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.

Apoptotic cell-derived exosomes: messages from dying cells

“…Moreover, a recent study showed that apoptotic cells can release MVs and exosomes in addition to ApoBDs 57 . Apoptotic MVs (0.2-1 µm in diameter), also called apoptotic microparticles, are presumed to be synthesized by plasma membrane budding in apoptotic processes and are known to induce proinflammatory cytokines through the transfer of their cargo to recipient dendritic cells or to suppress the immune system 43,[58][59][60] .…”

Activation of Toll‐like receptor 7 signaling in labial salivary glands of primary Sjögren's syndrome patients

“…An earlier investigation showed that apoptotic particles induced TLR-7 and TLR-9 expression in pDCs in vitro [18]. Although our prior study demonstrated that TLR-3 signal activation induced apoptosis in SGECs from individuals with pSS [9], it is not yet known whether stimulation of the TLR-7 signaling pathway induces apoptosis.…”

“…Our earlier investigation demonstrated the expression and function of TLR-2-4 in patients with SS [15], and in the present study we focused on TLR-7-9 from the viewpoint of receptors of nucleic acid sequences of viruses and/or self-antigens. Several studies showed that TLR-7-9 are expressed in PBMCs from SS patients [6,16,17] and one study suggested that apoptosis induced TLR-7 and -9 expressions in pDCs [18]. However, the expression of TLR-7-9 in salivary glands has not been well investigated.…”

Extracellular Vesicles Derived From Apoptotic Cells: An Essential Link Between Death and Regeneration

“…However, with the development of detection technology, researchers have found smaller vesicles ( Simpson and Mathivanan, 2012 ) produced by dying cells in addition to traditional apoptotic bodies. Although there is no well-defined criteria to distinguish ApoBDs from other ApoEVs, the vesicles can be classified by diameter: larger membrane-wrapped vesicles termed ApoBDs/ABs have diameters of 1000–5000 nm ( Atkin-Smith et al, 2015 ), and the smaller vesicles termed apoptotic microvesicles (ApoMVs) or exosome-like ApoEVs ( Park et al, 2018 ) have diameters of 50–1000 nm ( Schiller et al, 2012 ; Ainola et al, 2018 ). Lacking standard classification makes it difficult to draw accurate conclusions on the functions of ApoEVs.…”