ASSOCIATION OF AMINO-ACID-SEQUENCES IN THE HLA-DQB1 1ST DOMAIN WITH THE ANTITOPOISOMERASE-I - AUTOANTIBODY RESPONSE IN SCLERODERMA (PROGRESSIVE SYSTEMIC-SCLEROSIS)

Previous studies in Caucasians with progressive systemic sclerosis (PSS) have suggested associations of antitopoisomerase I (antitopo I) autoantibodies with either serologically defined HLA-DR2 or DR5. To better define class II HLA associations with the antitopo I response, 161 PSS patients (132 Caucasians and 29 American blacks) were studied for antitopo I autoantibodies by immunodiffusion and immunoblotting, and their HLA-DRB1, DRB3, DQA1, and DQB1 alleles were determined by restriction fragment length polymorphic analysis and DNA oligotyping. Among Caucasians with antitopo I, HLA-DR5(DRB1*1101-*1104), DRB3*0202 and DQw3 (DQw7,8,9) were significantly increased in frequency. In American blacks, however, only HLA-DQB1 *0301 (DQw7) was significantly increased. The presence of HLA-DQB1 *0301 (DQw7) and other HLA-DQB1 alleles bearing the uncharged polar amino acid residue tyrosine at position 30 of the outermost domain was found in all antitopo I-positive Caucasian PSS patients compared with 66% of antitopo I-negative PSS patients (pc = 0.007) and 70% of normal controls (pc = 0.008), as well as all antitopo I-positive black patients. The association with HLA-DQB1 was independent of HLA-DR5(DRB1*1101-*1104) or any other HLA-DRB1, DRB3, or DQA1 alleles. Alternative or additional candidate epitopes for this autoimmune response include alanine at position 38 and threonine at position 77 of these same DQB1 alleles. These data suggest that genetic predisposition to the antitopo I response in PSS is associated most closely with the HLA-DQB1 locus.