transforming-growth-factor-beta and Sjogren-s-Syndrome

There is considerable interest in delineating the molecular mechanisms of action of transforming growth factor-β (TGF-β), considered as central player in a plethora of human conditions, including cancer, fibrosis and autoimmune disease. TGF-β elicits its biological effects through membrane bound serine/threonine kinase receptors which transmit their signals via downstream signalling molecules, SMADs, which regulate the transcription of target genes in collaboration with various co-activators and co-repressors. Until now, therapeutic strategy for primary Sjögren's syndrome (pSS) has been focused on inflammation, but, recently, the involvement of TGF-β/SMADs signalling has been demonstrated in pSS salivary glands (SGs) as mediator of the epithelial-mesenchymal transition (EMT) activation. Although EMT seems to cause pSS SG fibrosis, TGF-β family members have ambiguous effects on the function of pSS SGs. Based on these premises, this review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-β in pSS that are dictated by orchestrations of SMADs, and describe TGF-β/SMADs value as both disease markers and/or therapeutic target for pSS.

Topics: Animals; Biomarkers; Cytokines; Disease Susceptibility; Epithelial-Mesenchymal Transition; Fibrosis; Gene Expression Regulation; Humans; Inflammation Mediators; Phosphorylation; Protein Binding; Signal Transduction; Sjogren's Syndrome; Smad Proteins; Transforming Growth Factor beta

Fibrosis is presented in various physiologic and pathologic conditions of the salivary gland. Transforming growth factor beta (TGF-β) pathway has a pivotal role in the pathogenesis of fibrosis in several organs, including the salivary glands. Among the TGF-β superfamily members, TGF-β1 and 2 are pro-fibrotic ligands, whereas TGF-β3 and some bone morphogenetic proteins (BMPs) are anti-fibrotic ligands. TGF-β1 is thought to be associated with the pro-fibrotic pathogenesis of sialadenitis, post-radiation salivary gland dysfunction, and Sjögren's syndrome. Potential therapeutic strategies that target multiple levels in the TGF-β pathway are under preclinical and clinical research for fibrosis. Despite the anti-fibrotic effect of BMPs, their in vivo delivery poses a challenge in terms of adequate clinical efficacy. In this article, we will review the relevance of TGF-β signaling in salivary gland fibrosis and advances of potential therapeutic options in the field.

Topics: Animals; Disease Susceptibility; Fibrosis; Humans; Radiation; Salivary Glands; Signal Transduction; Sjogren's Syndrome; Transforming Growth Factor beta

Topics: Animals; Apoptosis; Autoimmune Diseases; Cytokines; Humans; Lacrimal Apparatus; Mice; Mice, Knockout; Salivary Glands; Sjogren's Syndrome; Transforming Growth Factor beta

To assess the efficacy of sodium hyaluronate as vehicle for diluting autologous serum.. The concentration and temporal stability of EGF, TGF-β, PDGF-AB and albumin in fresh and frozen samples of autologous serum diluted with sodium hyaluronate and saline solution, as well as the pH, osmolarity and density was studied. In parallel, the clinic effects of autologous serum diluted to 20% with sodium hyaluronate were compared with another solution of autologous serum diluted to 20% with saline in a prospective, comparative, randomized and double-blind study in 26 patients (52 eyes) with Sjögren syndrome. Patients underwent a complete ophthalmic assessment including tear film evaluation and corneal and conjunctival impression cytology at the beginning of the study and 2 months later.. The growth factor (GF) concentration remained stable during 1 month at 4°C both in fresh and defrosted samples without any differences being found between both preparations. No differences were found related to osmolarity, pH and density between these preparations before and after frosting. Autologous serum diluted with sodium hyaluronate caused a significant improvement of the tear film stability, fluorescein and rose Bengal stain, break-up time, corneal and conjunctival squamous metaplasia as well as in the patient subjective perception.. Sodium hyaluronate is an excellent vehicle for diluting autologous serum due to the gradual release of GF and increasing their duration and effect on the ocular surface. Preparations diluted with sodium hyaluronate are better tolerated by patients and require a lower number of drops administrations.

Topics: Adult; Aged; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Humans; Hyaluronic Acid; Hydrogen-Ion Concentration; Male; Middle Aged; Ophthalmic Solutions; Osmolar Concentration; Pharmaceutical Vehicles; Platelet-Derived Growth Factor; Prospective Studies; Serum; Serum Albumin; Sjogren's Syndrome; Transforming Growth Factor beta

The aim of this study was to investigate the expression levels of the serum transforming growth factor-β1 (TGF-β1) CXC type chemokine ligand 13 (CXCL13) in primary Sjogren's syndrome (pSS) patients and its correlation with disease severity.. Thirty patients with pSS admitted to Nanjing Traditional Chinese Medicine Affiliated Hospital of Nanjing University of Traditional Chinese Medicine from January 2021 to December 2022 were included as the pSS group, while 30 patients who underwent physical examination during the same period were included as the control group. The levels of TGF-β1 and CXCL13 were detected. The diagnostic value of TGF-β1 and CXCL13 for pSS was analyzed. Detection of serum TGF-β1 and CXCL13 levels in pSS patients with different disease activities and lip gland pathological grading of pSS was done. We compared the correlation between TGF-β1 and CXCL13 levels and disease activity and labial gland pathological grading in pSS patients.. The TGF-β1 and CXCL13 levels in the pSS group were higher than those in the control group. The area under the receiver operating characteristic (ROC) curve (AUC) for TGF-β1 and CXCL13 diagnosis of pSS was 0.790 (95% confidence interval (CI): 0.720~0.861) and 0.838 (95% CI: 0.778~0.898), respectively. The serum TGF-β1 and CXCL13 levels of pSS patients significantly increase with the increase of disease activity and lip gland pathological grading. The TGF-β1 and CXCL13 levels in pSS patients were positively correlated with disease activity and lip gland pathological grading.. The levels of TGF-β1 and CXCL13 in pSS patients were increased, and it was closely related to disease activity and lip gland pathological grading, which can be used as an effective indicator for the diagnosis of pSS. Key Points • The TGF-β1 and CXCL13 levels in the pSS group were higher than those in the control group. • The TGF-β1 and CXCL13 levels in pSS patients were positively correlated with disease activity and lip gland pathological grading. • TGF-β1 and CXCL13 can be used as an effective indicator for the diagnosis of pSS.

