Immunoglobulin allotype gene polymorphisms in systemic sclerosis: interactive eVect of MHC class II and KM genes on anticentromere antibody production

Objective—To examine potential interactions between immunoglobulin (Ig)allotype gene polymorphisms and susceptibility to systemic sclerosis (SSc) as well as serological expression in SSc patients. Methods—IgG heavy chain allotypes G1M(f, z), G2M(n+, n-), G3M(b, g) and Ig light chain allotype KM(1, (1, 2), 3) were genotyped in 105 Japanese SSc patients and 47 race matched normal controls using polymerase chain reaction (PCR) based methods. Associations of each Ig allotype with SSc related antinuclear antibodies were examined in combination with or without MHC class II alleles. Results—GM/KM genotypic and allelic frequencies were similar in SSc patients and in normal controls. Frequencies of G1M(f) and G2M(n+) were significantly decreased in anticentromere antibody (ACA) positive SSc patients compared with ACA negative SSc patients (p = 0.04 and 0.02, respectively). Conversely, the presence of DQB1*0501 and KM(1, 2) significantly increased the risk of ACA positivity. Conclusion—Ig allotype gene polymorphisms were not associated with susceptibility to SSc. Instead, the results suggested that MHC class II and KM genes are associated with autoimmune responses by interactively promoting the production of ACA. (Ann Rheum Dis 1998;57:366–370) Systemic sclerosis (SSc) is a disease characterised by fibrosis of the dermis and internal organs, microvascular injury, and the presence of circulating antinuclear antibodies (ANAs) to various nuclear proteins such as DNA topoisomerase I (topo I) and centromere/ kinetochore. The aetiology of SSc remains unclear, but genetic factors are believed to influence its development, based on epidemiological studies showing familial clustering of SSc and SSc related disorders including Raynaud’s phenomenon. Genes located within the major histocompatibility complex (MHC) locus have been extensively analysed as candidate genes for susceptibility to SSc, but the findings have suggested that MHC class II genes were associated less with SSc in itself but were instead associated with the expression of SSc related ANAs. We have found MHC class II gene associations with serum SSc related ANAs in Japanese, including anti-topo I antibody with DRB1*1502 and anticentromere antibody (ACA) with DQB1*0501. Moreover, anti-U1 small nuclear ribonucleoprotein (U1snRNP) antibodies, primarily detected in SSc patients with overlap features of lupus and/or myositis, were associated with DQB1*0302 in Japanese patients with connective tissue disease. The immune response genes, which control immune responses to specific antigens, include MHC genes and genes coding for the immunoglobulin (Ig) allotypic markers, the latter are located in the constant regions of Ig heavy and light chains. Previous studies have shown associations between Ig allotypic phenotypes and susceptibility to several autoimmune diseases including systemic lupus erythematosus, myasthenia gravis, and Graves’ disease. 11 The presence of specific ANAs in patients with autoimmune diseases was also shown to be associated with Ig allotypes. 13 Interactive eVects of MHC antigens and Ig allotypes on the production of antibodies directed against foreign and self antigens have been demonstrated. 15 However, influences of Ig allotypes on serological expression in SSc patients are largely undefined. Recently, gene organisation of the Ig loci has been extensively analysed and polymerase chain reaction (PCR) based molecular typing methods for Ig allotypic markers have been established. In this study, therefore, we identified Ig allotype gene polymorphisms in Japanese patients with SSc and examined for associations of these markers with ANA status in SSc patients. Interactive eVects of the two independent immune response genes, MHC class II and Ig allotypes, on SSc related ANA responses were also investigated.