Abstract
BackgroundPrimary Sjogren’s syndrome (pSS) is a slowly progressive, inflammatory autoimmune disease characterized by lymphocytic infiltration into salivary and lacrimal glands. It becomes more recognized that morphology alterations of epithelial mitochondria are involved in altered cellular bioenergetics in pSS patients. The integrated analysis of the mitochondrial role in the pathogenesis and aberrant immune microenvironment in pSS remains unknown.MethodsThe mitochondria-related genes and gene expression data were downloaded from the MitoMiner, MitoCarta, and NCBI GEO databases. We performed novel transcriptomic analysis and constructed a network between the mitochondrial function and immune microenvironment in pSS-salivary glands by computer-aided algorithms. Subsequently, real-time PCR was performed in clinical samples in order to validate the bioinformatics results. Histological staining and transmission electron microscopy (TEM) were further studied on labial salivary gland samples of non-pSS and pSS patients characterized for mitochondria-related phenotypic observation in the different stages of the disease.ResultsThe bioinformatic analysis revealed that the expression of several mitochondria-related genes was altered in pSS. Quantitative real-time PCR showed that four hub genes, CD38, CMPK2, TBC1D9, and PYCR1, were differentially expressed in the pSS clinical samples. These hub genes were associated with the degree of immune cell infiltration in salivary glands, the mitochondrial respiratory chain complexes, mitochondrial metabolic pathway in gluconeogenesis, TCA cycle, and pyruvate/ketone/lipid/amino acid metabolism in pSS. Clinical data revealed that the gene expression of fission (Fis1, DRP1, and MFF) and fusion (MFN1, MFN2, and OPA1) was downregulated in pSS samples, consistent with the results from the public validation database. As the disease progressed, cytochrome c and Bcl-2 proteins were regionally distributed in salivary glands from pSS patients. TEM revealed cytoplasmic lipid droplets and progressively swollen mitochondria in salivary epithelial cells.ConclusionOur study revealed cross talk between mitochondrial dysfunction and the immune microenvironment in salivary glands of pSS patients, which may provide important insights into SS clinical management based on modulation of mitochondrial function.
Highlights
Primary Sjogren’s syndrome is a systemic autoimmune disease, typically presenting as keratoconjunctivitis sicca and xerostomia [1]
The results suggested that the genes CD38, CMPK2, and TBC1D9 were relatively overexpressed in labial salivary glands (LSGs) from all patients with Primary Sjogren’s syndrome (pSS), while PYCR1 was underexpressed (p < 0.05)
We found that CD38, CMPK2, TBC1D9, and PYCR1 are important across many metabolic pathways, which suggest substantial cross talk and potential overlap
Summary
Primary Sjogren’s syndrome (pSS) is a systemic autoimmune disease, typically presenting as keratoconjunctivitis sicca and xerostomia [1]. A significant percentage of patients are accompanied by fatigue, musculoskeletal pain, and systemic features, and complicated by lymphoma in around 2%–5% of patients [2, 3]. These symptoms have a major effect on quality of life in patients with pSS [4]. The histological hallmark of pSS is inflammatory mediators and lymphocytic infiltration to exocrine glands [1, 7]. Ectopic and germinal centers presented in salivary glands caused by B cell overactivation can increase the risk for lymphoma [9]. Primary Sjogren’s syndrome (pSS) is a slowly progressive, inflammatory autoimmune disease characterized by lymphocytic infiltration into salivary and lacrimal glands. The integrated analysis of the mitochondrial role in the pathogenesis and aberrant immune microenvironment in pSS remains unknown
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