Topics: Chemokines, CXC; Clinical Relevance; Humans; Ligands; Sjogren's Syndrome; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors

Primary Sjögren's syndrome (pSS) is a progressive systemic autoimmune disease characterized by lymphocytic infiltrates in exocrine glands, leading to the injury of salivary and lachrymal glands. Mesenchymal stem cells (MSCs) have been demonstrated to exert great potential in the treatment of various autoimmune diseases. Although MSCs have provide an effective therapeutic approach for SS treatment, the underlying mechanisms are still elusive. Our previous study has shown the reduced suppressive capacity of myeloid-derived suppressor cells (MDSCs) advanced the progression of experimental Sjögren's syndrome (ESS). In this study, we found that BM-MSCs significantly enhanced the suppressive function of MDSCs with high levels of Arginase and NO, decreased the levels of CD40, CD80, CD86, and MHC-II expression on MDSCs, thus attenuating the disease progression in ESS mice. Furthermore, the enhanced suppressive function of MDSCs was mediated by BM-MSC-secreted TGF-β, and the therapeutic effect of BM-MSCs in inhibiting ESS was almost abolished after silencing TGF-β in BM-MSCs. Taken together, our results demonstrated that BM-MSCs alleviated the ESS progression by up-regulating the immunosuppressive effect of MDSCs through TGF-β/Smad pathway, offering a novel mechanism for MSCs in the treatment of pSS.

Topics: Animals; Arginase; Cell Communication; Cells, Cultured; Disease Models, Animal; Disease Progression; Female; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Nitric Oxide; Phenotype; Salivary Glands; Sjogren's Syndrome; Transforming Growth Factor beta

Primary Sjogren's syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration of exocrine glands. We investigated whether the tolerogenic peptide, hCDR1, that ameliorates lupus manifestations would have beneficial effects on pSS as well. The in vitro effects of hCDR1 on gene expression of pro-inflammatory cytokines and regulatory molecules were tested in peripheral blood mononuclear cells (PBMC) of 16 pSS patients. hCDR1, but not a control peptide, significantly reduced gene expression of IL-1β, TNF-α, MX-1 and BlyS and up-regulated immunosuppressive (TGF-β, FOXP3) molecules in PBMC of pSS patients. hCDR1 did not affect gene expression in patients with rheumatoid arthritis and anti-phospholipid syndrome. Further, hCDR1 up-regulated the expression of Indoleamine 2,3-dioxygenase (IDO) via elevation of TGF-β. IDO inhibition led to a significant decrease in the expression of FOXP3 which is crucial for the induction of T regulatory cells. Thus, hCDR1 is potential candidate for the specific treatment of pSS patients.

Topics: Adult; Aged; Amino Acid Sequence; Antibodies, Monoclonal; Cytokines; Female; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Immunologic Factors; Leukocytes, Mononuclear; Male; Middle Aged; Peptide Fragments; Peptides; Sjogren's Syndrome; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy in which the role that the immune response plays in reducing exocrine gland function, including the glandular microenvironment of cytokines, has not been fully understood. Epithelial cells from biopsies of human parotid gland (HPG) were used to establish a model of human salivary gland in vitro. In this model, the functional consequences of several proinflammatory soluble factors present in the pSS glandular microenvironment were assessed. Stimulation with isoproterenol and calcium produced a significant increase in the basal activity of amylase in the HPG cell supernatants. Under these conditions, the presence of TNF-α and CXCL12 increased amylase mRNA cellular abundance, but reduced the amylase activity in the cell-free supernatant in a dose-dependent manner. IL-1β and IFN-γ, but not TGF-β, also diminished amylase secretion by HPG cells. These results suggest that the glandular microenvironment of cytokine, by acting post-transcriptionally, may be responsible, at least in part, for the reduced exocrine function observed in pSS patients. These data may help to a better understanding of the pathogenesis of SS, which in turn would facilitate the identification of new therapeutic targets for this disorder.

Topics: Amylases; Cell Proliferation; Cells, Cultured; Chemokine CXCL12; Epithelial Cells; Humans; Interferon-gamma; Interleukin-1beta; Salivary Glands; Sjogren's Syndrome; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Sjögren's syndrome (SjS) monocytes have a pro-inflammatory phenotype, which may influence SjS pathogenesis. MicroRNAs (miRNAs) are small endogenously expressed molecules that can inhibit protein expression of their targeted genes and have important functions in regulating cell signaling responses. We profiled miRNAs in SjS monocytes to identify a SjS-specific miRNA profile and determine the potential roles of miRNAs in SjS pathogenesis.. Total RNA was extracted from healthy control (HC, n = 10), SjS (n = 18), systemic lupus erythematosus (SLE, n = 10), and rheumatoid arthritis (RA, n = 10) peripheral blood CD14(+) monocytes for miRNA microarray analysis. To validate select miRNAs from the microarray analysis, the original cohort and a new cohort of monocyte RNA samples from HC (n = 9), SjS (n = 12), SLE (n = 8), and RA (n = 9) patients were evaluated by quantitative reverse transcription (RT)-PCR. Functional predictions of differentially expressed miRNAs were determined through miRNA target prediction database analyses. Statistical analyses performed included one-way analysis of variance with Bonferroni post tests, linear regression, and receiver operating characteristic curve analyses.. MiRNAs were predominantly upregulated in SjS monocytes in comparison with controls. Quantitative RT-PCR confirmations supported co-regulation of miR-34b-3p, miR-4701-5p, miR-609, miR-300, miR-3162-3p, and miR-877-3p in SjS monocytes (13/30, 43.3 %) in comparison with SLE (1/17, 5.8 %) and RA (1/18, 5.6 %). MiRNA-target pathway predictions identified SjS-associated miRNAs appear to preferentially target the canonical TGFβ signaling pathway as opposed to pro-inflammatory interleukin-12 and Toll-like receptor/NFkB pathways.. Our results underscore a novel underlying molecular mechanism where SjS-associated miRNAs may collectively suppress TGFβ signaling as opposed to pro-inflammatory interleukin-12 and Toll-like receptor/NFκB pathways in SjS pathogenesis.

