An anti‐idiotypic antibody has been raised which recognizes human immunoglobulins with cold agglutinin activity of anti‐I/i specificity. The pattern of reactivity of the antibody indicates that the structural basis for the epitope is located in the VH4‐21 gene segment of the VHIV family, which is preferentially utilized by these cold reactive antibodies.

Using this antibody, epitope expression was investigated in a panel of 72 human monoclonal allo‐antibodies specific for human blood group antigens, as compared with a control panel of 39 randomly selected human monoclonal IgM antibodies of unknown specificities. The anti‐blood group panel included 44 IgM and 28 IgG monoclonal antibodies against a variety of blood group antigens including the A antigen, Rh C, c, D, E, e, G antigens, and the Kidd antigens Jka and Jkb. The epitope was expressed by 64% (28/44) of the IgM anti‐blood group antibodies and by 21 % (6/28) of the IgG antibodies, but by only 7.7% (3/39) of the control IgM antibodies.

These data indicate that the human alloimmune response to blood group antigens is biased in the use of VH gene families, with a preference for the V_H4‐21 gene segment of the VHIV family, or closely related gene segments. The fact that this mirrors the findings for the autoimmune cold agglutinins suggests a link in immunoglobulin gene usage between antibodies against structurally diverse antigens on the red cell surface.