Scleroderma (systemic sclerosis, SSc) is a chronic complex autoimmune disease characterised by (a
) organ fibrosis involving the skin, lungs, gastrointestinal tract and/or heart; (b
) a proliferative vasculopathy primarily affecting small blood vessels and capillaries; (c
) immune activation with production of disease-specific autoantibodies.1–4
The disease is further classified into limited and diffuse forms based on extent and distribution of cutaneous thickening.
The most common SSc-specific autoantibodies are directed against centromeric proteins anticentromere (ACA) (CENP B and A), anti-topoisomerase I (ATA) (also termed Scl-70) and anti-RNA polymerase III (ARA); however, a variety of less common specificities, typically antinucleolar, can be found, which include anti-U3 ribonucleoprotein (fibrillarin) AFA), anti-Th/To, anti-Pm-Scl, anti-RNA polymerase I and anti-U1-ribonucleoprotein (RNP).5
Importantly, each patient with SSc typically produces only one of these autoantibodies and each one currently serves as a biomarker for different patterns of skin and visceral involvement, as well as prognosis. In addition, certain SSc-specific antibodies occur in different frequencies among different ethnic groups.
Scleroderma is thought to be a complex genetic disease, influenced by multiple genes, with a substantial environmental or non-germline component based on twin studies.6
African-American and Hispanic patients with scleroderma tend to have more severe disease than their Caucasian counterparts and disease in African-American subjects begins at an earlier age.7
The Choctaw Indians of southeastern Oklahoma have a nearly 10-fold prevalence of the disease compared with other ethnicities.8
It appears likely that there are different combinations of genes, the interacting effects of which influence disease susceptibility and severity. Recently, we have found that the same polymorphism in the PTPN22
gene associated with rheumatoid arthritis, systemic lupus erythematosus and other autoimmune diseases is also associated with SSc, especially in those patients having ATA or ACA antibodies.9–11
Additional ‘autoimmunity’ genes now reported to be associated with SSc include allograft inflammatory factor, IL1A
Major histocompatibility complex (MHC) or human leucocyte antigen-class II (HLA-class II) allelic associations with SSc have been reported in European and North American Caucasian subjects (DRB1*0301
) and Japanese and Koreans (DRB1*1502
) over the past two decades but have been relatively weak.5 17–22
Much stronger correlations, however, have been demonstrated between certain HLA-class II alleles and each of the SSc-specific autoantibodies.21 23–27
alleles, or combinations thereof, are associated with expression of ACA (DQB1*0501
and other DQB1
alleles encoding non-leucine residues at position 26 in the peptide binding groove),21 25 27
, especially the DRB1*1104
haplotype) in Caucasian subjects and DRB1*1502
in Japanese and Korean subjects,21–23
AFA antibody (the DRB1*1302
and anti-PM-Scl (DRB1*0301
No consistent HLA correlations heretofore have been made with ARA.28 29 38–40
Only a few studies have examined HLA-DPB1
alleles in SSc; however, one such allele (DPB1*1301
) has been associated with ATA.30–32
It has been unclear whether this allele is an independent disease correlate or the result of linkage disequilibrium (LD) with HLA-DRB1
haplotypes. Although genetic influences are thought to have an important role in susceptibility to SSc, genetic studies of scleroderma have included relatively small numbers of patients, especially black and Hispanic subjects. HLA associations with specific autoantibodies may be clinically relevant because each of the autoantibody subsets of scleroderma is associated with certain disease features and different prognostic implications.
Thus, the overall aims of this study were to determine specific HLA-class II alleles, haplotypes and epitopes influencing susceptibility to, and/or expression of, SSc itself, its limited or diffuse forms, or its various autoantibody subsets across ethnic lines in the largest cohort yet of American patients.