Topics: Gene Expression Profiling; Humans; Lipopolysaccharide Receptors; MicroRNAs; Monocytes; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Sjogren's Syndrome; Transcriptome; Transforming Growth Factor beta

Primary Sjögren's syndrome (PSS) is an autoimmune disease targeting exocrine glands. It ten times more dominantly affects women than men with an onset peak at menopause. The genetic factor predisposing women to PSS remains unclear. Therefore, we aimed to identify susceptibility loci for PSS in women. We performed genome-wide association study (GWAS) using 242 female PSS patients and 1444 female control in Han Chinese population residing in Taiwan. Replication was conducted in an independent cohort of 178 female PSS and 14,432 control subjects. We identified rs117026326 on GTF2I with GWAS significance (P = 1.10 × 10

Topics: Acinar Cells; Adult; Apoptosis; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Polymorphism, Single Nucleotide; RNA-Binding Proteins; Sjogren's Syndrome; Trans-Activators; Transcription Factors, TFII; Transforming Growth Factor beta

Tolerogenic dendritic cells (tDCs) are a promising therapeutic tool for specific induction of immunological tolerance. Human tDCs can be generated ex vivo using various compounds. However, the compound(s) most suitable for clinical application remain undefined. We compared the tolerogenic properties of tDCs treated with protein kinase C inhibitor (PKCI), dexamethasone, vitamin D3 (Vit D3), rapamycin (Rapa), interleukin (IL)-10, transforming growth factor (TGF)-β, and a combination of peroxisome proliferator-activated receptor γ agonist and retinoic acid. All tDCs had a semi-mature DC phenotype. PKCI-, TGF-β-, and Rapa-tDCs showed CCR7 expression and migration to CCL19, but other tDCs showed little or none. PKCI- and IL-10-tDCs induced functional regulatory T cells more strongly than other tDCs. The tolerogenic properties of all tDCs were stable against proinflammatory stimuli. Furthermore, PKCI-tDCs were generated from patients with rheumatoid arthritis and primary Sjögren's syndrome. Therefore, PKCI-tDCs showed the characteristics best suited for tolerance-inducing therapy.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Chemotaxis; Cholecalciferol; Cytokines; Dendritic Cells; Dexamethasone; Female; Humans; Immune Tolerance; Male; Middle Aged; Phagocytosis; PPAR gamma; Protein Kinase C; Protein Kinase Inhibitors; Sirolimus; Sjogren's Syndrome; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tretinoin

The aim of this study was to show the clinical and pathological characteristics of anti-centromere-antibody (ACA)-seropositive Sjögren's syndrome (SS) in two anti-human T-cell leukemia virus type I (HTLV-I)-seropositive patients.. One patient was an HTLV-I carrier whereas the other was diagnosed with HTLV-I-associated myelopathy (HAM). Background data including serum HTLV-I titers, viral loads, and cytokine profiles were recorded. Azocarmine with aniline blue (Azan)-Mallory staining and immunohistochemistry of the labial salivary glands (LSGs) and a muscle biopsy specimen from the HAM patient were performed.. Serum transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and HTLV-I viral load were high in the HAM-SS patient compared with the HTLV-I carrier. Fibrous change in LSG was prominent in the HAM-SS patient. Although TGF-β expression was similar in the two patients, expression of HTLV-I-related proteins including p12, p28, group-specific antigen (GAG), and nuclear factor kappa-B (NF-κB) in the LSG were dominantly detected in the HAM-SS patient. Frequency of TGF-β staining in HTLV-I-seropositive SS patients without ACA, HTLV-I-seronegative SS patients with ACA, and HTLV-I-seronegative SS patients without ACA was lower than that of the previous two patients.. A high HTLV-I viral load in situ is supposed to promote the production of cytokines, especially TGF-β, resulting in the fibrous change of LSG in ACA-seropositive SS patients.

Topics: Antibodies, Antinuclear; Biomarkers; Carrier State; Centromere; Female; Fibrosis; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Lip; Middle Aged; Mouth Mucosa; Muscle, Skeletal; Salivary Glands, Minor; Sjogren's Syndrome; Transforming Growth Factor alpha; Transforming Growth Factor beta; Viral Load; Viral Proteins; Xerostomia

To determine the cytokine production profile of cultured salivary gland epithelial (SGE) cells obtained from patients with Sjögren's syndrome (SS).. SGE cells obtained from 9 SS patients and 6 normal controls were cultured in the presence of exogenous IFNγ. Cell proliferation and apoptosis in response to IFNγ were determined by WST1 assay and by FACS analysis. The concentrations of IL-6 and TGFβ secreted into culture supernatants were analyzed by ELISA.. IFNγ did not significantly affect the proliferation or apoptosis of SGE cells. However, IL-6 concentrations were higher, and TGFβ concentrations were lower, in culture supernatants of SGE cells from SS patients than from normal controls.. Cytokine production by SGE cells from SS patients showed a skewed balance compared with normal controls, with increased IL-6 and decreased TGFβ secretion. This imbalance may be critical in the regulation of Treg/Th17 cells and may foster a pathogenic milieu that may be causative and predictive in SS.

