Structural profile of idiotype, anti-idiotype and anti-anti-idiotype monoclonal antibodies in the HLA-DQ3 antigenic system

Interest in the characterization of idiotype cascades in the HLA antigenic system has been stimulated by their potential role in the immune response to mismatched HLA allospecificities and in the survival of kidney allografts. Since no information is available about the structural organization of idiotypic cascades in the HLA system, we have sequenced the variable regions of the heavy (V_H) and light (V_L) chains of mouse anti-HLA-DQ3 monoclonal antibody (mAb) KS13 elicited by cell membrane-bound antigens, of syngeneic anti-HLA-DQ3 mAb S2B154 elicited by anti-idiotypic (anti-id) mAb K03-34 and of five syngeneic anti-id mAb elicited by mAb KS13. mAb KS13 and S2B154, which have been previously shown to be very similar in their specificity and idiotypic profile, share several structural characteristics. Their V_H and V_L regions are encoded by the same V_H. V_K and J_H genes, display relatively similar V(D)J rearrangements and differ only through a few amino acid substitutions. Among the five anti-id mAb elicited by mAb KS13, mAb R1-38 and R18-9 utilize multiple genetic elements that are different from those used by anti-id mAb KO3-34, K03-256 and K03-335. These results indicate that diverse V region combinations can confer an anti-id specificity in the antigenic system analyzed. mAb K03-34, K03-256 and K03-335 originate from the same B cell clone, since they use the same V, D and J genes and possess identical V(D)J rearrangements. The latter three anti-id mAb differ only by point mutations, which have dramatic effects on the HLA-DQ3 antigen mimicry properties of the three anti-id mAb. mAb K03-34 is the only one to induce anti-HLA-DQ3 antibodies both in syngeneic and xenogeneic hosts. The antigen mimicry properties of anti-id mAb K03-34 depend upon its three-dimensional conformation, since no significant amino acid sequence homology has been found between its V_H and V_L regions and α₁ and β₁ domains of HLA-DQ3 antigens.