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Autoantibodies, genetic polymorphisms and clinical subsets in systemic sclerosis

Systemic sclerosis is an autoimmune disease characterised by fibrosis and serological autoantibodies (Aabs), some of which are indicative of disease subtype. A degree of Aab mutual exclusivity gives rise to three, major serological groups. Genetic associations with SSc become stronger when autoantibody subgroups are considered. There are ethnic differences in the pattern of disease and autoantibody frequencies. The aims of this thesis are to further understanding of the aetio-pathogenesis of SSc by; investigating autoantibody specificity, identifying possible genetic predetermination or restriction of Aab generation and exploring the relationship of these two factors with disease profile, course and outcome. A variety of standard serological and genetic methods have been used in this investigation. Several important findings have been made in the present study: I) Although patients with anti-topoisomerase I antibodies (ATA) or anti-RNA polymerase III antibodies (ARA III) represented distinct groups, their mutual exclusivity could not be explained by the genetic analysis in this study: II) ATA positive SSc patients and normal controls showed T cell proliferative responses to recombinant topoisomerase I, and shared a common genetic background. This is consistent with the notion that auto-reactive T cells are part of the immune system repertoire and the ability to mount a T cell proliferative response is genetically restricted: III) HLA background, autoantibody profile and clinical course are ethnically variable, however associations between these three factors are independent of ethnicity: IV) The majority (91%) of ACA positive patients had IcSSc and an association with HLA DR1 and DR4: V) Consideration of the genetic contribution to fibrosis identified microsatellite marker associations with TGFp2 and TGFP3 indicating that polymorphisms exist in these genes that predispose individuals to SSc. Stratification according to serological groups showed similar associations with microsatellite marker as stratification according to skin type. Together these results provide evidence to suggest a genetic susceptibility to specific autoimmune responses in SSc. Existing HLA associations are supported and new ones are proposed. Polymorphisms of specific fibrosis genes may exist that are associated with disease. Overall, the relationship between HLA-autoantibody-disease subset has been supported and defined to some degree. Increased understanding of this relationship may further elucidate the pathogenic mechanism underlying SSc and ultimately improve the diagnostic and prognostic value of autoantibodies as disease markers.