Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP

Abstract

Scleroderma is a condition of variable phenotype characterised by fibrosis of the skin and internal organs. There is a range of disease-specific autoantibodies found in the sera of patients. The aims of this study were to: (1) investigate the role of the MHC and particularly HLA-DP in the production of autoantibodies; (2) investigate clinical associations with autoantibodies. We have performed HLA class II typing using PCR with sequence-specific primers on DNA samples from 202 scleroderma patients and 307 UK control subjects. All patients had well defined clinical phenotypes. Sera from patients were examined for the presence of disease specific autoantibodies in particular the anti-topoisomerase autoantibody (ATA), the anti-centromere autoantibody (ACA) and the anti-RNA polymerase autoantibody (ARA). There was a striking association between HLA-DPB1*1301 and ATA (Pcorr = 0.0001). In addition, ATA was associated with HLA-DRB1*11 and the anticentromere autoantibody (ACA) with HLA-DRB1*04, HLA-DRB1*08 (P = 0.001) and HLA-DQB1 alleles with a glycine residue at position 26. Very strong associations were detected between clinical phenotypes and autoantibodies. ATA was associated with pulmonary fibrosis (P = 0.00002), anti-RNA polymerase autoantibody (ARA) with renal involvement (P = 0.0000006) and diffuse skin disease (P = 0.00001), and ACA with limited skin involvement (P = 0.00002) and protection against pulmonary fibrosis (P = 0.0000003). We have identified a significant association between the ATA and HLA-DPB1*1301 which may provide an insight into how this autoantibody is formed. Patient clinical characteristics depend on the autoantibodies they carry.

The TNF‐863A allele strongly associates with anticentromere antibody positivity in scleroderma

“…We have recently shown that the production of another major autoantibody found in scleroderma patients, antitopoisomerase, is tightly linked both to the presence of fibrosis and to the HLA class II alleles DRB1*1101/04 and DPB1*1301 (14). However, we and other investigators have found only weak associations between DRB1*0101 and DQB1*05 and the production of ACA (15)(16)(17).…”

“…Partial support for this comes from Kuwana et al, who reported that antibodies to HLA-DR and HLA-DQ blocked antitopoisomerase production in vivo (29). However, this leaves our HLA-DP association unexplained (14), since DP and TNF are not in linkage disequilibrium, and antibodies to DP did not block antitopoisomerase production in the system of Kuwana et al…”

Genetics of fibrosing lung diseases

“…There are three predominant antibodies: anticentromere antibodies, antitopoisomerase antibodies (ATAs), and anti-RNA polymerase antibodies. These autoantibodies are almost totally mutually exclusive and define different clinical subsets of the disease with reasonable accuracy [83,84]. In particular, the presence of ATAs (also known as anti-Scl-70 antibodies) in a scleroderma patient is very strongly associated with the risk of development of pulmonary fibrosis (relative risk 17) [83,84].…”

Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses

“…The majority of SSc patients produce antibodies directed at nuclear antigens, which are strongly associated with organ involvement and disease outcome. [9][10][11][12] Although the etiology of SSc is unknown, genetic factors are thought to be important. Several polymorphic genes-which are either risk factors for the development of SSc or influence disease-associated autoimmune responsiveness-have been identified.…”