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Longitudinal analysis of tear cathepsin S activity levels in male non-obese diabetic mice suggests its potential as an early stage biomarker of Sjogren's Syndrome.

ABSTRACT: CONTEXT:Cathepsin S (CTSS) activity is elevated in Sjögren's Syndrome (SS) patient tears. OBJECTIVE:To evaluate longitudinal expression of tear and tissue CTSS activity relative to other disease indicators in Non-Obese Diabetic (NOD) mice. METHODS:CTSS activity was measured in tears and lacrimal glands (LG) from male 1-6?month (M) NOD and 1 and 6?M BALB/c mice. Lymphocytic infiltration was quantified by histopathology, while disease-related proteins (Rab3D, CTSS, collagen 1) were quantified using q-PCR and immunofluorescence. RESULTS:In NOD LG, lymphocytic infiltration was noted by 2?M and established by 3?M (p?

SUBMITTER: Janga SR

PROVIDER: S-EPMC6414277 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Longitudinal analysis of tear cathepsin S activity levels in male non-obese diabetic mice suggests its potential as an early stage biomarker of Sjögren's Syndrome.

Janga Srikanth R SR Shah Mihir M Ju Yaping Y Meng Zhen Z Edman Maria C MC Hamm-Alvarez Sarah F SF

Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 20180912 1

<h4>Context</h4>Cathepsin S (CTSS) activity is elevated in Sjögren's Syndrome (SS) patient tears.<h4>Objective</h4>To evaluate longitudinal expression of tear and tissue CTSS activity relative to other disease indicators in Non-Obese Diabetic (NOD) mice.<h4>Methods</h4>CTSS activity was measured in tears and lacrimal glands (LG) from male 1-6 month (M) NOD and 1 and 6 M BALB/c mice. Lymphocytic infiltration was quantified by histopathology, while disease-related proteins (Rab3D, CTSS, collagen 1 ...[more]

PMID: 30126300

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Reversal of Sjogren's-like syndrome in non-obese diabetic mice.

Project description:BackgroundNon-obese diabetic (NOD) mice exhibit autoimmune diabetes and Sjögren's-like syndrome.ObjectiveTo test whether a treatment that reverses end-stage diabetes in the NOD mouse would affect their Sjögren's-like syndrome.MethodsNOD mice have a proteasome defect. Improperly selected naive T cells escape, but can be killed by reintroducing major histocompatibility complex class I self-peptides on matched normal splenocytes. The proteasome defect also impairs nuclear factor kB, a transcription factor in pathogenic memory T cells, increasing their susceptibility to tumour necrosis factor-induced apoptosis stimulated through complete Freund's adjuvant (CFA). The impact of this two-limb therapy (injections of matched normal splenocytes and CFA) on the autoimmune salivary gland disease of the NOD mice was studied.ResultsAll NOD mice receiving the above treatment had a complete recovery of salivary flow and were protected from diabetes. Restoration of salivary flow could be the result of a combination of rescue and regeneration of the gland, as confirmed by immunohistochemical analysis. All untreated NOD mice showed a continuous decline in salivary flow, followed by hyperglycaemia and death.ConclusionThis study establishes that a brief intervention in NOD mice with Sjögren's-like syndrome can reverse salivary gland dysfunction.

| S-EPMC1954678 | biostudies-literature

Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjogren's Syndrome patients.

Project description:Cathepsin S (CTSS) activity is elevated in Sjögren's Syndrome (SS) patient tears. Here we tested whether protease inhibition and cystatin C (Cys C) levels are reduced in SS tears, which could lead to enhanced CTSS-driven degradation of tear proteins. CTSS activity against Cys C, LF and sIgA was tested in SS or healthy control tears. Tears from 156 female subjects (33, SS; 33, rheumatoid arthritis; 31, other autoimmune diseases; 35, non-autoimmune dry eye (DE); 24, healthy controls) were analyzed for CTSS activity and Cys C, LF, and sIgA levels. Cys C and LF showed enhanced degradation in SS tears supplemented with recombinant CTSS, but not supplemented healthy control tears. CTSS activity was significantly increased, while Cys C, LF and sIgA levels were significantly decreased, in SS tears compared to other groups. While tear CTSS activity remained the strongest discriminator of SS in autoimmune populations, combining LF and CTSS improved discrimination of SS beyond CTSS in DE patients. Reductions in Cys C and other endogenous proteases may enhance CTSS activity in SS tears. Tear CTSS activity is reconfirmed as a putative biomarker of SS in an independent patient cohort while combined LF and CTSS measurements may distinguish SS from DE patients.

