MHC class II associations with autoantibody and T cell immune responses to the scleroderma autoantigen topoisomerase I.

Topoisomerase I (topo I) is a major autoantigen recognized by autoantibodies in about 30% of sera from patients with systemic sclerosis (SSc). Certain HLA-DRB1 and HLA-DQB1 alleles have been reported to be associated with autoantibody and T-cell responses to topo I suggesting a T-cell dependent process. We have examined the MHC class II allele associations with anti-topo I antibodies in 16 patients with SSc compared to 250 healthy controls. Furthermore, we have studied the T cell responses to a recombinant full-length topo I molecule purified from a baculovirus expression system in eight patients with SSc and eight controls (five healthy and three with autoimmune disease). HLA-DR5 was significantly increased in patients with anti-topo I antibodies (P< 0.02). Proliferative peripheral blood mononuclear cell (PBMC) responses to soluble topo I were present in nine of 16 individuals (four of eight with SSc and five of eight controls), including the three SSc patients with anti-topo I antibodies. Homozygosity for HLA DQB1:30:Y alleles was present in five of nine responders (P< 0.03) compared to none of the non-responders. Our findings support the notion that the MHC class II background influences the ability to generate an autoimmune response to intracellular autoantigens to which the immune system may not have been tolerized. Additional factors associated with the generation of autoantibodies appear to be more intimately associated with the development of SSc.