IgM valency and complement activation

Reaction of pentameric IgM with haptens or small antigens results in the occupancy of all Fab antigen-binding sites, making IgM decavalent. Due to steric hindrance, reaction of IgM with larger ligands may result in occupancy of only five, or fewer, antigen-binding sites, suggesting that the valency of IgM is a function of the nature of the actual ligand. Owing to its high valency, the overall avidity of a whole IgM molecule for a given antigen, displaying repetitive epitopes, greatly exceeds the value of the intrinsic affinity of each Fab for the single epitope. Thus, the antigen size and nature have an important impact not only on the valency of an IgM molecule, but also on its binding strength. This is an important feature when one considers that naturally occurring proteinic and/or polysaccharidic antigens on bacteria, viruses and other microorganisms do often display repetitive epitopes.

The first step in the activation of the classical complement pathway is the binding of the Clq moiety of the latent CI esterase to IgG or IgM. While at least two antigen-bound IgG are required for complement fixation, a single IgM molecule can efficiently activate complement after binding Ag. In IgM, the Clq binding sites are located on the C„3 and/or C^ domains (Figure 1). In its planar conformation, IgM bears a single Clq-binding site, allowing the binding of only one of the six globular heads present on each Clq molecule. This monovalent binding is characterized by a high dissociation constant (Kd), in the order of magnitude of 104-105m_i (low affinity). Dislocation of the IgM (Fc), disc brought about by binding of the Fab arms to a multivalent particulate antigen leads to exposure of at least one more Clq-binding site on the (Fc),- disc. This allows multivalent binding of Clq, resulting in a 2-3 orders of magnitude increase in binding strength. Multivalent binding of Clq is enhanced in the IgM hexamer which activates complement up to 20-fold more efficiently than the canonical pentamer. Consistent with the notion that enhanced Clq binding by IgM results from a distortional process rather than an allosteric change, is the observation that antigen-IgM complexes efficiently activate C I when prepared in antibody, but not antigen, excess. Thus, the engagement of IgM in a lattice is an absolute prerequisite for complement fixation by IgM following the binding of soluble antigens. It is conceivable that such an engagement entails a distortion of the Fab arms that results in a better exposure of the (Fc),-disc, in a fashion similar to that following the bind-

ing of IgM to particulate antigens. Activation of the CI esterase by IgM leads to the assembly of the C3-convertase, C4b2a, and subsequent deposition of C3b, and its inactivated forms, iC3b and C3d, on the antibody molecules engaged in the lattice. C3b, iC3b and C3d can greatly enhance the engulfment of antigen by readily mediating attachment of the anti-gen-IgM complexes to the complement receptors CRI, CR3, and CR2 or CR4, respectively, that are present on the surface of different blood cells, including erythrocytes, granulocytes, monocytes, macrophages, natural killer (NK) cells, B lymphocytes and T lymphocytes.

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