transforming-growth-factor-beta and Sarcoidosis

Sarcoidosis is a multisystemic granulomatous inflammation associated with Th17/regulatory T cell (Treg) polarization. As a marker of inflammation, serum amyloid A (SAA) could upregulate the expression of chemokine ligand 20 (CCL20), which induces the migration of Treg cells and Th17 cells by binding and activating thechemokine C-C receptor (CCR) 6. Our goal was to determine whether SAA/anti-CCL20 induces Th17/Treg rebalance in pulmonary sarcoidosis. The deposition of SAA- and Th17/Treg-related proteins in SodA-induced granulomas was tested using immunohistochemistry. Mice with SodA-induced sarcoidosis were treated with SAA or SAA + anti-CCL20, and then Th1/Th2 and Th17/Treg cells were detected by fluorescence-activated cell sorting (FACS) analysis. The expression of SAA/CCL20 and IL-23/IL-17A was detected by enzyme-linked immunosorbent assay (ELISA) and multiplex. Key proteins in the TGF-β/Smad signaling pathway were tested by western blot. SAA mainly plays a pro-inflammatory role by promoting the expression of CCL20 and IL-17A in bronchoalveolar lavage fluid (BALF) and serum, exacerbating this elevation of CD4+/CD8+ T cells in both mediastinal lymph nodes (LNs) and BALF, as well as proliferating Th1 in LNs in SodA-induced pulmonary sarcoidosis. In addition, SAA could also promote the proliferation of Tregs in LNs. Intriguingly, blocking of CCL20 could partially reverse the expression of Th17-related cytokine, ameliorate Th1/Th2 and Treg/Th17 bias in mice with SodA-induced pulmonary sarcoidosis, and rescue the overactivation of the TGF-β/Smad2/Smad3 signaling pathway. Anti-CCL20 may have the potential for therapeutic translation, targeting on the immunopathogenesis of pulmonary sarcoidosis.

Topics: Animals; Chemokines; Inflammation; Interleukin-17; Ligands; Mice; Sarcoidosis; Sarcoidosis, Pulmonary; Serum Amyloid A Protein; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

"Idiopathic" is the most common category of uveitis, representing cases in which a specific diagnosis has not been established despite work-up. Sarcoidosis is a systemic granulomatous disorder affecting multiple organs including the lungs, skin, kidneys, and eyes. We used microRNA (miRNA) microarrays to investigate serum miRNA profiles of patients with ocular sarcoidosis as diagnosed by specific criteria (diagnosed ocular sarcoidosis), and patients with idiopathic uveitis characterized by ocular manifestations of sarcoidosis (suspected ocular sarcoidosis). Principal component analysis (PCA) and hierarchical clustering showed that serum miRNA profiles of diagnosed ocular sarcoidosis and suspected ocular sarcoidosis were both clearly distinguishable from healthy controls. Furthermore, comparative analysis of the miRNA profiles showed highly similar patterns between diagnosed ocular sarcoidosis and suspected ocular sarcoidosis. Pathway analysis revealed common pathways were involved in the two groups, including those of WNT signaling and TGF-beta signaling. Our study demonstrated a high overlap of differentially expressed serum miRNAs in patients with diagnosed ocular sarcoidosis and suspected ocular sarcoidosis, suggesting that these groups share a similar underlying pathology and may represent possible variants of the disease. Characterization of serum miRNA profiles may provide an opportunity for earlier diagnosis and treatment, and may inform more accurate clinical prognosis in patients with an ocular sarcoidosis phenotype.

Topics: Endophthalmitis; Eye; Humans; MicroRNAs; Sarcoidosis; Transforming Growth Factor beta; Uveitis

