chain (not shown).
IgM antibodies frequently recognize repetitive epitopes such as those on bacterial cell-wall polysaccharides, but individual binding sites are often of low affinity because IgM is made early in immune responses, before somatic hypermutation and affinity maturation. Multisite binding makes up for this, markedly improving the overall functional binding strength. This implies that binding of a single IgM pentamer to a target could be sufficient to mediate biological effector activity, whereas in the case of IgGs, two independent target molecules may need to be located in close proximity.
Summary.