Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome

Maria, Naomi I.; Steenwijk, Eline C.; IJpma, Arne; Helden-Meeuwsen, Cornelia G van; Vogelsang, Petra; Beumer, Wouter; Brkić, Zana; Daele, Paul L A van; Hagen, P. Martin van; Spek, Peter J. van der; Drexhage, Hemmo A.; Versnel, Marjan A.

doi:10.1136/annrheumdis-2016-209589

Cited by 72 publications

(82 citation statements)

References 51 publications

(50 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Zheng et al reported that TLR-7 and TLR-9 were predominantly expressed in lymphocytes of the parotid glands from pSS patients compared to those of control subjects [6]. In contrast, Maria et al reported that TLR-7 was expressed by few cells within the lymphocytic foci [16]. Our present findings demonstrate that TLR-7 was expressed more strongly than TLR-9 in mononuclear cells of labial salivary glands.…”

Section: Discussioncontrasting

confidence: 51%

“…However, the expression of TLR-7-9 in salivary glands has not been well investigated. In contrast, Maria et al reported that TLR-7 was expressed by few cells within the lymphocytic foci [16]. In contrast, Maria et al reported that TLR-7 was expressed by few cells within the lymphocytic foci [16].…”

Section: Discussionmentioning

confidence: 93%

“…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.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2018

View full text Add to dashboard Cite

The aim of this study was to determine the expressions of Toll-like receptors (TLRs) 7-9 and type I interferon (IFN) signal in labial salivary glands (LSGs) and cultured salivary gland epithelial cells (SGECs) from primary Sjögren's syndrome (pSS) patients. We performed an immunohistochemistry analysis of LSGs from 11 patients with pSS as defined by American-European Consensus Group classification criteria and five healthy subjects. The pSS patients' SGECs were analyzed by immunofluorescence and western blotting. IFN-α expression was examined by immunosorbent assay and flow cytometry. Mononuclear cells (MNCs) from pSS patients' LSGs showed TLR-7-dominant expression. B cells, plasma cells and plasmacytoid dendritic cells (pDCs) co-expressed with TLR-7.Myeloid differentiation primary response gene 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6) and interferon regulatory factor 7 (IRF7) co-expressed with the pDC marker CD303 in LSGs. Ducts from pSS patients dominantly expressed TLR-7, and TLR-7 in the ducts coexpressed with MyD88, TRAF6 and IRF7. Type I IFNs including IFN-α and IFN-β were detected in MNCs and ducts in pSS patients' LSGs. Increased TRAF6 expression and the nuclear translocation of IRF7 in SGECs were detected by immunofluorescence following loxoribine (a TLR-7 ligand) stimulation despite IFN-β pretreatment. Western blotting showed increased TRAF6 expression in SGECs following IFN-β and loxoribine stimulation. Although no increase in IFN-α was detected in supernatant from stimulated SGECs, the IFN-α in supernatant from stimulated peripheral blood pDCs from pSS patients was significantly increased. Our findings suggest that TLR-7 is dominantly expressed in both MNCs and ducts with downstream signals for type I IFNs, indicating that TLR7-dominant innate immunity is related to the development of sialadenitis in pSS.

show abstract

Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…A recent examination of the relationship between type I IFN and pDCs in SS conducted a genome-wide microarray analysis of isolated pDCs and CD14 + monocytes obtained from 115 patients with pSS and 42 healthy subjects [109]. In accordance with the above-cited studies, TLR7 gene (but not TLR9 gene) was up-regulated when the cell types were restricted to IFN-positive cells.…”

Section: The Involvement Of Tlrs In Sjögren’s Syndromementioning

confidence: 96%

Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren’s Syndrome

Nakamura

Horai

Shimizu

et al. 2018

IJMS

View full text Add to dashboard Cite

The pathogenesis of Sjögren’s syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients’ SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor.

show abstract

“…However, B cells from pSS patients secrete increased amounts of several pro-inflammatory cytokines when stimulated with agonists for TLR7 or TLR9, suggesting that TLR signaling in B cells may contribute to the chronic inflammatory landscape observed [106]. Interestingly, a recent study found that when pSS patients were segregated on the basis of type I IFN expression, pDCs and monocytes from the IFN-expressing subset expressed elevated levels of TLR7, whereas IFN negative patients expressed normal levels of TLR7 [107]. Thus, these studies suggest that endosomal TLRs contribute to SS and may be particularly important in IFN positive patients, although further work is required to understand the way in which TLR signaling pathways mediate pathology in SS.…”

Section: Mechanisms Of Innate Immune Activation In Ssmentioning

confidence: 99%

Innate immunity in Sjögren's syndrome

Kiripolsky

McCabe

Kramer

2017

Clinical Immunology

View full text Add to dashboard Cite

Sjögren’s syndrome (SS) is an autoimmune disease of exocrine tissue that primarily affects women. Although patients typically experience xerostomia and xerophthalmia, numerous systemic disease manifestations are seen. Innate immune hyperactivity is integral to many autoimmune diseases, including SS. Results from SS mouse models suggest that innate immune dysregulation drives disease and this is a seminal event in SS pathogenesis. Findings in SS patients corroborate those in mouse models, as innate immune cells and pathways are dysregulated both in exocrine tissue and in peripheral blood. We will review the role of the innate immune system in SS pathogenesis. We will discuss the etiology of SS with an emphasis on innate immune dysfunction. Moreover, we will review the innate cells that mediate inflammation in SS, the pathways implicated in disease, and the potential mechanisms governing their dysregulation. Finally, we will discuss emerging therapeutic approaches to target dysregulated innate immune signaling in SS.

show abstract

Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome

Abstract: Here we conclude a contrasting expression pattern of the RNA-sensing receptors TLR7, RIG-I and MDA5 in pDCs and monocytes of patients with IFNpos pSS. This profile could explain the pathogenic IFN production and might reveal novel therapeutic targets in these patients.

Cited by 72 publications

References 51 publications

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

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

Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren’s Syndrome

Innate immunity in Sjögren's syndrome

Contact Info

Product

Resources

About