Topics: Adult; Aged; Apoptosis; Cell Proliferation; Cells, Cultured; Epithelial Cells; Female; Humans; Interferon-gamma; Interleukin-6; Male; Middle Aged; Salivary Glands; Sjogren's Syndrome; Transforming Growth Factor beta

Recently recognized as a distinct CD4(+) T helper (Th) lineage, Th17 cells have been implicated in host responses to infections and in pathogenesis associated with autoimmune diseases. This cytokine is implicated in primary Sjögren's syndrome (pSS) immunopathology because of the increased levels of circulating interleukin (IL)-17 in pSS. Plasma and minor salivary glands (MSGs) from patients with pSS were therefore evaluated for CD4(+) T cells, T regulatory cells, IL-17, and supporting cytokines by immunohistochemistry, RT-PCR, and microbead assays. MSGs from pSS patients contain IL-17-expressing cells as a dominant population within inflammatory lesions. IL-17 protein expression progressively increased with higher biopsy focus scores (P < 0.0001), in parallel with detection by RT-PCR. Transforming growth factor-beta, IL-6 and IL-23, which are requisite promoters of Th17 differentiation, were found in abundance compared with the amounts in control tissues. Although transforming growth factor-beta is also a pivotal differentiation factor for immunosuppressive Foxp3(+) T regulatory cells (Tregs), an increase in Foxp3(+) Tregs was evident in biopsy specimens with mild and moderate inflammation but this increase was disproportionate to escalating pro-inflammatory Th17 populations in advanced disease. Furthermore, the Th17-centric cytokines IL-17, IL-6, IL-23, and IL-12 were significantly elevated in pSS plasma. These data identify a profusion of IL-17-generating cells and supporting cytokines within diseased pSS MSGs without a compensatory increase in immunomodulatory Tregs; this imbalance seems to foster a pathogenic milieu that may be causative and predictive of infiltrative injury and amenable to therapeutic intervention.

Topics: Adult; Aged; Biopsy; Female; Forkhead Transcription Factors; Humans; Immunohistochemistry; Interleukin-12; Interleukin-17; Interleukin-23; Interleukin-6; Male; Middle Aged; Pilot Projects; Salivary Glands; Sjogren's Syndrome; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Transforming growth factor beta (TGFbeta) plays a key role in the onset and resolution of autoimmune diseases and chronic inflammation. The aim of this study was to delineate the precise function of TGFbeta signaling in salivary gland inflammation.. We impaired TGFbeta signaling in mouse salivary glands by conditionally inactivating expression of TGFbeta receptor type I (TGFbetaRI), either by using mouse mammary tumor virus-Cre mice or by delivering adenoviral vector containing Cre to mouse salivary glands via retrograde infusion of the cannulated main excretory ducts of submandibular glands.. TGFbetaRI-conditional knockout (TGFbetaRI-coko) mice were born normal; however, female TGFbetaRI-coko mice developed severe multifocal inflammation in salivary and mammary glands and in the heart. The inflammatory disorder affected normal growth and resulted in the death of the mice at ages 4-5 weeks. Interestingly, male TGFbetaRI-coko mice did not exhibit any signs of inflammation. The female TGFbetaRI-coko mice also showed an increase in Th1 proinflammatory cytokines in salivary glands and exhibited an up-regulation of peripheral T cells. In addition, these mice showed an atypical distribution of aquaporin 5 in their salivary glands, suggesting likely secretory impairment. Administration of an adenoviral vector encoding Cre recombinase into the salivary glands resulted in inflammatory foci only in the glands of female TGFbetaRI-loxP-flanked (floxed) mice (TGFbetaRI-f/f mice), but not in those of male and female wild-type mice or male TGFbetaRI-f/f mice.. These results suggest that female mice are uniquely more susceptible to developing inflammatory disorders due to impaired TGFbeta signaling in their salivary glands.

Topics: Activin Receptors, Type I; Animals; Disease Models, Animal; Disease Susceptibility; Female; Gene Deletion; Gene Expression Regulation; Genetic Predisposition to Disease; Inflammation; Male; Mice; Mice, Transgenic; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Salivary Glands; Sex Characteristics; Signal Transduction; Sjogren's Syndrome; Transforming Growth Factor beta

Interleukin-12 (IL-12), a Th1 proinflammatory cytokine, is reported to be increased in Sjögren syndrome. To evaluate the effects of local Th1/Th2 deregulation, we generated a transgenic mouse model that overexpresses IL-12 in the lungs. IL-12 transgenic mice developed bronchial and alveolar abnormalities strikingly similar to those found in the lungs of Sjögren patients. Pathologically, lung abnormalities began at approximately 4 mo of age and were characterized by lymphocytic infiltrates around the bronchi, intraluminal periodic acid Schiff-positive debris, increased cell proliferation in the alveolar region, and increased interstitial and alveolar macrophages. Functionally, these abnormalities translated into decreased mucociliary clearance (P<0.05 vs. wild-type littermates) and increased oxidative stress (P<0.01). The pathological and functional abnormalities were accompanied by significant changes in lung natural killer (NK) cells. The number of NK cells was fourfold higher in IL-12 transgenic than wild-type lungs (20% of all lymphoid cells vs. 5%) during the first month of life. NK cells then decreased within a narrow window of time (from 30 to 50 days of age), reaching a nadir of approximately 2% on day 50, and remained at these low levels thereafter. This new mouse model highlights the role of IL-12 in the initiation of Sjögren syndrome.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Interleukin-12; Killer Cells, Natural; Lacrimal Apparatus; Lung; Lung Diseases; Lymphocytes; Macrophages; Mice; Mice, Transgenic; Mucociliary Clearance; Oxidative Stress; Periodic Acid-Schiff Reaction; Salivary Glands; Signal Transduction; Sjogren's Syndrome; Transforming Growth Factor beta

To determine whether cytokine gene polymorphisms of interferon-gamma (IFNgamma), interleukin-6 (IL-6), IL-10, tumor necrosis factor alpha (TNFalpha), and transforming growth factor beta1 (TGFbeta1) predispose subjects to the development of primary Sjögren's syndrome (SS).. Single-base-exchange cytokine gene polymorphisms were analyzed in 129 French patients with primary SS who fulfilled the American-European Consensus Group criteria, as well as in 96 unrelated healthy subjects.. The frequency of the TNF-308A (TNF2) allele was significantly higher in the SS patients (26% versus 11%). This TNF2 association was restricted to patients with anti-SSB (37% versus 11% in controls). Stratification did not reveal an independent effect of TNF2 and HLA-DRB1*03 on disease or on anti-SSB antibody secretion. The frequency of allele C at codon 10 of TGFbeta1 was strongly increased in the subgroup of patients with anti-SSB; this allele acted synergistically with DRB1*03 to predispose patients to the secretion of anti-SSB. The IL-10 GCC haplotype carrier rate was significantly higher in SS patients than in controls (67% versus 48%), but the IL-10 allele and genotype frequencies were not significantly different. No association was found between IL-6 or IFNgamma polymorphisms and primary SS.. TNF2 was associated with anti-SSB antibody secretion, although this association was not independent of the association with DRB1*03. Allele C at codon 10 of TGFbeta1 was found to act synergistically with DRB1*03 in predisposing patients to the secretion of anti-SSB. These results therefore suggest that most of the known genetic predisposition to primary SS might concern the pattern of autoantibody diversification.

