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

Abstract

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 ,81 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 j1 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 antitopo I antibody titers. These results suggest that the HLA-DR and DQ genes together control the autoimmune response to topo I in systemic sclerosis. (J. Clin. Invest. 1993. 92:1296-1301

Thyroid peroxidase autoantibody epitopic ‘fingerprints’ in juvenile Hashimoto’s thyroiditis: evidence for conservation over time and in families

“…For example, inheritance of the ability to mount an autoantibody response to epidermal cadherin in healthy relatives of patients with pemphigus vulgaris is linked to HLA [41]. Similarly, HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis [42]. In contrast, antibody responses to a major malarial antigen and some of its immunodominant epitopes, which were found to be more concordant between monozygotic than dizygotic twins, are not associated with HLA-DRB, DQA or DQB alleles [43].…”

Is systemic sclerosis an antigen‐driven T cell disease?

“…It appears that HLA associations in SSc may be more involved with disease susceptibility, because of a substantially stronger HLA association with autoantibody profiles than with the disease itself (64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74).…”

“…DNA topo I elicits both autoantibody responses (32,68) and cellular responses in patients with SSc (137)(138)(139). Collaboration of T and B cells is required for autoantibody responses to DNA topoisomerase (32).…”

“…Anti-topo I antibodies are characteristic of the diffuse type of SSc (1,120). The possibility that an autoantigen elicits both an autoantibody response and a cellular response is supported by the findings of a substantially stronger HLA association with autoantibody profiles than with the disease itself (64)(65)(66)(67)(68)140). Kuwana et al reported that HLA-DQ and DR genes together control the anti-topo I antibody response in patients with SSc (68).…”

Enhancement of anti‐DNA topoisomerase I autoantibody response after lung cancer in patients with systemic sclerosis: A report of two cases

“…The production of anti-top0 I antibody in SSc patients is believed to be due to an antigen-driven process because: (a) there is isotype switching (8-10); (b) there are high titers of anti-top0 I antibody (8-10); (c) patients' sera recognize multiple epitopes on top0 I (11); and (d) the presence of anti-top0 I antibody is associated with certain HLA class I1 alleles (7). We have recently shown that anti-top0 I antibody production in SSc patients is dependent on top0 I-specific helper T cells that provide help to B cells resulting in anti-top0 I antibody production (5,6).…”