Background Systemic sclerosis (SSc) is an autoimmune disease characterized by immune activation, vascular damage, and fibrosis of the skin and/or internal organs. Patients are classified as having diffuse cutaneous SSc (dcSSc) with antibodies to topoisomerase 1 or fibrillarin or limited cutaneous (lcSSc) with antibodies to centromeric antigens (ACA). The immunopathogenic mechanisms responsible for disease are poorly defined.
Objectives (1) To determine whether serum from systemic sclerosis (SSc) patients with different clinical subsets and defined autoantibodies induce interferon (IFN)-α production when exposed to antigen in the presence of plasmacytoid dendritic cells (pDCs). (2) To determine the mechanisms by which IFN-α production is induced in a defined test system.
Methods SSc sera containing one of three different autoantibody specificities against topoisomerase I, fibrillarin, and centromeric proteins (ACA) were cultured with a source of antigens obtained from a crude nuclear extract and added to peripheral blood mononuclear cell (PBMC) cultures. In some experiment, inhibitors of CD32a (specific antibody), endocytosis (bafilomycin A1, chloroquine), or Toll-like receptors (IRS 661, IRS 869) were used. The produced IFN-α was measured my immunoassay.
Results SSc sera containing topoisomerase I or fibrillarin but not that containing ACA induced IFN-α production statistically significantly greater than observed with normal controls in the presence of antigen. This response was decreased by blockade of CD32, the endocytic pathway, or TLR7.
Conclusions The difference in IFN-α production between dcSSc sera (patients with antibodies to topoisomerase I or fibrillarin) and lcSSc (patients with ACA) suggests that production of IFN-α may be important for shedding light on the immunologic differences between dcSSc and lcSSc. In addition, the interaction of CD32 and TLRs in IFN-α production is important in revealing molecular mechanisms behind the pathogenesis of systemic sclerosis and other autoimmune diseases characterized by autoantigens associated with nucleic acids.