HLA ASSOCIATIONS IN 3 MUTUALLY EXCLUSIVE AUTOANTIBODY SUBGROUPS IN UKSYSTEMIC-SCLEROSIS PATIENTS

Systemic sclerosis (SSc) is characterized by the presence of autoantib odies, mostly IgG, which target a limited set of nuclear proteins. The se antinuclear antibodies (ANA) associate with disease subgroups and s pecific organ involvement. Here we show that there is mutual exclusivi ty of individual ANA in 130 UK SSc patients, confirm clinical associat ions with antibody profile and extend the analysis to include genetic data. The ANA mutual exclusivity observed leads to the possibility tha t SSc, in these patients, is in fact three separate diseases. An alter native explanation for exclusivity relates to the fact that optimal pr oduction of IgG antibody requires T-cell help, a process restricted by the HLA class II presentation of antigen peptide. If each autoantibod y has a different and tight MHC restriction, then there is a possibili ty that these groups arose from a common pathway and were modified by genetics into the mutually exclusive groups observed, making the separ ate disease theory less tenable. In order to answer this question, we have determined MHC class II restriction precisely using high-resoluti on HLA genotyping (SSP) coupled with an amino acid analysis program in our 130 UK SSc patients. DRB111 was associated with anti-topoisomera se-I antibody (ATA)-positive patients, (P = 0.007) and when combined w ith ATA (RR = 15.82), dcSSc (RR = 11.45), or both (RR = 21.9), represe nted the strongest risk factor for pulmonary fibrosis. Patients with a ntibodies to RNA polymerases I, II and III were associated with DQB10 201. At the amino acid level, 20 positions in DRB1 and 20 positions in DQB1 showed some significant correlation with an ANA group. Clearly, however, the linkages to MHC class II alleles are not nearly strong en ough to explain the mutually exclusive nature of the autoantibody grou ps and our results support, but do not prove, the separate disease the ory.