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Inhibition of Cathepsin S Reduces Lacrimal Gland Inflammation and Increases Tear Flow in a Mouse Model of Sjogren's Syndrome.

Project description:Cathepsin S (CTSS) is highly increased in Sjögren's syndrome (SS) patients tears and in tears and lacrimal glands (LG) of male non-obese diabetic (NOD) mice, a murine model of SS. To explore CTSS's utility as a therapeutic target for mitigating ocular manifestations of SS in sites where CTSS is increased in disease, the tears and the LG (systemically), the peptide-based inhibitor, Z-FL-COCHO (Z-FL), was administered to 14-15 week male NOD mice. Systemic intraperitoneal (i.p.) injection for 2 weeks significantly reduced CTSS activity in tears, LG and spleen, significantly reduced total lymphocytic infiltration into LG, reduced CD3+ and CD68+ cell abundance within lymphocytic infiltrates, and significantly increased stimulated tear secretion. Topical administration of Z-FL to a different cohort of 14-15 week male NOD mice for 6 weeks significantly reduced only tear CTSS while not affecting LG and spleen CTSS and attenuated the disease-progression related reduction of basal tear secretion, while not significantly impacting lymphocytic infiltration of the LG. These findings suggest that CTSS inhibitors administered either topically or systemically can mitigate aspects of the ocular manifestations of SS.

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Differentially Expressed Tear Proteins in Sjogren's Syndrome Keratoconjunctivitis Sicca.

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Anti-IL-7 receptor-? treatment ameliorates newly established Sjogren's-like exocrinopathy in non-obese diabetic mice.

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Temporal changes in salivary glands of non-obese diabetic mice as a model for Sjogren's syndrome.

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Tear Levels of IGFBP-3: A Potential Biomarker for Diabetic Nerve Changes in the Cornea.

Project description:IntroductionType 2 diabetes mellitus has reached epidemic levels in the United States and worldwide. Ocular complications from this disease include diabetic retinopathy and keratopathy, both of which can lead to significant vision loss. While frequently underappreciated, diabetic keratopathy is associated with painful ocular surface disorders, including corneal erosions and delayed wound healing. Recent work in our laboratory has focused on the role of the insulin-like growth factor (IGF) system in diabetic corneal disease.MethodsHere, we review recent findings on the presence of IGF-1, insulin, and the insulin-like binding protein (IGFBP-3) in human tear fluid and evaluate their potential use as biomarkers in diabetes. We further examine clinical evidence using in vivo confocal microscopy as an important imaging biomarker in diabetes and discuss associations between tear film changes in diabetes and corneal nerve loss.ResultsIGFBP-3 was the only tear film marker significantly associated with nerve loss in type 2 diabetes, whereas tear levels of IGF-1 were associated with aging. Interestingly, tear levels of IGFBP-3 were not directly related to serum levels of HbA1c, suggesting that hyperglycemia alone is not driving increased secretion of this protein.ConclusionsOverwhelming evidence supports the use of in vivo confocal microscopy as a tool to evaluate corneal nerve and epithelial changes induced by diabetes in research settings. The newly identified relationship between morphological changes in the corneal subbasal nerve plexus in diabetes and the increase in tear levels of IGFBP-3 suggest that this protein may represent an innovative new biomarker to assess risk of ocular and nonocular complications in type 2 diabetes mellitus.

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Herbal Formula SS-1 Increases Tear Secretion for Sjogren's Syndrome.

