Progenitor cell niche senescence reflects pathology of the parotid salivary gland in primary Sjögren’s syndrome

Abstract

Objective Salivary gland (SG) progenitor cells (SGPCs) maintain SG homeostasis. We have previously shown that in primary Sjögren’s syndrome (pSS), SGPCs are likely to be senescent, and may underpin SG dysfunction. This study assessed the extent of senescence of cells in a SGPC niche in pSS patients’ SGs, and its correlation with functional and clinical parameters. Methods The expression of p16 and p21 as markers of senescence in both total SG epithelium and a SGPC niche (basal striated duct cells, BSD) was examined in SGs of pSS (n = 35), incomplete pSS (n = 13) (patients with some signs of pSS, but not fulfilling all classification criteria) and non-SS sicca control (n = 21) patients. This was correlated with functional and clinical parameters. Results pSS patient SGs contained significantly more p16+ cells both in the epithelium in general (P <0.01) and in the BSD layer (P <0.001), than non-SS SGs. Significant correlations were found in pSS patients between p16+ BSD cells and secretion of unstimulated whole saliva, stimulated whole saliva, stimulated parotid saliva, CD45+ infiltrate, ultrasound total score and ACR-EULAR classification score, but not with EULAR Sjögren’s syndrome disease activity index (ESSDAI) and EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) scores. Correlations with total epithelium p16+ cells were weaker. Incomplete pSS patients also had increased numbers of p16+ epithelial and BSD cells. Based on protein and mRNA expression, p21+ appears not to play a significant role in the SG in pSS. Conclusion These findings suggest SGPC senescence may be an early feature of primary Sjögren’s syndrome and may contribute to defective SG function in pSS but not to systemic disease activity.

Epithelial–immune cell interplay in primary Sjögren syndrome salivary gland pathogenesis

“…The telomeres of SGPCs from patients with pSS are shorter, suggesting that some SGPCs have indeed undergone replicative senescence 68 . In one study, the degree of senescence of cells located in the basal layer of the striated ducts (where progenitor cells probably reside), as inferred from the expression of the senescence marker p16, correlated with the production of saliva by the parotid salivary gland, the extent of CD45 + cell infiltration and the ultrasound score 69 . The expression of p16 by all acinar and ductal cells combined also correlated with saliva production and CD45 + cell infiltration, but to a lesser extent 69 .…”

“…In one study, the degree of senescence of cells located in the basal layer of the striated ducts (where progenitor cells probably reside), as inferred from the expression of the senescence marker p16, correlated with the produc tion of saliva by the parotid salivary gland, the extent of CD45 + cell infiltration and the ultrasound score 69 . The expression of p16 by all acinar and ductal cells combined also correlated with saliva production and CD45 + cell infiltration, but to a lesser extent 69 . Senescent cells in general have a senescenceassociated secretory pheno type (SASP), consisting of the expression of a panel of proinflammatory cytokines (including IL1α, IL1β, IL6, IL7, IL13, IL15, TGFβ, GMCSF and TNF), chemokines (including IL8, GROα, GROβ, CCL2, CCL3, CCL5, CCL16, CCL26 and CCL20), growth fac tors (including HGF and FGF), matrix metalloproteases and proteases [70][71][72] .…”

Imaging in Primary Sjögren’s Syndrome

“…Another explanation could be that sialectasis represents extravasation of contrast material into the glandular parenchyma. A possible explanation for the leakage of contrast medium in pSS patients is dysfunction of tight junctions between striated ductal cells, due to the presence of proinflammatory cytokines [ 30 ]. In addition to sialectasis, sparsity of the ductal branching pattern can be found during sialography [ 3 , 31 , 32 ].…”

“…One explanation for this association could be that hypoechogenic areas originate from leakage of saliva that is transported through the ductal system into the periductal infiltrate, and eventually into the salivary gland parenchyma. Leakage of saliva from the ductal system can be a comparable phenomenon to leakage of contrast medium during sialography, due to dysfunction of tight junctions between striated ductal cells [ 30 ]. However, collections of saliva in the periductal infiltrates or parenchyma are not commonly seen in salivary gland biopsies of pSS patients.…”

A comprehensive overview of major salivary gland ultrasonography in (suspected) primary Sjögren’s syndrome

“…Wang et al 56 hypothesized that presence of hypoechogenic areas could be caused by leakage of saliva into the periductal infiltrate and eventually into the salivary gland parenchyma, due to dysfunction of tight junctions between striated ductal cells. Pro-inflammatory cytokines are able to reduce the function of tight junctions.…”