Sarcoidosis is a chronic granulomatous disease that develops with non-caseified granuloma formation. Galectin-3 is a multifunctional protein operating in biological processes such as fibrosis, angiogenesis, and immune activation.. This study evaluates the levels of serum galectin-3 and TGF-beta in sarcoidosis patients to determine a possible correlation with clinical findings.. Forty-four biopsy-proven sarcoidosis patients followed in a single centre and 41 age and sex-matched healthy volunteers were included in the study. The levels of serum galectin-3 and TGF-beta were evaluated by ELISA method.. Among the 44 sarcoidosis patients, 13(29.5%) were male and 31(70.5%) were female. The average patient age was 47.4 and the average disease duration was 3.2 years. The level of serum galectin-3 was found to be the same as in the control group and had no significance statistically (p=.977). No correlation was determined between the level of serum galectin-3 and clinical and laboratory findings of sarcoidosis (p>.05). The level of serum TGF-beta was found to be higher in the sarcoidosis patients when compared to that of the control group (p=.005). While a correlation was found between serum TGF-beta and enthesitis, sacroiliitis, and arthralgia (p=.006, p=.034, p=.02), no correlation was determined on the other clinical and laboratory findings (p>.05).. While the level of serum galectin-3 was determined to be normal in sarcoidosis patients, a high level of serum TGF-beta was found. These findings show that TGF-beta may play an important role in sarcoidosis pathogenesis and the formation of granuloma.

Topics: Female; Fibrosis; Galectin 3; Humans; Male; Middle Aged; Neovascularization, Pathologic; Sarcoidosis; Transforming Growth Factor beta

The aetiology of sarcoidosis is unclear. Single nucleotide polymorphisms (SNPs) in transforming growth factor (TGF)-β2 and -β3 have been reported to be associated with the development of lung fibrosis in patients with sarcoidosis. SNPs in TGF-β2 (rs1891467) and TGF-β3 (rs3917200) were investigated in 296 patients with sarcoidosis (acute/self remitting, n = 70 (including 62 patients with Löfgren's syndrome); chronic, n = 168; acute/chronic, n = 58) by real-time PCR. 32 patients showed radiological signs of lung fibrosis. The genotype frequencies were compared among the sarcoidosis groups as well as to 377 healthy controls. We found a significant association with the G-allele in rs1891467 in TGF-β2 and an acute/self remitting course of sarcoidosis compared to a chronic course (p = 0.001). The results were even more evident for patients with Löfgren's syndrome (p<0.001). Moreover, we could demonstrate a borderline significance between TGF-β3 (rs3917200) and lung fibrosis (p = 0.050). Carriers of the G-allele in rs1891467 might be protected from developing a chronic course. Moreover, there is evidence that rs3917200 is involved in the development of lung fibrosis in sarcoidosis. This study is the first in sarcoidosis patients to suggest a genetic implication of TGF-β2 as a protective factor in the course of sarcoidosis.

Topics: Adult; Aged; Alleles; Case-Control Studies; Female; Fibrosis; Genotype; Humans; Lung; Male; Middle Aged; Models, Genetic; Phenotype; Polymorphism, Genetic; Real-Time Polymerase Chain Reaction; Sarcoidosis; Transforming Growth Factor beta

African-Americans experience an excessive prevalence of a number of apparently disparate disorders that all appear to be, at least in part, mediated by the over-expression or activation of transforming growth factor-beta (TGF-beta) signaling pathways, and that certain genotypes including the codon 10 polymorphism occur more commonly among African-Americans and appears to predispose to these disorders. These disorders, fibrosing in nature, include hypertension, focal glomerulosclerosis, diabetic nephropathy, end stage renal disease, sarcoidosis, uterine leiomyoma, keloids, myocardial fibrosis, and glaucoma. The specific polymorphism for TGF-beta, codon 10, has been implicated in glomerulosclerosis and diabetic nephropathy as well as cardiac transplant rejection. Although TGF-beta over-expression is not the sole factor in these disorders, it is suggested that by designing future clinical studies that consider genomic differences in TGF-beta expression, a more complete understanding of these clinical disorders will be possible. A more thorough understanding of the genetic basis of disease will like promote improved therapeutic regimens and may help reduce the disparate health outcomes for African-Americans as well as improve treatment of individuals of various and diverse ethnic backgrounds.

