Activation of the type I interferon system in primary Sjogren's syndrome -: A possible etiopathogenic mechanism

Objective. The etiopathogenesis of primary Sjogren's syndrome (SS) is largely unknown. In other autoimmune diseases, type I interferon (IFN) may play a pivotal role by triggering and sustaining the disease process. We therefore aimed to determine whether patients with primary SS had an activated type I IFN system. Methods. Salivary gland biopsy specimens and sera from patients with primary SS were investigated for the occurrence of IFN alpha-producing cells and measurable IFN alpha levels, respectively. The ability of primary SS sera together with apoptotic or necrotic cells to induce IFN alpha production in normal peripheral blood mononuclear cells was examined. The IFN alpha inducer was characterized, and IFNa-producing cells were identified. Clinical data were correlated with the IFN alpha-inducing capacity of primary SS sera. Results. Numerous IFN alpha-producing cells were detected in salivary gland biopsy specimens, despite low serum IFN alpha levels. Autoantibodies to RNA-binding proteins, combined with material released by necrotic or late apoptotic cells, were potent inducers of IFNa production in plasmacytoid dendritic cells (PDCs). This appeared to be attributable to RNA-containing immune complexes triggering PDCs by means of RNA and interaction with Fc gamma receptor IIa. The IFN alpha-inducing capacity of sera was associated with positive results of a labial salivary gland biopsy (focus score >= 1) and with dermatologic, hematologic, and pulmonary manifestations. Conclusion. Patients with primary SS have an activated type I IFN system. Although virus may initiate the production of IFN, the continued IFN alpha synthesis is caused by RNA-containing immune complexes that activate PDCs to prolong IFN alpha production at the tissue level. This IFN alpha promotes the autoimmune process by a vicious circle-like mechanism, with increased autoantibody production and formation of more endogenous IFN alpha inducers.