Structural basis of internal antigen mimicry

Only the study of the three-dimensional structure of antigen-Abl (idiotype) and of Abl and Ab2[3 was able to provide exhaustive information on the molecular basis of internal image immunoglobulin.

Fields et al determined the crystal structure of an idiotype and anti-idiotype to a resolution of 1.9 A. Fv fragments were obtained from D1.3, a monoclonal antibody (mAb) specific for lysozymc, and from the E5.2 anti-idiotypic mAb. F5.2 exhibits the properties of an Ab2(3 because when injected into BALB/c or C57BL/6 mice it elicits the production of anti-lysozyme antibodies.

Of the 18 residues of D1.3 that contact the anti-Id antibody and the 17 that interact with lysozvme, 13 were in contact with both lysozyme and the anti-Id antibody. The position of the atoms by which the anti-idiotype contacts the anti-lysozyme antibody art-close to those by which D1.3 contacts lysozyme. The structural mimicry observed involves van der Waals forces, hydrogen bonds and solvent interactions.

Ban and colleagues determined the crystal structure of the Fab complex of a mAb specific for the F2 peplomer of feline infectious peritonitis virus and of an anti-Id antibody. This anti-Id also exhibited Ab2(3 properties since when it was injected into animals it elicted the production of virus-neutralizing antibodies. The two Fab fragments interact by direct juxtaposition of their complementary CDRs. The CDR loops of the two Fabs were in contact through van der Waals forces and hydrogen bonds between 58 atoms of the virus-specific antibody and 59 atoms of the anti-Id. In total 19 residues of idiotype and 17 residues of anti-idiotype participate in the interaction. The CDR1 loops of the anti-Id light and heavy-chains have a near identity with a hexapeptide of the antigen. These two regions of homology of the CDR1 of the light and heavy chain of Ab2 provide important contacts with the idiotype of the antibody-specific for viral antigen.

These results indicate that the structural correlates of Ab2|3 mimicry can be related to discontinuous determinants with contact residues located in various CDR loops. However, in other cases such as the feline peritonitis virus system some linear sequences located in CDRs can play a major role in antigen mimicry.

While there is a wealth of evidence that the surface Ig of B cells can recognize either discontinuous or linear epitopes on the native antigen, T cells recognize only peptides generated from the fragmentation of antigens which are then bound to self MHC antigens. This implicates that internal image-bearing peptides recognized by T cells are derived from immunoglobulin processed by antigen-presenting cells and selected by binding to cither class 1 or class 11 major histocompatibility complex (MHC) antigens. The peptides associated with class I recognized by CDS T cells are generally nonamers, whereas those associated with class II antigens recognized by

CD4 T cells are larger. Thus, an internal image immunoglobulin able to stimulate T cells should generate peptides identical to those generated by the processing of foreign antigens.

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