Abstract
BackgroundWhile all salivary glands (SGs) can be involved in primary Sjögren’s syndrome (pSS), their respective role in pathogenesis remains unclear. Our objective was to assess immunopathway activation in paired parotid and labial gland tissue from biopsy-positive and biopsy-negative pSS and non-SS sicca patients.MethodsParaffin-embedded, paired parotid and labial salivary gland tissue and peripheral blood mononuclear cells were obtained from 39 pSS and 20 non-SS sicca patients. RNA was extracted, complementary DNA libraries were prepared and sequenced. For analysis of differentially expressed genes (DEGs), patients were subdivided based on fulfillment of ACR-EULAR criteria and histopathology.ResultsWith principal component analysis, only biopsy-positive pSS could be separated from non-SS sicca patients based on SG gene expression. When comparing the transcriptome of biopsy-positive pSS and biopsy-negative non-SS sicca patients, 1235 and 624 DEGs (FDR<0.05, log2FC<-1 or >1) were identified for parotid and labial glands, respectively. The number of DEGs between biopsy-negative pSS and non-SS sicca patients was scarce. Overall, transcript expression levels correlated strongly between parotid and labial glands (R2 = 0.86, p-value<0.0001). Gene signatures present in both glands of biopsy-positive pSS patients included IFN-α signaling, IL-12/IL-18 signaling, CD3/CD28 T-cell activation, CD40 signaling in B-cells, DN2 B-cells, and FcRL4+ B-cells. Signature scores varied considerably amongst pSS patients.ConclusionTranscriptomes of paired major and minor SGs in pSS were overall comparable, although significant inter-individual heterogeneity in immunopathway activation existed. The SG transcriptome of biopsy-negative pSS was indistinguishable from non-SS sicca patients. Different patterns of SG immunopathway activation in pSS argue for personalized treatment approaches.
Highlights
In primary Sjögren’s syndrome, salivary and lacrimal glands are considered main targets of the disease [1]
Gene signatures present in both glands of biopsy-positive primary Sjögren’s syndrome (pSS) patients included IFN-a signaling, IL-12/IL-18 signaling, CD3/CD28 T-cell activation, CD40 signaling in B-cells, double negative type-2 (DN2) B-cells, and FcRL4+ B-cells
The salivary glands (SGs) transcriptome of biopsy-negative pSS was indistinguishable from non-SS sicca patients
Summary
In primary Sjögren’s syndrome (pSS), salivary and lacrimal glands are considered main targets of the disease [1]. In addition to the presence of disease-associated autoantibodies, another important diagnostic feature of pSS is periductal focal lymphocytic sialadenitis (FLS) in salivary glands (SGs) [3]. While the intimate interaction between glandular epithelium and immune cells is likely critical to pSS pathogenesis [6], a clear correlation between immune cell infiltration and main patient-reported symptoms (i.e. dryness, pain and fatigue) or salivary flow rates is lacking [7,8,9]. While all salivary glands (SGs) can be involved in primary Sjögren’s syndrome (pSS), their respective role in pathogenesis remains unclear. Our objective was to assess immunopathway activation in paired parotid and labial gland tissue from biopsy-positive and biopsy-negative pSS and non-SS sicca patients
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