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 DQA1*0501 and DQB1*0201 were most frequent, followed by DQA1 and DQB1 alleles comprising DQw6. In patients not possessing DQw2.1 and/or DQw6 alleles, HLA-DQB1*0302 and HLA-DQA1*0401 (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.
Reveille
J D
JD
Department of Internal Medicine, University of Texas Health Science Center, Houston 77225.
Macleod
M J
MJ
Whittington
K
K
Arnett
F C
FC
D000483:Alleles; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000276:immunology*; D001483:Base Sequence; D005787:Gene Frequency; D006683:HLA-DQ Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D020733:RNA, Small Cytoplasmic; D012261:Ribonucleoproteins / Q000276:immunology*; D000097585:SS-B Antigen; D000099207:SS-A Antigen
D001323:Autoantibodies; D001324:Autoantigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D020733:RNA, Small Cytoplasmic; D012261:Ribonucleoproteins; D000097585:SS-B Antigen; D000099207:SS-A Antigen; C116006:RO60 protein, human