Activation of plasmacytoid dendritic cells by apoptotic particles – mechanism for the loss of immunological tolerance in Sjögren's syndrome

Abstract

Sjögren's syndrome (SS) is a common autoimmune disease targeting salivary and lacrimal glands. It is strongly female-dominant, characterized by low oestrogen levels combined with a local intracrine dihydrotestosterone defect. We hypothesized that these hormonal deficits lead to increased apoptosis of the epithelial cells and plasmacytoid dendritic cell (pDC)-mediated proinflammatory host responses. Expression of Toll-like receptors (TLRs)-7 and -9 and cytokine profiles was studied in pDCs treated with apoptotic particles collected in consecutive centrifugation steps of media from apoptotic cells. Expression and localization of SS autoantigens in these particles was also analysed. Furthermore, the effects of sex steroids were studied in pDCs cultured with several concentrations of dihydrotestosterone and 17-β-oestradiol, and in saliva of patient treated with dehydroepiandrosterone. Apoptosis of the epithelial cells led to cleavage and translocation of SS-autoantigens, α-fodrin and SS-A, into apoptotic particles. The apoptosis-induced apoptotic particles also contained another SS-autoantigen, hy1-RNA. These particles were internalized by pDCs in a size-dependent manner and affected TLR-7 and -9 expression and the production of proinflammatory cytokines. The analysed androgens protected cells from apoptosis, influenced redistribution of autoantigens and diminished the apoptotic particle-stimulated increase of the TLRs in pDCs. Our findings suggest that the formation of apoptotic particles may play a role in loss of immune tolerance, manifested by production of autoantibodies and the onset of autoinflammation in SS.