Although HLA genes have been shown to be associated with certain diseases, the basis for this association is unknown. Recent studies, however, have documented patterns of nucleotide sequence variation among some HLA genes associated with a particular disease. For
rheumatoid arthritis, HLA genes in most patients have a shared nucleotide sequence encoding a key structural
element of an HLA class II
polypeptide; this sequence
element is critical for the interaction of the HLA molecule with antigenic
peptides and with responding T cells, suggestive of a direct role for this sequence
element in
disease susceptibility. We describe the serological and cellular immunologic characteristics encoded by this
rheumatoid arthritis-associated sequence
element. Site-directed mutagenesis of the DRB1 gene was used to define
amino acids critical for antibody and T-cell recognition of this structural
element, focusing on residues that distinguish the
rheumatoid arthritis-associated alleles Dw4 and Dw14 from a closely related allele, Dw10, not associated with disease. Both the gain and loss of
rheumatoid arthritis-associated
epitopes were highly dependent on three residues within a discrete domain of the
HLA-DR molecule. Recognition was most strongly influenced by the following
amino acids (in order): 70 greater than 71 greater than 67. Some alloreactive T-cell clones were also influenced by
amino acid variation in portions of the DR molecule lying outside the shared sequence
element.