The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma).
HLA class II alleles were determined using the PCR-RFLP method in Japanese systemic sclerosis (scleroderma) patients with (n = 28) or without (n = 34) anti-topoisomerase I antibodies (anti-topo I). Either the DQB1*0601 or *0301 allele was recognized in all anti-topo I positive patients, compared with 44% of anti-topo I negative patients (P < 0.00001, relative risk [RR] > 41) or 58% of Japanese healthy control subjects (P < 0.00001, RR > 24). Tyrosine at position 26 in the second hypervariable region in the beta 1 domain of the DQB1 gene is common to these two alleles and is not present in any other known DQB1 alleles. We also examined immunoreactivities of anti-topo I positive sera to four different autoantigenic B cell epitopes of topo I molecule that were expressed as recombinant fusion proteins. One major B cell epitope, located within the region corresponding to amino acid residues 74-248, was perfectly associated with the amino acid sequence FLEDR at positions 67-71 in the beta 1 domain of the DRB gene. Two other epitopes, corresponding to 316-441 or 658-700, were associated with the serologically defined HLA-DR52 antigen. Patients with both FLEDR and DR52 demonstrated higher anti-topo I antibody titers. These results suggest that the HLA-DR and DQ genes together control the autoimmune response to topo I in systemic sclerosis.
Kuwana
M
M
Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Kaburaki
J
J
Okano
Y
Y
Inoko
H
H
Tsuji
K
K
D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000235:genetics*; D004264:DNA Topoisomerases, Type I / Q000276:immunology*; D000939:Epitopes; D005787:Gene Frequency; D005802:Genes, MHC Class II; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology
D000939:Epitopes; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D004264:DNA Topoisomerases, Type I