Topics: Black People; Female; Glaucoma; Heart Transplantation; Humans; Keloid; Leiomyoma; Male; Sarcoidosis; Transforming Growth Factor beta

Montelukast, a potent cysteinyl receptor antagonist, may be an antifibrotic therapeutic agent for lung fibrosis. Seven sarcoidosis patients and 10 with unusual interstitial pneumonia underwent conventional bronchoalveolar lavage, from which myofibroblasts were recovered. Myofibroblast proliferation was assayed, alpha smooth muscle actin levels were measured, TGFbeta mRNA RT-PCR transcripts were semiquantitated, and secretion was evaluated in myofibroblast supernatants. Montelukast at 10(-8) M concentration had a suppressive effect on cell proliferation (31 +/- 18%), which was significantly enhanced by LTD4 10(-8) M. No differences were found between sarcoidosis (31.28 +/- 15.9%) and unusual interstitial pneumonia (30.56 +/- 24.3%) lines. Fetal calf serum (20%) produced an enhancing effect (29.8 +/- 21.6%) in all lines. Myofibroblasts recovered from sarcoidosis patients showed lower alpha-smooth muscle actin contents than unusual interstitial pneumonia lines (0.09 +/- 0.02 vs. 0.34 +/- 0.16, p =0.039, respectively). Montelukast suppressed alpha-actin in short-term cultures in sarcoidosis myofibroblasts and in long-term unusual interstitial pneumonia myofibroblasts. Montelukast at 10(-6) M concentratin decreased the TGFbeta-induced alpha-actin expression in all lines tested. Montelukast decreased mRNA expression of TGFbeta. Montelukast may be a therapeutic agent in pathological conditions involving fibrotic and remodeling processes.

Topics: Acetates; Actins; Adult; Cell Proliferation; Cells, Cultured; Cyclopropanes; Female; Fibroblasts; Fibrosis; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Quinolines; RNA, Messenger; Sarcoidosis; Sulfides; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) plays an important role in many diseases, influencing as it does such processes as immune responses, fibrosing processes, and angiogenesis. Recently, polymorphisms have been described for TGF-beta that are associated with the risk of several diseases. In this study, we investigated whether TGF-beta 1 polymorphism has an effect on sarcoidosis and tuberculosis.. TGF-beta 1 Codon 10 T869C polymorphism was investigated in 110 healthy control subjects, 104 sarcoidosis patients, and 101 tuberculosis patients.. The TGF-beta genotype was determined using polymerase chain reaction restriction fragment length polymorphism.. We found no significant differences in TGF-beta genotypes between sarcoidosis patients and healthy controls or tuberculosis patients and controls. The long axis of the tuberculin skin test was larger in the CC type compared with the CT type. However, there was no association between the TGF-beta genotype and the roentgenographic stage, the disappearance of shadows, or organ involvement in sarcoidosis, nor any association between genotype, the extent or type of roentgenographic shadow, or detected volume of tubercle bacilli in tuberculosis.. From the results, we believe that TGF-beta polymorphisms on the whole do not have a strong influence on disease onset or clinical progression in sarcoidosis and tuberculosis, although this polymorphism might have an effect on the immune response in a tuberculosis host.

Topics: Adult; Aged; Codon; Disease Progression; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Sarcoidosis; Severity of Illness Index; Skin Tests; Transforming Growth Factor beta; Tuberculosis, Pulmonary

Interleukin-10 (IL-10) and transforming growth factor-beta 1 (TGF-beta 1) are anti-inflammatory cytokines that play important roles in the immunoregulatory processes of numerous granulomatous diseases. In sarcoidosis polymorphisms (PMs) within these cytokine genes are suspected of modifing the course of the disorder. Therefore, we were interested in whether the genotype frequencies for a PM at position -1082 of the IL-10 or in codon 25 of the TGF-beta 1 gene differ in sarcoidosis or its distinct phenotypes in comparison with healthy individuals.. In 51 sarcoidosis patients and 72 healthy blood donors, genotyping for the named PMs was performed by PCR methodology and restriction enzyme digestion. Patients were retrospectively classified according to their course of disease, namely spontaneous remission, regressive under therapy, or chronic-progressive.. For TGF-beta 1 PM the genotype frequencies ranged between 81.8-90.5, 9.6-13.9 and 0-5.3 percent for genotype GG, CG and CC respectively. For IL-10 PM the values ranged between 17.7-23.2, 54.4-68.4 and 21.1-26.4 percent for AA, AG and GG. Statistical comparisons of the allele and genotype frequencies between the clinical defined sarcoidosis groups and the healthy blood donors revealed no significant differences.

