Genetic studies of the HLA locus in rheumatic diseases

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) share a complex etiology consisting of both genetic and environmental components. Stimulation of lymphocytes and various other immune cells, release of cytokines, activation of complement and production of autoantibodies due to loss of tolerance to self-antigens, contributes to the pathogenesis of both RA and SLE. These two complex diseases also share genetic factors such as those in the HLA, PTPN22, STAT4 and 6q23 loci, but their respective clinical phenotypes are clearly different. RA is characterized by symmetric arthritis of peripheral joints, which is chronic and progressive. In contrast, arthritis is only one among several clinical manifestations of SLE. Malar rash, photosensitivity, serositis and nephritis are a few indicatives of SLE but not of RA. The two clinical diseases seldom overlap and it is therefore thought that different etiological factors lie behind these two complex diseases. Such etiologic factors could be genetic factors with some being specific for SLE and others being specific for RA or alternatively the differential factors could be environmental. To scrutinize the genetic and environmental factors as well as the clinical characteristics within RA and SLE may allow us to easier characterize important subgroups within these two heterogeneous diseases. The overall aim of this thesis was to re-evaluate the contribution of the HLA loci in rheumatic diseases in view of new data regarding autoantibody status in RA and SLE. We provide novel data for RA in two different disease subtypes, i.e. with presence or absence of anti-citrullinated peptide antibodies (ACPA). Our data supports different genetic and etiological backgrounds for these two subsets by demonstrating distinct associations of risk and/or protection conferred by different genes/alleles within the extended HLA locus. For ACPA-positive RA we demonstrate a new finding where HLA-DPB1 was shown to associate with this subset o