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

Summary 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 increase...

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Bibliographic Details
Published in:Clinical and experimental immunology 2018-03, Vol.191 (3), p.301-310
Main Authors: Ainola, M., Porola, P., Takakubo, Y., Przybyla, B., Kouri, V. P., Tolvanen, T. A., Hänninen, A., Nordström, D. C.
Format: Article
Language:English
Subjects:
Adult
Aged
Apoptosis
autoimmunity
Carrier Proteins - immunology
Carrier Proteins - metabolism
Cell Differentiation
Cells, Cultured
cytokines
Cytokines - metabolism
dendritic cells
Dendritic Cells - immunology
Dihydrotestosterone - metabolism
Epithelial Cells - immunology
Epithelial Cells - metabolism
Estrogens - metabolism
Extracellular Vesicles - immunology
Extracellular Vesicles - metabolism
Female
Humans
Immune Tolerance
Inflammation Mediators - metabolism
Male
Microfilament Proteins - immunology
Microfilament Proteins - metabolism
Middle Aged
Original
Ribonucleoproteins - metabolism
Salivary Glands - metabolism
Salivary Glands - pathology
Sjogren's Syndrome - immunology
Toll-Like Receptor 7 - genetics
Toll-Like Receptor 7 - metabolism
Toll-Like Receptor 9 - genetics
Toll-Like Receptor 9 - metabolism
Toll‐like receptors (TLRs)
Young Adult
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Summary:Summary 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. Hormonal deficits in Sjögren's syndrome may lead to increased apoptosis of the epithelial cells and thus plasmacytoid dendritic cell (pDC) mediated pro‐inflammatory host responses. Cell derived apoptotic particles were attached to the surface or taken into pDCs. The intake of apoptotic particles increased TLRs and proinflammatory cytokines in pDCs, but not IFNs, and the effects depend on the size of particles, as apoptotic bodies (1‐4 µm) were mainly secreted in pellet 3 (P3) and microparticles (200‐1000 nm) in pellet 5.
ISSN:0009-9104
1365-2249
DOI:10.1111/cei.13077