Topics: Antibodies, Antinuclear; Cohort Studies; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Polymorphism, Genetic; Sjogren's Syndrome; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The aim of this study was to examine the mechanism of Epstein-Barr virus (EBV) activation by soluble factors from the inflamed salivary glands of patients with Sjogren's syndrome (SS). Saliva from SS patients was used to examine the regulation of EBV activation by an inflammatory salivary microenvironment. Transient transfection of the EBV-negative salivary gland cell line (HSY) with BZLF1, a trans-activating EBV gene promoter-fusion construct (Zp-luc), was used in this study. The results showed that under conditions where the BZLF1 promoter is activated by potent stimuli, SS saliva (from eight of 12 patients) exerts a significant effect on expression of the luciferase gene. A specific inhibitor of protein kinase C did not affect the SS saliva-induced Zp-luc activity, whereas treatment with inhibitors of calmodulin, calcineurin and IP3, dose-dependently decreased this induction. Transforming growth factor beta1 (TGF-beta1), which is known to be expressed in SS salivary glands, dose-dependently induced Zp-luc activity. Hence, these results demonstrate the activation of EBV by SS saliva and suggest that EBV activation at the inflammatory site may occur in the presence of TGF-beta1 via triggering of the mitogen-activated protein kinase (MAPK) kinase signalling pathway.

Topics: Adult; Biological Factors; Calcium-Calmodulin-Dependent Protein Kinases; Cell Line; DNA-Binding Proteins; Enzyme Inhibitors; Female; Herpesvirus 4, Human; Humans; MAP Kinase Signaling System; Promoter Regions, Genetic; Protein Kinase C; Saliva; Salivary Glands; Signal Transduction; Sjogren's Syndrome; Trans-Activators; Transfection; Transforming Growth Factor beta; Transforming Growth Factor beta1; Viral Proteins; Virus Activation

Primary Sjögren's syndrome (SS) is characterized by inflammation in salivary and lachrymal glands, with a local predominance of Th1-like cytokines, as well as the pleiotropic cytokine interleukin (IL) 18. High serum levels of polyclonal IgG are common, with a subclass imbalance in which IgG1 is increased and IgG2 is normal or low. IL-18 is also of pathogenetic importance in rheumatoid arthritis. In the present study we looked for any relationship between serum IL-18 as well as transforming growth factor (TGF) beta1 versus IgA, IgM, and IgG subclass levels in SS (n = 16), rheumatoid arthritis (RA) (n = 15), and healthy controls (n = 15). SS was defined by the revised American-European classification criteria. IL-18 and TGF-beta1 were analyzed with enzyme immunoassays (EIA), and IgG1, IgG2 and IgG3 by single radial immunodiffusion. In the composite group of RA, SS and normal controls, IgG1 and IL-18 were related (R = 0.52, P = 0.0005). No relation was found neither between IL-18 versus IgG2, IgG3 or IgA, nor between serum TGF-beta1 versus any of the immunoglobulins. Since serum levels of IL-18 are related to serum IgG1, IL-18 may be of importance for IgG1 switch and/or release.

Topics: Adult; Aged; Arthritis, Rheumatoid; Case-Control Studies; Female; Humans; Immunoglobulin A; Immunoglobulin G; Interleukin-18; Middle Aged; Sjogren's Syndrome; Statistics, Nonparametric; Transforming Growth Factor beta

Transforming growth factor beta (TGF-beta) is involved in the control of autoimmune reactions, cell proliferation, and the accumulation of lymphocytes within organs. The aim of this study was to determine the expression of TGF-beta in salivary glands from patients with primary Sjogren's syndrome (SS) and benign lymphoepithelial lesions (BLEL) with emphasis on ductal epithelium.. Immunoperoxidase staining for TGF-beta isoforms and Ki67 antigen was performed on formalin fixed sections of labial glands from patients with primary SS (n = 15) and controls (n = 5) and parotid glands reported as BLEL (n = 5) or normal (n = 5). Ductal expression of TGF-beta was quantified by absorbance measurements using image analysis. The specificity of staining was confirmed by peptide blocking studies.. All TGF-beta isoforms were detected within the cytoplasm of most lymphocytes, endothelial cells, and ducts in all specimens. Acinar expression was variable and weaker than that seen in ducts. Absorbance measurements revealed that the expression of all isoforms was greater in ducts within primary SS glands than in control glands. Ductal expression in control parotid glands was greater than that seen in BLEL glands, irrespective of the presence of adjacent lymphoid infiltrates. Comparisons between control specimens showed that ductal expression of all isoforms was highest in parotid glands, whereas no differences were detected between primary SS and BLEL glands. Ki67 positive lymphocytes and duct cells were mainly restricted to pathological specimens, with BLEL glands containing larger populations of positive cells than primary SS glands.. These results demonstrate complex and variable changes in ductal expression of TGF-beta in primary SS and BLEL, which may be important in the control of lymphoid infiltration and the proliferation of lymphocytes and ductal epithelium.