Topics: Adult; Disease Progression; Female; Genotype; Humans; Interleukin-10; Male; Middle Aged; Polymorphism, Genetic; Prognosis; Retrospective Studies; Sarcoidosis; Transforming Growth Factor beta

The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for lymphocytic alveolitis in interstitial lung disease (ILD), alphaE expression on CD4+ and CD8+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF; n = 18), hypersensitivity pneumonitis (HP; n = 20) and sarcoidosis (n = 44) in comparison with healthy controls (n = 15). In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar CD8+ T cells consistently co-expressed alphaE. Absolute alveolar CD8+alphaE+ cell numbers/ml were up to 30-fold increased in HP patients. Proportions of alphaE-bearing CD4+ cells in BALF were significantly elevated in IPF (74.0 +/- 2.7%) and HP (70.0 +/- 2.4%) compared with normals (30.0 +/- 1.8%) (mean +/- s.e.m.; P < 0.01). In sarcoidosis, the alphaE expression on BALF CD4+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I (14.3 +/- 1.5%), but increased proportions in stages II (50.0 +/- 3.8%) and III (64.0 +/- 4.8%). Correlations between common markers of T cell activation or BALF transforming growth factor-beta (TGF-beta ) bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar CD8+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar CD4+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung.

Topics: Adolescent; Adult; Aged; Alveolitis, Extrinsic Allergic; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Humans; Integrins; Male; Middle Aged; Pulmonary Fibrosis; Sarcoidosis; Transforming Growth Factor beta

Topics: Bronchoalveolar Lavage Fluid; Humans; Lymphocyte Activation; Prognosis; Receptors, Interleukin-2; Sarcoidosis; Transforming Growth Factor alpha; Transforming Growth Factor beta

To improve our understanding of the role of extracellular matrix (ECM) proteins and integrins during the processes of granuloma formation in sarcoidosis, we examined the distribution of ECM proteins and the expression of integrins in sarcoid lymph nodes by immunohistochemical methods. We also examined the expression of transforming growth factor-beta1 (TGF-beta1), which is one of major regulators for synthesis of ECM proteins. Most ECM proteins were detected in the periphery of the granulomas in a concentric pattern, and fibronectin was diffusely detected from an early to a regressive stage. Compared with normal lymph nodes, most beta1-integrin subfamilies (alpha1, alpha4, alpha5 and alpha6) were more strongly expressed on lymphocytes around the granulomas. Epithelioid cells exhibited strong expression of the alpha5 molecule. Fibroblasts exhibited the expression of the alpha2 and alpha5 molecules surrounding ECM proteins. The alpha5beta1 molecule had a distribution similar to that of fibronectin. TGF-beta1 was detected in epithelioid cells throughout the various evolutional stages and its expression was especially marked in mature granulomas. Interaction of fibronectin and the alpha5beta1 molecule may have an important role in the process of formation of sarcoid granuloma. The expression of TGF-beta1 may be involved in the regression of sarcoid granuloma by initiating fibrosis and atrophy of epithelioid cells.

Topics: Extracellular Matrix Proteins; Humans; Immunohistochemistry; Integrins; Lymph Nodes; Sarcoidosis; Transforming Growth Factor beta

