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

Abstract

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 (VH) and light (VL) 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 VH and VL regions are encoded by the same VH, VK and JH 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 VH and VL regions and alpha 1 and beta 1 domains of HLA-DQ3 antigens.

Generation of anti-idiotypic reagents in the EGFRvIII tumor-associated antigen system

“…7). The results in both species support the proposal that the induction of Ab1¢ activity may be primarily via conformational epitope parameters, rather than primary amino acid sequence, largely, but not solely based on the capacity of Ab2 vs anti-carbohydrate Ab1 to induce anti-carbohydrate reactive Ab1¢ [7,12,16,18,34]. As the anti-EGFRvIII activity was restricted to cellexpressed EGFRvIII, and not to linear peptide, the assumption would be that secondary and tertiary conformational structures are important in the anti-id cascade described here.…”

“…2 and 3). As the humoral mimotopic activity of Ab2b is presumably conformational in nature [16], the difference between these two Ab1 in generating functional Ab2b is most likely a reflection of a less immunogenic topography of mAb L8A4.…”

Idiotypic diversity and variable region gene usage by mouse anti-HLA-DQ3 mAb

“…mAb V~ and V~ region sequences were determined and analyzed as previously described (Iwasaki et al 1994). …”

Anti‐anti‐idiotypic (Ab3) antibodies that bind progesterone‐11α–bovine serum albumin differ in their combining sites from antibodies raised directly against the antigen

“… 13,17 One result obtained consistently is that among Ab3 antibodies are some which do indeed closely resemble the Ab1 in that they possess the same idiotopes, bind to the same antigen and derive from similar variable (V) genes. However, whilst the resemblance between Ab1′ and Ab1 can be very close, 13,15,17 many permutations of results have been seen. For example, binding of Ab3 to the antigen may not occur even although the same V‐gene segments are selected, e.g.…”

“…The relationship between Ab1 and Ab1′ antibodies has been explored in a number of different antigenic systems, including (4‐hydroxy‐3‐nitrophenyl)acetyl (NP), 10 p ‐azophenylarsonate (ARS), 11 poly(Glu 60 ,Ala 30 ,Tyr 10 ) (GAT), 12 angiotensin, 13,14 human leucocyte antigen (HLA) class II 15 and lysozyme, 16,17 and with either monoclonal 10–12 or polyclonal anti‐Id reagents. 13,17 One result obtained consistently is that among Ab3 antibodies are some which do indeed closely resemble the Ab1 in that they possess the same idiotopes, bind to the same antigen and derive from similar variable (V) genes.…”