Topics: Adolescent; Adult; Aged; Endothelium; Female; Humans; Immunohistochemistry; Lymphocytes; Male; Middle Aged; Protein Isoforms; Salivary Glands; Sjogren's Syndrome; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3

To determine levels of interleukin 10 (IL-10) and IgG subclasses in serum from 53 patients with primary Sjögren's syndrome (SS).. Serum levels of IL-10 were measured using specific sandwich ELISA in 25 patients with "definite" SS, 28 with "possible" SS, and 32 healthy controls. Interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) were also measured by immunoassays. Immunoglobulin classes, IgG subclasses, and C-reactive protein were measured by nephelometry.. Circulating IL-10 was elevated in 25 patients. The increase reached significance in the group with possible SS (p = 0.03) versus controls. In the group with definite SS, IL-10 level was correlated with IgG1 level (p = 0.01, r = 0.67) and with focus score (p = 0.01). IFN-gamma was undetectable in most patients. TGF-beta1 was higher (not significantly) in possible SS than in definite SS.. IL-10 is increased in SS and may account for the overproduction of IgG1 in the syndrome. High IL-10 in the absence of increased IgG1 in possible SS suggests that IL-10 may be necessary but not sufficient for IgG1 overproduction and that other factors are involved. Whereas the correlation of IL-10 level with focus score was expected, it is intriguing that IL-10 was more frequently increased in the incomplete (possible) form of SS than the complete (definite) form. Elevated IL-10 may characterize the lower stage of eccrine dysfunction and perhaps contributes to limiting its severity.

Topics: Female; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Interferon-gamma; Interleukin-10; Male; Middle Aged; Sjogren's Syndrome; Transforming Growth Factor beta

To evaluate the efficacy of autologous serum application for the treatment of dry eye in Sjögren's syndrome.. The stability of essential components (EGF, vitamin A, and TGF-beta) in preserved serum were examined following preservation at 4 degrees C and -20 degrees C. In a primary clinical trial, 12 patients with Sjögren's syndrome were treated with autologous serum (diluted to 20% with sterile saline) for 4 weeks, and vital staining of the ocular surface was compared before and after treatment. The effects of serum on mucin (MUC-1) expression were observed in cultured conjunctival epithelial cells in vitro.. EGF, vitamin A, and TGF-beta were well preserved for up to 1 month in the refrigerator at 4 degrees C and up to 3 months in the freezer at -20 degrees C. Rose bengal and fluorescein scores improved significantly from the initial scores of 5.3 and 5.6 to 1.7 and 2.5 after 4 weeks, respectively. The additive effect of human serum for cultured conjunctival epithelial cells showed significant MUC-1 upregulation on the cell surface.. Autologous serum application is a safe and efficient way to provide essential components to the ocular surface in the treatment of dry eye associated with Sjögren's syndrome.

Topics: Blood; Dry Eye Syndromes; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Mucin-1; Ophthalmic Solutions; Sjogren's Syndrome; Tears; Transforming Growth Factor beta; Vitamin A

To compare epidermal growth factor (EGF) concentration in tear fluid and levels of inflammatory cytokines in the conjunctival epithelium of patients with Sjögren's syndrome keratoconjunctivitis sicca with those of normal controls.. Schirmer 1 tear testing, corneal fluorescein staining and conjunctival impression cytology for quantitation of goblet cell density were performed in ten patients with Sjögren's syndrome-associated keratoconjunctivitis sicca and ten asymptomatic normal controls. ELISA was used to detect the concentration of EGF in tear fluid and interleukin 6 in lysates of conjunctival cytology specimens obtained from all subjects. The levels of RNA transcripts encoding inflammatory cytokines [interleukin 1alpha_(IL-1alpha), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor alpha_(TNF-alpha), and transforming growth factor beta1 (TGF-beta1)] as well as a housekeeping gene (G3PDH) were evaluated in conjunctival cytology specimens taken from all subjects by semiquantitative competitive reverse transcriptase polymerase chain reaction (RT-PCR).. Decreased tear fluid EGF concentration was noted in Sjögren's syndrome patients (mean 0.68 +/- 0.59 ng/ml) compared to controls (mean 1.66 +/- 0.45 ng/ml, P = 0.004). Significantly increased levels of IL-1alpha, IL-6, IL-8, TNF-alpha and TGF-beta1 RNA transcripts were found in the conjunctival epithelium of Sjögren's syndrome patients compared to controls (P < 0.05), while the level of G3PDH was similar in both groups. The concentration of IL-6 protein was significantly higher in Sjögren's syndrome conjunctiva samples (P = 0.012). Tear EGF concentration correlated with Schirmer 1 scores (rho 0.767, P < 0.001), corneal fluorescein staining scores (rho -0.562, P = 0.01), conjunctival goblet cell density (rho 0.661, P = 0.001) and the levels of IL-1alpha_and IL-8 RNA in the conjunctival epithelium (rho -0.677 and -0.747, respectively, P = 0.001). Both IL-1alpha_and IL-8 RNA in the conjunctival epithelium increased as Schirmer 1 scores decreased (P

Topics: Adult; Aged; Cell Count; Conjunctiva; Cytokines; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Epithelial Cells; Female; Humans; Interleukins; Keratoconjunctivitis Sicca; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sjogren's Syndrome; Tears; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Animals; Cyclophosphamide; Cytokines; Disease Models, Animal; Female; Inflammation; Interleukins; Lacrimal Apparatus; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; RNA, Messenger; Sjogren's Syndrome; Submandibular Gland; Testosterone; Transcription, Genetic; Transforming Growth Factor beta

The gene encoding interleukin-1 receptor antagonist (IL-1ra) has a variable allelic polymorphism. The IL1RN*2 allele was recently described as a factor of severity in several autoimmune diseases and was paradoxically associated with increased production of IL-1ra by monocytes in vitro. We studied this polymorphism in 36 patients with possible or definite primary Sjögren's syndrome and found that IL1RN*2 was significantly more frequent in the definite than in the possible form. In rheumatoid arthritis, the frequency of the allele was not different from that of controls. The serum levels of IL-1ra were markedly higher in Sjögren patients than in those of healthy subjects. By contrast, the salivary IL-1ra levels were decreased. Patients with the allele generally had lower salivary levels and higher serum levels than patients without the allele. In the group of patients with the definite syndrome, CRP and TGF-beta 1, two in vitro stimulators of IL-1ra production, were correlated with IL-1ra serum levels. Our results suggest that IL1RN*2 is a marker of more severe forms of Sjögren's syndrome. Its effect on salivary and serum IL-1ra may be distinct, suggesting separate regulatory mechanisms.

