Abstract
PurposeTo develop a novel method to quantify the amount of fibrosis in the salivary gland and to investigate the relationship between fibrosis and specific symptoms associated with Sjögren’s syndrome (SS) using this method.Materials and MethodsParaffin-embedded labial salivary gland (LSG) slides from 20 female SS patients and their clinical and LSG pathology data were obtained from the Sjögren’s International Collaborative Clinical Alliance. Relative interstitial fibrosis area (RIFA) in Masson’s trichrome-stained LSG sections was quantified from digitally scanned slides and used for correlation analysis. Gene expression levels were assessed by microarray analysis. Core promoter accessibility for RIFA-correlated genes was determined using DNase I hypersensitive sites sequencing analysis.ResultsRIFA was significantly correlated with unstimulated whole saliva flow rate in SS patients. Sixteen genes were significantly and positively correlated with RIFA. In a separate analysis, a group of differentially expressed genes was identified by comparing severe and moderate fibrosis groups. This combined set of genes was distinct from differentially expressed genes identified in lung epithelium from idiopathic pulmonary fibrosis patients compared with controls. Single-cell RNA sequencing analysis of salivary glands suggested most of the RIFA-correlated genes are expressed by fibroblasts in the gland and are in a permissive chromatin state.ConclusionRIFA quantification is a novel method for assessing interstitial fibrosis and the impact of fibrosis on SS symptoms. Loss of gland function may be associated with salivary gland fibrosis, which is likely to be driven by a unique set of genes that are mainly expressed by fibroblasts.
Highlights
Salivary and lacrimal gland hypofunction are hallmarks of Sjögren’s syndrome (SS) and are associated with a decreased quality of life [1]
To establish a numerical quantification of interstitial fibrosis, the relative interstitial fibrosis area (RIFA) was measured by assessing the interstitial fibrosis area per mm2 of total glandular area on images from Masson’s trichrome–stained labial salivary gland (LSG) sections (Figure 2)
In the categorical classification defined by s International Collaborative Clinical Alliance (SICCA), patients with FLS have minimal or no fibrosis formation, whereas FLS/sclerosing chronic sialadenitis (SCS) and non-specific chronic sialadenitis (NSCS) are characterized by intermediate fibrosis, and the most severe form of fibrosis is seen in SCS [4]
Summary
Salivary and lacrimal gland hypofunction are hallmarks of Sjögren’s syndrome (SS) and are associated with a decreased quality of life [1]. Daniels et al identified lymphocytic infiltration and interstitial fibrosis as two characteristic microscopic changes in LSG biopsy in SS [4]. It is important to understand if other pathological changes such as interstitial fibrosis is associated with salivary gland hypofunction in SS. Four LSG microscopic groups were proposed to assess the degree of interstitial fibrosis and lymphocytic infiltration in SS in our study. These include the following: non-specific chronic sialadenitis (NSCS; presence of scattered or focal infiltrates of lymphocytes with moderate interstitial fibrosis and gland atrophy), FLS (presence of one or more focal lymphocytic foci as the most prominent feature), sclerosing chronic sialadenitis (SCS; predominant changes are interstitial fibrosis and acinar atrophy), and FLS/SCS (combination of FLS and SCS features)
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