As noted above, the traditional and accepted functional anatomy of immunoglobulins attributes antigen binding (both specificity and affinity) to the V modules in the Fab arms and effector function activation to the Fc region. Although this scheme is both well supported and appealing, structural variations in heavy chain domains (ie, C domains and hinge) can in some cases influence both discrimination among and the affinity of the antibody for antigens. 132 - 137 Although these instances of C domain influence on ligand binding (through the V domains) primarily involve multivalent antigens, there are also reports that suggest C domain influence in instances of monovalent recognition. 138 - 140 Mechanisms for these effects in the context of binding multivalent antigens include isotype-related differences in segmental flexibility as well as the tendency for self-association. Results from a study comparing resistance to pneumococcal infection for IgG3-deficient and IgG3-producing mice are consistent with the notion that the cooperative binding permitted by murine IgG3 antibodies contributes to the effectiveness of humoral immunity.