The identification of rules for peptide binding to MHC class II molecules could also have interesting applications in the treatment of autoimmune disease.
Autoimmune diseases result from the activation of self-reactive T cells by autoantigens. A striking characteristic of autoimmune diseases is the increased frequency of certain HLA class II alleles in affected individuals. Moreover, as demonstrated in rheumatoid arthritis and insulin-dependent diabetes mellitus, for example, alleles that positively associate with autoimmune diseases share unique amino acid residues in the hypervariable regions involved in peptide binding. Although the pathogenesis of autoimmune diseases is not known, one possibility is that disease-associated HLA class II molecules are able to bind and to present autoantigenic peptides to T cells. These peptides activate autoreactive CD4+ T cells, which in turn induce a cascade of chronic-inflammation.
Blocking the antigen-presenting activity of disease-associated HLA class II molecules could represent an important way to prevent and possibly treat autoimmune diseases.
The knowledge of the anchor position, as well as the other general rules for peptide binding to MHC molecules, should prove very useful for the design of MHC-specific antagonists. This strategy ought to be directed towards the development of a low molecular weight antagonist, possibly nonpeptic, that blocks the peptide-binding site of disease-linked class II MHC molecules. Such an antagonist is expected to interfere with the presentation of antigenic peptide ligands, including those involved in the activation of autoimmune T cells.
See also: Antigen-presenting cells; MHC disease associations; MHC, functions of; T cell receptor, recognition by; Vaccines.
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