Project description:Background: Sjögren's syndrome (SS) is an autoimmune inflammatory disease that primarily affects the exocrine glands, leading to glandular dysfunction. The hallmark symptoms of SS are dry eyes and mouth, compromising the quality of life of patients and decreasing their capacity to perform their daily activities. Objective: This study aims to evaluate the efficacy of the herbal formula SS-1 for its potential therapeutic benefits for patients with Sjögren's syndrome. Materials and Methods: The bioactivity profile of SS-1 was determined using four different SS-1 concentrations across 12 human primary cell systems of the BioMAP profile. After that, a randomized, double-blind, crossover, placebo-controlled trial was performed including 57 patients treated with SS-1 for 28 weeks. Results: Biologically multiplexed activity profiling in cell-based models indicated that SS-1 exerted anti-proliferative activity in B cells and promoted anti-inflammatory and immunomodulatory activity. In the clinical trial, Schirmer's test results revealed significant improvements in both eyes, with increases of 3.42 mm (95% CI, 2.44-4.41 mm) and 3.45 mm (95% CI, 2.32-4.59 mm), respectively, and a significant reduction in artificial tear use, which was -1.38 times/day, 95% CI, -1.95 to -0.81 times/day. Moreover, the increases in B-cell activating factor (BAFF) and B-cell maturation antigen (BCMA) levels were dampened by 53.20% (295.29 versus 555.02 pg/ml) and 58.33% (99.16 versus 169.99 pg/ml), respectively. Conclusion: SS-1 treatment significantly inhibited B-cell maturation antigen. No serious drug-related adverse effects were observed. Oral SS-1 administration may be a complementary treatment for Sjögren's syndrome.

| S-EPMC8498214 | biostudies-literature

Anti-inflammatory effect of peroxisome proliferator-activated receptor-? (PPAR-?) on non-obese diabetic mice with Sjogren's syndrome.

Project description:OBJECTIVE: To investigate the anti-inflammatory effect of peroxisome proliferator-activated receptor-? (PPAR-?) on non-obese diabetic mice (NOD mice) with Sjogren's syndrome. METHODS: 22 eight-week-old female NOD mice were randomly divided into 2 groups. Rosiglitazone and normal saline were administered in the PPAR-? group and the control group respectively. At the age of 9, 12 and 15 weeks, one mouse in each group was sacrificed respectively, and the remaining mice were sacrificed at the age of 18 weeks. Blood were obtained by cardiac puncture, and salivary glands were resected. The degree of salivary gland damage and infiltration of lymphocytes were examined by H&E staining. The level of IL-1?, IL-4, IL-6 and TNF-? in serum were measured by ELISA. The mRNA expression level of IL-1?, IL-4, IL-6 and TNF-? in MSG were detected by Real-time PCR. Expression of PPAR-? in the salivary glands was detected by Immunohistochemistry. RESULTS: Compared with the control group, mice in the PPAR-? group showed that (1) histopathologic changes in the salivary glands were significantly ameliorated; (2) at the age of 18 weeks, IL-6 [(25.86 ± 7.32) vs (37.41 ± 11.34)] and TNF-? [(56.88 ± 22.19) vs (78.61 ± 20.76)] were expressed significantly lower and IL-4 [(25.76 ± 12.65) vs (12.11 ± 3.70)] was expressed significantly higher in serum (P < 0.05); (3) the expression of TNF-? was significantly decreased and the expression of IL-4 was significantly increased in MSG (P < 0.05). CONCLUSION: PPAR-? ameliorates Sjogren's syndrome on NOD mice effectively. The mechanism may be related to the reduction of Th1 cytokines and change of T helper cell balance from Th1 to Th2.

| S-EPMC4152049 | biostudies-literature

Hyperglycemia and Salivary Gland Dysfunction in the Non-obese Diabetic Mouse: Caveats for Preclinical Studies in Sjogren's Syndrome.

Project description:The Non-obese Diabetic (NOD) mouse model for type I diabetes also develops some features of Sjögren's syndrome (SS). Since the source of the mice and the environment exert a strong influence on diabetes, this study investigated SS development in NOD mice obtained from two vendors. Female NOD mice from The Jackson Laboratory (JAX) and Taconic Biosciences were monitored for blood glucose and pilocarpine-induced salivation. The gut microbiome was analyzed by 16S rRNA sequencing of stool DNA. At euthanasia, serum cytokines and sialoadenitis severity were evaluated. The onset of diabetes was significantly accelerated in JAX mice compared to Taconic mice. Although the gut microbiome between the two groups was distinct, both groups developed sialoadenitis. There was no correlation between the severity of sialoadenitis and reduced saliva production. Instead, salivary gland dysfunction was associated with hyperglycemia and elevation of serum IL1?, IL16, and CXCL13. Our data suggest that inflammatory pathways linked with hyperglycemia are confounding factors for salivary gland dysfunction in female NOD mice, and might not be representative of the mechanisms operative in SS patients. Considering that NOD mice have been used to test numerous experimental therapies for SS, caution needs to be exerted before advancing these therapeutics for human trials.

| S-EPMC6884560 | biostudies-literature

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