T lymphocytes expressing the alpha E beta 7 integrin are localized and selectively retained in mucosal tissues. To investigate a potential relationship between alpha E beta 7 expression and pulmonary inflammation, the distribution of alpha E beta 7-bearing CD4+ and CD8+ T cells in peripheral blood and bronchoalveolar lavage (BAL) fluids obtained from patients with allergic asthma, sarcoidosis, hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis (IPF) was determined. In contrast to the distribution in peripheral blood, BAL fluid from these patients contained high number of cells expressing alpha E beta 7 with markedly different expression patterns on CD4 or CD8 cells as well as among the various diseases. Despite similar numbers of activated CD4 cells, alpha E beta 7+CD4+ T cells ranged from 15% in asthmatics to 70% in IPF. In contrast, even in normal individuals, 60% to 90% of BAL fluid CD8+ T cells express alpha E beta 7, suggesting differential induction mechanisms on CD4 and CD8 cells. In vitro experiments revealed that a substantial proportion of peripheral blood CD+ T cells express alpha E beta 7 after stimulation with anti-CD3 antibodies, and up to 80% positive cells were found after the addition of TGF-beta. In contrast, less than 10% of CD4 cells express this particular integrin after in vitro stimulation, and the presence of TGF-beta only increased the number to 30%. Supernatants from in vitro-activated BAL cells as well as concentrated BAL fluid from patients with high alpha E beta 7 expression had no further enhancing effect. However, crosslinking of alpha 4 beta 1-, but not beta 2-integrins, significantly increased the number of alpha E beta 7 expressing CD4+ and CD8+ T cells, even in the absence of TGF-beta. These data indicate that in addition to TGF-beta, the interaction of particular T-cell subsets with specific endothelial cell and extracellular matrix proteins may upregulate alpha E beta 7 integrin expression and thereby contribute to the selective accumulation of these cells in inflammatory lung diseases.

Topics: Adult; Alveolitis, Extrinsic Allergic; Antibodies; Asthma; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cross-Linking Reagents; Eosinophils; Female; HLA-DR Antigens; Humans; Integrin alpha4beta1; Integrins; Leukocyte Common Antigens; Lung Diseases, Interstitial; Lymphocyte Activation; Lymphocyte Subsets; Macrophages, Alveolar; Male; Middle Aged; Neutrophils; Pulmonary Fibrosis; Receptors, Interleukin-2; Receptors, Lymphocyte Homing; Sarcoidosis; T-Lymphocytes; Transforming Growth Factor beta

Interactions between mononuclear cells, vascular endothelium, fibroblasts, and cytokines during the inflammatory reaction within a granuloma have the potential to contribute to the progression to fibrosis.. Biopsy specimens of six tuberculous and eight sarcoidosis skin lesions were examined by immunohistochemistry to seek evidence for the presence of inflammatory and fibrotic reactions in human granulomatous disease. Additionally, to understand how a T cell mediated delayed type hypersensitivity reaction--a component of chronic granulomatous inflammation--could progress to fibrosis, the human in vivo model of the cutaneous tuberculin Heaf reaction to purified protein derivative (PPD) was studied in a group of 48 subjects.. Granulomas from tuberculous and sarcoidosis skin biopsy specimens were seen to contain cells with marked staining by antibodies to fibronectin, transforming growth factor beta (pan TGF-beta), and type 1 procollagen (PCP-1). Accentuated staining of extracellular matrix was seen both in the granulomas and in the peri-granulomatous regions. Less prominent staining was observed using antibodies against interleukin 1 beta (IL-1 beta) and alpha-smooth muscle actin (alpha-SMA). Biopsies of Heaf reactions revealed cells staining for IL-1 beta, tumour necrosis factor alpha (TNF-alpha), platelet derived growth factor B (PDGF-B), and fibronectin which were detected as early as day 1 and persisted throughout the 14 day study period. Cells staining for PCP-1 increased to greatest abundance at day 14. All these cytokines were present in low abundance in biopsy specimens from sites inoculated with saline only.. Evidence is provided that granulomas in tuberculosis and sarcoidosis behave as active centres of fibrogenesis. Using the Heaf model, the temporal relationship between the early appearance of cytokines and the later increase in the collagen precursor PCP-1 linked the immune mediated chronic inflammatory response with subsequent fibrosis and suggested that the tuberculin Heaf reaction will serve as a model for studying the early events of granuloma formation in patients with tuberculosis and sarcoidosis.

Topics: Actins; Cytokines; Extracellular Matrix; Fibroblasts; Fibronectins; Humans; Hypersensitivity, Delayed; Immunohistochemistry; Interleukin-1; Macrophages; Platelet-Derived Growth Factor; Procollagen; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-sis; Sarcoidosis; Skin Diseases; Time Factors; Transforming Growth Factor beta; Tuberculin Test; Tuberculosis, Cutaneous; Tumor Necrosis Factor-alpha