Specific amino acid residues in the second hypervariable region of HLA-DQA1 and DQB1 chain genes promote the Ro (SS-A)/La (SS-B) autoantibody responses.

In order to define the HLA-DR and DQ alleles, as well as the specific DQA1 and DQB1 chain genes involved in the anti-Ro/La autoantibody responses, RFLP analysis and sequence-specific oligonucleotide typing was carried out on 58 Caucasians and 48 American blacks with SLE or Sjögren's syndrome and anti-Ro antibodies. Among both Caucasian and black patients, the highest relative risk for the anti-Ro response (both with and without accompanying anti-La) was conferred by heterozygosity for the DQw2.1 (in linkage disequilibrium with HLA-DR3) and DQw6 (a subtype of DQw1) alleles compared with either 269 normal race-matched controls or 80 anti-Ro negative SLE/Sjögren's syndrome patients. Analysis of individual DQA1 and DQB1 chain alleles revealed that DQA10501 and DQB10201 were most frequent, followed by DQA1 and DQB1 alleles comprising DQw6. In patients not possessing DQw2.1 and/or DQw6 alleles, HLA-DQB10302 and HLA-DQA10401 (especially in blacks) were significantly increased. Nucleotide sequence analysis of these associated alleles showed that 100% of patients with anti-Ro had a glutamine residue at position 34 of the outermost domain of the DQA1 chain and/or a leucine at position 26 of the outermost domain of the DQB1 chain. Patients with anti-Ro plus La were more likely to have all four of their DQA1/DQB1 chains containing these amino acid residues than either anti-Ro-negative SLE patients or controls. These data implicate specific amino acid residues on both DQA1 and DQB1 chains located in the floor of the Ag binding cleft of the HLA-DQA1:B1 heterodimer and further suggest a role for "gene dosage" in the anti-Ro (+/- La) autoantibody response.