Topics: Alleles; Arthritis, Rheumatoid; C-Reactive Protein; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Polymorphism, Genetic; Sialoglycoproteins; Sjogren's Syndrome; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To characterize the initiation and progress of localized autoimmune damage in Sjögren's syndrome (SS), an autoimmune disease that is also considered to be a lymphoaggressive disorder, by examining the pattern of cytokine production at the site of autoimmune damage.. Using a polymerase chain reaction-based method, cytokine messenger RNA (mRNA) expression in the labial salivary glands of 15 patients with SS was investigated. In addition, the infiltrating lymphocytes in the labial salivary glands were examined immunohistochemically.. Messenger RNAs of Th1 cytokines, such as interleukin-2 (IL-2) and interferon-gamma, were consistently detected in all patients, while Th2 cytokine mRNAs, such as IL-4 and IL-5, were detected in some cases, in association with strong B cell accumulation in the labial salivary glands. Other cytokine mRNAs produced by a variety of cell types, including IL-10, IL-6, and transforming growth factor beta (TGF beta), were also consistently detected in all patients, while IL-12 mRNA was detected in some of the patients.. These results suggest that Th1 cytokines, as well as IL-10, IL-6, and TGF beta, are essential in the induction and/or maintenance of SS, while Th2 cytokines are involved in the progression of the disease process, especially local B cell activation.

Topics: Adult; Aged; Base Sequence; Biomarkers; Biopsy; Clone Cells; Cytokines; DNA, Complementary; Female; Gene Expression; Humans; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-2; Interleukin-4; Interleukin-5; Interleukin-6; Lip; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; RNA, Messenger; Salivary Glands, Minor; Sjogren's Syndrome; T-Lymphocytes; Transforming Growth Factor beta

The targeted disruption of the TGF-beta1 gene in mice (TGF-beta1 -/-) leads to extensive inflammation in vital organs, cachexia, and death within 3 to 4 wk. Significant inflammatory lesions develop initially in the periductal regions of the salivary glands and escalate as the animals become symptomatic. These inflammatory sites, characterized by lymphocytic infiltration and increased proliferation, cytokine mRNA expression, and IgG-positive cells, resemble lesions of Sjögren's syndrome. Moreover, the inflammatory pathology, enhanced MHC expression, and Ab production are consistent with an autoimmune-like etiology. Glandular atrophy and loss of acini with reduced saliva production appear to contribute to the wasting syndrome characteristic of the TGF-beta1 -/- mice. To determine whether the structural and functional defects were developmental due to the absence of TGF-beta1 or secondary to the inflammation, TGF-beta1 -/- mice were treated with synthetic fibronectin peptides, which block leukocyte infiltration. Daily systemic injections of RGD, CS-1, and/or peptides derived from the heparin-binding region of the A chain not only prevented leukocyte infiltration in the salivary glands of the TGF-beta1 -/- mice, but also reversed the acinar and ductal derangements. These data suggested that salivary gland development is not jeopardized in the absence of TGF-beta1, but that the extensive infiltration of inflammatory cells compromises glandular structure and function. The essential nature of TGF-beta1 in controlling inflammatory and immune processes is confirmed by these studies. Moreover, these TGF-beta1 -/- mice provide an important model of autoimmune disease that can be used in the design of therapeutic interventions.

Topics: Animals; Autoimmunity; Base Sequence; Cell Division; Fibronectins; Interferon-gamma; Interleukin-2; Interleukin-6; Mice; Molecular Sequence Data; Receptors, Interleukin-2; RNA, Messenger; Saliva; Salivary Glands; Sjogren's Syndrome; Transforming Growth Factor beta

To determine whether transforming growth factor-beta 1 (TGF-beta 1) has a pathogenetic role in disease of the salivary glands.. An indirect immunohistochemical technique was used to analyse TGF-beta 1 expression in six specimens of normal salivary gland and 23 surgical specimens.. TGF-beta 1 was strongly expressed in the ductal epithelial cells of normal salivary gland tissues (six of six cases) and in inflammatory conditions (eight of 11 cases). In contrast, TGF-beta 1 was not detectable in ductal epithelial cells expressing HLA-DR around infiltrating CD4+ CD45RO+ activated T cells, in the salivary gland tissue of patients with Sjögren's syndrome.. Because TGF-beta 1 has an essential role in the mucosal immunity of salivary glands, abnormal expression of this cytokine must be regarded as a candidate in the pathogenesis of Sjögren's syndrome.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; CD4-Positive T-Lymphocytes; Epithelium; Female; HLA-DR Antigens; Humans; Immunohistochemistry; Leukocyte Common Antigens; Male; Middle Aged; Sialadenitis; Sjogren's Syndrome; Transforming Growth Factor beta

To compare the distribution and the amount of transforming growth factor beta (TGF beta) in labial salivary glands (LSG) in patients with Sjögren's syndrome (SS) and healthy controls.. LSG from SS patients (n = 10) and healthy controls (n = 6) were labelled with peroxidase-antiperoxidase staining for TGF beta 2, which was quantitated in image analysis using Video Interactive Display System software.. In all LSGs in SS and healthy controls, TGF beta 2 was found in endothelial cells of the capillaries and in the capsular and stromal fibroblasts. In LSGs in SS, TGF beta 2 was also found in some lymphocytes in the inflammatory cell foci and in fibroblasts in fibrotic areas. The TGF beta 2 staining index (microns 2/mm2 tissue) was greater in SS than in control LSGs (3670 (SEM 430) v 2061 (176); p < 0.01), with no difference between the primary and secondary forms of SS (p > 0.05).. The localisation and the level of expression of TGF beta 2 indicate its involvement in local tissue fibrosis, and may reflect attempts at immunosuppression.

