This study represents the first characterization of SGSCs in pSS, and also the first linkage between an autoimmune disease and a parenchymal premature ageing phenotype. The knowledge garnered in this study argues that disease modifying anti-rheumatic drugs used to treat pSS are not likely to restore saliva production, but should be supplemented with fresh SGSCs to recover saliva production. This article is protected by copyright. All rights reserved.
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.
Background: Salivary glands (SGs) can be damaged by immune checkpoint inhibitor (ICI) therapy. In patients with ICI-induced SG dysfunction, 60% progress to fulfill classification criteria for primary Sjögren's syndrome (pSS), owing to immune foci in SGs and/or anti-SSA autoantibody positivity. We report the SG tissue analysis of a patient with SG dysfunction after treatment with a programmed death ligand-1 (PD-L1) inhibitor, compared to that of a dry mouth ("sicca") control and pSS patient.Case presentation: The patient received the PD-L1 inhibitor durvalumab (10 mg/kg, every 2 weeks by intravenous infusion) as adjuvant treatment for stage 3 non-small cell lung carcinoma, following concurrent chemo radiotherapy. At 43 weeks after 21 cycles of Durvalumab, the patient was not capable of producing unstimulated or stimulated parotid gland saliva, and a biopsy was taken. Immunohistochemical analysis showed no classical AQP5 + CK7 − acinar cell clusters (CK7 marks intercalated ducts, IDs). In contrast, the parenchyma was dominated by hybrid epithelial "structures" with ID-like morphology, containing a mixture of AQP5 + CK7 − , AQP5 − CK7 + , and AQP5 + CK7 + cells (30 structures/mm 2 ). These structures were present at lower frequencies in sicca control (2/mm 2 ) and pSS (10/mm 2 ) tissue. Hybrid structures contained proliferating (Ki67 + ) cells and senescent (p16 + ) cells. Striated ducts showed no abnormal morphology post PD-L1 treatment, in contrast to pSS tissue. PD-L1 expression was detected in the SG parenchyma following anti-PD-L1 therapy. The SG post-PD-L1 therapy further demonstrated focal lymphocytic sialadentitis, harboring disperse, and focal CD4 + T cell-rich infiltrates. CD8 + T cells were also present. In this patient, these CD4 + and CD8 + T cells were observed in-between and inside hybrid structures. CD20 + B-cells were infrequently detected following PD-L1 blockade, in contrast to their preponderance in pSS SG tissue.Conclusion: This patient lacked conventional SG acinar cells following anti-PD-L1 therapy and demonstrated presence of hybrid intercalated duct-like structures.Pringle et al. Lack of Acinar Cells With Anti-PD-L1 TherapyUnderstanding which mechanisms and dynamics underpinning this aberrant parenchyma may be crucial to understand how SG dysfunction post ICI therapy, and potentially other affected organs. Furthermore, although the patient treated with anti-PD-L1 antibody examined here fulfills the criteria for pSS and demonstrated focal lymphocytic sialadentitis, the further histopathological characteristics do not resemble pSS.
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