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THU0270 Activation of Plasmacytoid Dendritic Cells by Apoptotic Particles - Mechanism for The Loss of Immunologic Tolerance in Androgen-Depleted Sjögren's Syndrome
  1. M. Ainola1,
  2. P. Porola1,
  3. Y. Takakubo2,
  4. B. Przybyla3,
  5. T. Tolvanen4,
  6. A. Hänninen5,
  7. Y. Konttinen1,6,
  8. D. Nordström1,6
  1. 1Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
  2. 2Department of Orthopaedic Surgery, Yamagata University, Yamagata, Japan
  3. 3Hematology and Cancer Center, Helsinki University Central Hospital
  4. 4Department of Pathology, University of Helsinki, Helsinki
  5. 5Department of Medical microbiology and immunology, University of Turku, Turku
  6. 6Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland

Abstract

Background Sjögren's syndrome (SS) is a common autoimmune disease targeting salivary and lacrimal glands. It is strongly female-dominant characterized by low estrogen (E) levels combined with a local intracrine dihydrotestosterone defect (DHT) [1, 2]. It is assumed that the primary effect in SS is the abnormal apoptosis of salivary gland cells, combined with increased production and abnormal handling of the apoptotic particles [3].

Objectives The working hypothesis was that these hormonal defects lead to increased apoptosis of the epithelial cells and pro-inflammatory plasmacytoid dendritic cell (pDC) mediated host responses. Apoptosis induced particles contain SS autoantigens, which may affect immune cells.

Methods Apoptotic particles were collected by different centrifugation steps. The expression and localization of SS autoantigens (α-fodrin and SS-A) was analysed with flow cytometry. Isolated apoptotic particles were used to stimulate pDCs. The effect of the particles on TLR7/9 expression in pDCs was studied with qPCR and the elicited cytokine/interferon (IFN) profile with xMAP and ELISA measurements. To study the effects of sex steroids, pDCs were cultured without and with various concentrations of dehydroepiandrosterone (DHEA), DHT and 17-β-estradiol (E2).

Results Apoptosis-induced apoptotic particles contained SS-autoantigens and hy1-RNA. These particles were internalized by pDCs, which stimulated the TLR expression and the production of proinflammatory cytokines TNF-α, interleukin-6 (IL-6) and IL-8. On the contrary, type I IFN production was not induced. Androgens inhibited the particle-induced increase of TLR9 expression in pDCs.

Conclusions Apoptosis of epithelial cells leads to translocation of SS-autoantigens and single-stranded hy1-RNA to apoptotic blebs and membrane particles. The apoptotic particles are internalized by pDCs, which in response mature and produce proinflammatory cytokines. Androgens affect to redistribution of autoantigens and diminish the particle-elicited increase of TLR expression in pDCs. Apoptosis of salivary gland cells lead to formation of apoptotic particles, which might affect immunotolerance, production of autoantibodies and onset of autoinflammation. This event might describe how the immunologic tolerance is broken in the early stages of SS.

  1. Porola P, Virkki L, Przybyla BD, Laine M, Patterson TA, Pihakari A, Konttinen YT. Androgen deficiency and defective intracrine processing of dehydroepiandrosterone in salivary glands in SS. J Rheumatol 35(11):2229–35, 2008

  2. Konttinen YT, Stegajev V, Al-Samadi A, Porola P, Hietanen J, Ainola M. SS and extragonadal sex steroid formation: A clue to a better disease control? J Steroid Biochem Mol Biol 145C:237–244, 2015

  3. Konttinen YT, Fuellen G, Bing Y, Porola P, Stegaev V, Trokovic N, Falk SS, Liu Y, Szodoray P, Takakubo Y. Sex steroids in SS. J Autoimmun 39(1–2):49–56, 2012

Disclosure of Interest None declared

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