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Gene expression alterations in salivary gland epithelia of Sjogren's syndrome patients are associated with clinical and histopathological manifestations.

ABSTRACT: Sjögren's syndrome (SS) is a complex autoimmune disease associated with lymphocytic infiltration and secretory dysfunction of salivary and lacrimal glands. Although the etiology of SS remains unclear, evidence suggests that epithelial damage of the glands elicits immune and fibrotic responses in SS. To define molecular changes underlying epithelial tissue damage in SS, we laser capture microdissected (LCM) labial salivary gland epithelia from 8 SS and 8 non-SS controls for analysis by RNA sequencing (RNAseq). Computational interrogation of gene expression signatures revealed that, in addition to a division of SS and non-SS samples, there was a potential intermediate state overlapping clustering of SS and non-SS samples. Differential expression analysis uncovered signaling events likely associated with distinct SS pathogenesis. Notable signals included the enrichment of IFN-γ and JAK/STAT-regulated genes, and the induction of genes encoding secreted factors, such as LTF, BMP3, and MMP7, implicated in immune responses, matrix remodeling and tissue destruction. Identification of gene expression signatures of salivary epithelia associated with mixed clinical and histopathological characteristics suggests that SS pathology may be defined by distinct molecular subtypes. We conclude that gene expression changes arising in the damaged salivary epithelia may offer novel insights into the signals contributing to SS development and progression.

SUBMITTER: Dela Cruz A

PROVIDER: S-EPMC8159963 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Gene expression alterations in salivary gland epithelia of Sjögren's syndrome patients are associated with clinical and histopathological manifestations.

Dela Cruz Ariana A Kartha Vinay V Tilston-Lunel Andrew A Mi Rongjuan R Reynolds Taylor L TL Mingueneau Michael M Monti Stefano S Jensen Janicke L JL Skarstein Kathrine K Varelas Xaralabos X Kukuruzinska Maria A MA

Scientific reports 20210527 1

Sjögren's syndrome (SS) is a complex autoimmune disease associated with lymphocytic infiltration and secretory dysfunction of salivary and lacrimal glands. Although the etiology of SS remains unclear, evidence suggests that epithelial damage of the glands elicits immune and fibrotic responses in SS. To define molecular changes underlying epithelial tissue damage in SS, we laser capture microdissected (LCM) labial salivary gland epithelia from 8 SS and 8 non-SS controls for analysis by RNA sequen ...[more]

PMID: 34045583

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Project description:Primary Sjögren's syndrome is a multisystem autoimmune disease characterized by hypofunction of salivary and lacrimal glands and possible multi-organ system manifestations. Over the past 15 years, three sets of diagnostic criteria have been proposed, but none has included salivary gland ultrasonography. However, recent studies support its role in the diagnosis and prognostic evaluation of patients with Sjögren's syndrome. This study aimed to determine the value of salivary gland ultrasonography in the diagnosis and prognosis of Sjögren's syndrome by relating ultrasonography severity scores to clinical and laboratory data.Seventy patients who fulfilled the 2002 American-European Consensus Group diagnostic criteria for primary Sjögren's syndrome were selected from 84 patients receiving care in specialized outpatient clinics at our institution from November 2013 to May 2016. Their serology, European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI), salivary flow rate, immunoglobulin G, and salivary and serum beta-2 microglobulin levels were measured. Salivary gland ultrasonography was performed by an experienced radiologist, using scores of 1-4 to classify salivary gland impairment.Salivary gland ultrasonography scores of 1 or 2 were associated with an ESSDAI < 5. Ultrasonography scores of 3 or 4 were associated with an ESSDAI ≥5 (p = 0.064), a positive antinuclear antibody test (p = 0.006), positive anti-Ro/SSA antibodies (p = 0.003), positive anti-La/SSB antibodies (p = 0.077), positive rheumatoid factor (p = 0.034), and immunoglobulin G levels > 1600 mg/dL (p = 0.077). Salivary flow rate was lower in patients with scores 3 or 4 (p = 0.001).This study provides further evidence that salivary gland ultrasonography can be used not only for diagnosis but also for prognostic evaluation of primary Sjögren's syndrome. These findings confirm what has been reported in the literature. However, further analyses involving larger matched samples are required to support this finding and include salivary gland ultrasonography as part of the diagnostic criteria for Sjögren's syndrome.

Project description:ObjectiveA major characteristic of the autoimmune disease primary Sjögren's syndrome (SS) is salivary gland (SG) hypofunction. The inability of resident SG stem cells (SGSCs) to maintain homeostasis and saliva production has never been explained and limits our comprehension of mechanisms underlying primary SS. The present study was undertaken to investigate the role of salivary gland stem cells in hyposalivation in primary SS.MethodsSGSCs were isolated from parotid biopsy samples from controls and patients classified as having primary SS or incomplete primary SS, according to the American College of Rheumatology/European League Against Rheumatism criteria. Self-renewal and differentiation assays were used to determine SGSC regenerative potential, RNA was extracted for sequencing analysis, single telomere length analysis was conducted to determine telomere length, and frozen tissue samples were used for immunohistochemical analysis.ResultsSGSCs isolated from primary SS parotid gland biopsy samples were regeneratively inferior to healthy control specimens. We demonstrated that SGSCs from samples from patients with primary SS are not only lower in number and less able to differentiate, but are likely to be senescent, as revealed by telomere length analysis, RNA sequencing, and immunostaining. We further found that SGSCs exposed to primary SS-associated proinflammatory cytokines we induced to proliferate, express senescence-associated genes, and subsequently differentiate into intercalated duct cells. We also localized p16+ senescent cells to the intercalated ducts in primary SS SG tissue, suggesting a block in SGSC differentiation into acinar cells.ConclusionThis study represents the first characterization of SGSCs in primary SS, and also the first demonstration of a linkage between an autoimmune disease and a parenchymal premature-aging phenotype. The knowledge garnered in this study indicates that disease-modifying antirheumatic drugs used to treat primary SS are not likely to restore saliva production, and should be supplemented with fresh SGSCs to recover saliva production.

Dataset Information

Gene expression alterations in salivary gland epithelia of Sjogren's syndrome patients are associated with clinical and histopathological manifestations.

Publications

Gene expression alterations in salivary gland epithelia of Sjögren's syndrome patients are associated with clinical and histopathological manifestations.

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