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uman autoimmune diseases have a striking genetic as- sociation with particular alleles of major histocompati- bility complex (MHC) class I or II genes. The field was established by the seminal discovery of HLA-B27-1inked susceptibility to ankylosing spondylitis, a chronic inflammatory joint disease (1, 2). MHC-associated susceptibility has now been documented for a variety of human autoimmune diseases, including insulin-dependent diabetes meUitus (IDDM), rheu- matoid arthritis (RA), pemphigus vulgaris (PV), multiple sclerosis, and myasthenia gravis, just to name a few (3-8). A genome-wide search for diabetes susceptibility genes using microsatellite markers has demonstrated that several genes contribute to the disease process, but that the MHC is the most important susceptibility locus (9). Despite this remark- able progress, several critical questions remain to be answered to establish a causal relationship between the genetics and the immunopathogenesis: (a) Is the role of MHC molecules in autoimmunity based on the presentation of (self) peptides? (b) What is the biochemical nature of these peptides? (c) Are these peptides specific for a particular disease associated MHC molecule and the target organ of the immune attack? (d) What mechanisms induce an autoaggressive T cell response to these self determinants? Recent developments in the field, particularly the structural characterization of MHC-peptide complexes and the identi- fication of allele-specific peptide-binding motifs, have trans- formed the field (10-13). Based on this knowledge, the struc- tural basis for MHC-linked susceptibility to autoimmune diseases can be reassessed at a level of detail sufficient for solving longstanding questions in the field. Motifs for peptide binding to MHC class I and II molecules were defined by sequence analysis of naturally processed peptides and by mutational analysis of known epitopes. MHC class I-bound peptides were found to be short (generally 8-10 amino acids long) and to possess two dominant MHC anchor residues; MHC class II-bound peptides were found to be longer and more hetero- geneous in size (10-17). The size heterogeneity has made it more difficult to define MHC class II-binding motifs based on sequence alignments; the crystal structure of HLA-DK1 has, however, clearly demonstrated that there is a dominant hydrophobic anchor residue close to the NHz terminus of the peptide, and that secondary anchor residues are found at several other peptide positions (13, 15, 18).

the journal of experimental medicine/the journal of experimental medicine

Selective binding of self peptides to disease-associated major histocompatibility complex (MHC) molecules: a mechanism for MHC-linked susceptibility to human autoimmune diseases.