Topics: Adult; Aged; Female; Humans; Immunohistochemistry; Lip; Male; Middle Aged; Salivary Glands; Sjogren's Syndrome; Transforming Growth Factor beta

The present study was carried out to determine whether restricting dietary calories prevents salivary gland abnormalities and modulates expression of transforming growth factor beta and proinflammatory cytokines, IL-6, and TNF alpha in major salivary glands (SG) of autoimmune lupus-prone (NZB x NZW)F1 (B/W) female mice. These mice develop focal lymphocytic interstitial and periductal round cell infiltrates in salivary glands similar to those of humans with Sjogren's syndrome. Weanling B/W mice were fed a nutritionally adequate semipurified diet either ad libitum (AL) or a calorie-restricted (CR; 40% less calories than AL) diet. The mice were sacrificed at 3.5 months (young) and 8.5 months (old) of age. Histopathologic and histomorphometric analyses as well as growth factor and cytokine protein and mRNA expression were carried out in the SG. Histomorphometric analysis of SG from young mice showed no differences between AL and CR mice, but old AL (vs old CR) had a 7.3-fold higher focus score and a 34-fold increase in percentage area inflammation. mRNA analysis revealed significantly higher levels of TGF beta 1 in SG of old CR (6.8-fold) mice. In contrast, CR reduced mRNA expression of proinflammatory cytokines (IL-6, 2.9-fold for young and 4.8-fold for old; TNF alpha, old 3.9-fold). By immunoblotting, significantly higher levels of TGF beta 1 protein was detected in old CR mice (vs old AL; 13.2-fold). IL-6 and TNF alpha proteins were undetectable in both young and old CR groups, whereas an increase in IL-6 (4.7-fold) and TNF alpha (9.3-fold) was observed in old AL mice. These results indicate that amelioration of the histological severity of disease in SG of B/W mice is paralleled and possibly mediated by increased expression of immunosuppressive TGF beta 1 and decreased expression of proinflammatory cytokines.

Topics: Animals; Blotting, Northern; Blotting, Western; Cytokines; Energy Intake; Female; Interleukin-6; Leukocytes, Mononuclear; Mice; Mice, Inbred NZB; RNA, Messenger; Salivary Glands; Sjogren's Syndrome; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Mice bearing the TGF-beta 1 null mutation (-/-) develop lymphoid infiltrates in the heart, lungs, salivary glands, and other organs similar to those seen in the pseudolymphoma of Sjögren's Syndrome. We studied sera from -/- mice and found elevated Ab levels to dsDNA, ssDNA, and Sm ribonucleoprotein. No Abs to SSA/Ro or SSB/La and no IgM rheumatoid factor were found. Serum autoantibodies were predominately IgG and were specific as shown by ELISA inhibition studies. Antinuclear Ab patterns on Western blots varied from one mouse to the next, indicating a random process responsible for the diversity. Wild-type and heterozygote mice had no autoantibodies. Ig glomerular deposits were found in -/- mice, indicating that these autoantibodies may be pathogenic. Treatment of -/- mice with dexamethasone or TGF-beta 1 failed to suppress autoantibody production. These mice represent an overlap combining the autoimmune serology of SLE with the tissue infiltrates of SS. Our results support the concept that TGF-beta 1 is an important naturally occurring immunosuppressive cytokine whose absence can lead to a systemic autoimmune disease.

Topics: Animals; Antibodies, Antinuclear; Autoantibodies; Kidney Glomerulus; Mice; Mice, Knockout; Sjogren's Syndrome; Transforming Growth Factor beta

To investigate the role of cytokines and cell adhesion molecules in the pathogenesis of Sjögren's syndrome (SS).. Using an indirect immunoperoxidase technique we assessed the expression of the cytokines interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8), transforming growth factor beta (TGF beta) and granulocyte macrophage colony stimulating factor (GM-CSF), of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), lymphocyte function associated antigen-1 (LFA-1), the activated molecular form of LFA-1 (NKI-L16), CD2, and LFA-3, and of a panel of cellular markers in the minor salivary glands.. In SS and chronic sialoadenitis (CS), the ductal epithelial cells and acini expressed all the cytokines examined. The percentage of glandular mononuclear cells which stained positive for cytokines did not differ significantly between SS and CS. NKI-L16 was detected on 33.6 (SD 10.1)% and 15.3 (4.3)% of LFA-1 cells in SS and CS, respectively (p < 0.002).. SS and CS did not differ in the pattern of cytokines examined. The characteristic cell clustering seen in the salivary glands in SS may be caused by the upregulation of NKI-L16.

Topics: Adult; Aged; Cell Adhesion Molecules; Chronic Disease; Cytokines; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoenzyme Techniques; Interleukins; Leukocytes, Mononuclear; Lymphocyte Subsets; Middle Aged; Salivary Glands, Minor; Sialadenitis; Sjogren's Syndrome; Transforming Growth Factor beta

Cytokines play a major role in tissue destruction caused by autoimmune dysregulation. In Sjögren's syndrome (SS) patients, salivary glands are the target organs for autoimmune tissue damage. In the present study, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to look for cytokine mRNA expressed in SS salivary glands. Focus score was used to determine the severity of the lesions. Cytokine production in supernatants of the salivary gland cell culture was measured by enzyme-linked immunosorbent assay (ELISA). Immunohistochemical staining was used to identify the local presence of transforming growth factor beta (TGF-beta). Interleukin (IL)-2, IL-6, and IL-10 mRNA were expressed in moderate to severe SS salivary gland lesions. TGF-beta mRNA was constitutively expressed in normal and SS salivary glands. In SS salivary gland cell cultures, IL-6 and IL-10 proteins were produced. TGF-beta production was reduced in high focus score SS glands. Normal and minimally involved SS salivary gland ductal epithelium and acinar cells were found to produce TGF-beta by immunostaining. In conclusion, an excess production of IL-2, IL-6, and IL-10 and a reduced production of the immunosuppressive cytokine, TGF-beta, may be responsible for the progression of the salivary gland lesion in SS. Specific immunotherapy can now be designed based on mechanisms to correct this cytokine imbalance and benefit patients with autoimmune diseases, such as SS.

Topics: Adult; Aged; Base Sequence; Cells, Cultured; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunohistochemistry; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; RNA, Messenger; Salivary Gland Diseases; Sjogren's Syndrome; Transforming Growth Factor beta