Role of the mTOR pathway in minor salivary gland changes in Sjogren’s syndrome and systemic sclerosis

Abstract

BackgroundTo examine the activity of the mammalian target of rapamycin (mTOR) pathway and its regulators, transforming growth factor (TGF)-β1 and phosphatase and tensin homolog (PTEN), in minor salivary gland biopsies of Sjogren’s syndrome (SS) and systemic sclerosis (SSc) patients.MethodsWe retrospectively evaluated SS, SSc, and SS-SSc overlap patients admitted to our outpatient rheumatology clinic between January 2007 and December 2015 who underwent a minor salivary gland biopsy. Patient demographics and some clinical features were obtained from hospital records. Immunohistochemistry was used to analyze total mTOR, total PTEN, and TGF-β1 expression in the biopsied tissues. The biopsy specimens were also examined for the presence and degree of fibrosis.ResultsMinor salivary gland biopsies of 58 SS, 14 SSc, and 23 SS-SSc overlap patients were included in the study. There was no significant difference in mTOR expression between these groups (P = 0.622). PTEN protein was expressed in 87.2% of patients with SS, 57.9% with overlap syndrome, and 100% of the SSC patients, and these differences were statistically different (P = 0.023). Although ductal epithelial TGF-β1 expression was similar between the groups (P = 0.345), acinar cell expression was found to be more frequent in the SSc (72.7%) and overlap patients (85.7%) in comparison with the SS cases (58.2%; P = 0.004).ConclusionmTOR may be one of the common pathways in the pathology of both SS and SSc. Hence, there may be a role for mTOR inhibitors in the treatment of both diseases. Additionally, PTEN and TGF-β1 expression may be a distinctive feature of SSc.

Small-molecule inhibitors and the salivary gland epithelium in Sjögren’s syndrome

“…Studies relating specifically to the SG parenchyme and autophagy are fairly preliminary. In a comparison of minor SGs from patients with pSS scleroderma and systemic sclerosis, elevated activity of the mTOR pathway (and thus inhibited autophagy) was observed in the epithelium as a whole, although the lack of a healthy control comparison makes the results of this study challenging to interpret [29]. Proctor et al showed that application of rapamycin, and thus increased autophagy, in a duct ligation injury model transiently stabilized the atrophic murine SG, although this effect was relatively short-lived [98].…”

“…Indeed, TLR3 stimulated SGECs also demonstrated an enhanced mRNA level expression of the Ro60, Ro52 and SSB autoantigens on their surfaces as a consequence of apoptosis facilitating initiation of an immune response by immune cells [25][26][27]. In addition to the increased apoptosis of epithelial cells, the SG epithelium has also been demonstrated to contain autophagy machinery that is less active [25,26,28,29]. Using SG organoid cultures, we have recently demonstrated that the proinflammatory cytokines IFNα, TNFα, and IL-6 induce proliferation of SG ductal cells, appearing to promote their premature transition into replicative senescence [20].…”

“…During stress situations, the autophagic machinery recycles cellular resources to enable their applications where most needed. Autophagy has been demonstrated to be less active in pSS, pointing to a need to normalize this imbalance in order to restore saliva production [28,29].…”

Vasoactive intestinal peptide exerts therapeutic action by regulating PTEN in a model of Sjögren's disease

“…B cell lymphoma in SS frequently occurs in salivary glands, whereas PTEN suppresses tumor cell growth and survival. Soypacaci et al 30 have reported that PTEN protein is expressed in 87.2% of SS outpatients in the salivary gland in a retrospective evaluation. However, the disadvantage of this research is the absence of a healthy control group.…”

Redox Pathogenesis in Rheumatic Diseases

“…NAC blocks mTOR activation in lupus T cells, 67 and rapamycin affords clinical benefit in patients with SLE. 64,74,75,144 Along these lines, mTOR is activated, [145][146][147][148] and rapamycin has demonstrated therapeutic benefit in mice 149,150 and patients with SjS. 151,152 Scleroderma and progressive systemic sclerosis Scleroderma or progressive systemic sclerosis (PSS) is a connective tissue disorder characterized by fibroblast activation, extracellular collagen matrix synthesis, skin and organ fibrosis, vascular hyperactivity and remodeling, and autoimmunity.…”