Association of polar amino acids at position 26 of the HLA-DQB1 first domain with the anticentromere autoantibody response in systemic sclerosis (scleroderma).

Abstract

HLA class II alleles (detected by DNA typing) were determined in 116 Caucasians with systemic sclerosis positive and negative for anticentromere autoantibodies (ACA). Significantly increased frequencies of HLA-DR5(DRw11) (P = 0.009) and the Dw13(DRB1*0403, *0407) subtypes of DR4 (probability corrected, Pc = 0.005) were seen in ACA positive patients, and HLA-DR1 and DRw8 were also increased. These findings appeared to reflect linkage disequilibrium of DR5(DRwll) and many DR4(Dw13) haplotypes with HLADQw7 and DRi with DQw5. In fact, the presence of a DQB1 allele having a polar glycine or tyrosine at position 26 of the DQB1 first domain versus a hydrophobic leucine accounted for 100% of ACA positive Caucasian systemic sclerosis patients compared to 69% ofthe ACA negative SS patients (P = 0.0008) and 71% of Caucasian controls (P = 0.0003) as well as all 7 ACA patients of non-Caucasian background. Furthermore, the genotype frequency of DQB1 alleles lacking leucine at position 26 was 73% in ACA positive SS patients, compared to 42% of ACA negative patients (P = 1.2 X 10-`) and 38% of controls (P = 5.8 X 10-7). These data, then, suggest that the second hypervariable region of the HLA-DQB1 chain may form the candidate epitope associated with the ACA response. (J.

The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma).

“…Tyrosine at position 26 in the DQB1 (31 domain was also shown to be one of the amino acid residues associated with another SSc-specific autoantibody, anticentromere (53). Thus, it appears that the putative antigen binding cleft at position 26 in the DQB1 31 outermost domain is important for these two autoantibody production, and different HLA-DR genes define the reactivity to the two different antigens.…”

Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic, serologic, and clinical analysis

“…The ACA response has been associated with HLA-DQBl*O5 alleles (48,49), and less commonly with DQBl*O301 and DQBl*O401 or "0402 (48). All of these ACA-associated DQBl alleles possess nonpolar amino acid residues (glycine or tyrosine as opposed to leucine) in position 26 of their outermost domains.…”

Association of amino acid sequences in the HLA-DQB1 first domain with antitopoisomerase I autoantibody response in scleroderma (progressive systemic sclerosis).

“…It should be noted that ACApositive PSS patients were considered separately because ofthe association of this autoantibody response also with HLA-DQB 1 *0301 (DQw7) (37) (Table III).…”

“…Using restriction fragment length polymorphisms (RFLPs) and oligonucleotide typing of class II MHC alleles, we have reported recently that HLA-DQB1 alleles possessing a polar amino acid (either tyrosine or glycine) at position 26 of the outermost domain constitute the strongest association with the ACA autoimmune response in PSS patients (37). In the present study, we used the same techniques in a large number of PSS patients to compare HLA-DRB1, DRB3, DQA1, and DQB 1 alleles in antitopo I-positive and -negative PSS patients and controls to show that the antitopo I response also is correlated most closely with specific HLA-DQB 1 from Miami, as well as 9 from Georgia who were part of an epidemiological study reported previously (38 Genetic analysis ofHLA-DRBI, DRB3, DQAJ, and DQBI alleles.…”

“…The PCR was carried out for 30 cycles under the following parameters: denaturation 1 min at 96°C, annealing I min at 55°C, extension 2 min at 72°C. Hybridization and washing conditions were as described previously (43 DRw6(DRw13,14), and DRw8 by RFLP or oligotyping underwent group-specific PCR amplification of DRB1 alleles using the primers DRBAMP-3 (5'-CACGTTTCTTGGAGTACTCTAC-3') and DRBAMP-B under conditions outlined for DRBAMP-A and B, except the annealing step for the PCR was at 60°C for 30 s. HLA-DRl and DR4 subtypes were determined by group-specific amplification of HLA-DRBl alleles using the primers DRBAMP-l (5'-TTCTTGTGGCAGCTTAAGTT-3') and DRBAMP-4(5'-GTTTCTTGGAGCAGGTTAAAC-3') along with DRBAMP-B under the same PCR conditions (37). HLA-DRB3(DRw52) alleles were determined by PCR amplification with the primers DRBAMP-52 (5'-CCCAGCACGTTTCTTGGAGCT-3') and DRBAMP-B.…”