TGF-beta 1 variants in chronic beryllium disease and sarcoidosis.
ABSTRACT Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-beta1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-beta1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-beta1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-beta1 variants or haplotypes. The -509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the -509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the -509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the -509C and codon 10T, implicated in lower levels of TGF-beta1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-beta1, although future studies will be needed to correlate TGF-beta1 protein levels with known TGF-beta1 genotypes and assess whether there is a shared mechanisms for TGF-beta1 in these two granulomatous diseases.
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ABSTRACT: Abstract Exhaled breath condensate (EBC) is a non-invasive method of sampling airway lining fluids in respiratory diseases. This may be useful in identifying exhaled biomarkers of granulomatous inflammation and pulmonary fibrosis in patients with sarcoidosis. The aim of this pilot study was to identify markers of granulomatous airway inflammation and disease activity including neopterin, transforming growth factor-β1 (TGF-β1) and angiotensin converting enzyme (ACE) in EBC. EBC was collected from 16 patients with sarcoidosis and 22 healthy control subjects. EBC neopterin, and active-TGF-β1 were measured by ELISA. EBC–ACE activity was measured using a colorimetric assay. EBC neopterin was detectable in 3/20 controls and 7/16 patients with sarcoidosis. Patients with sarcoidosis had greater mean neopterin levels compared to control subjects (0.57 ± 0.45 nmol l−1 versus 0.41 ± 0.22 nmol l−1, p = 0.04). TGF-β1 was detectable in the EBC of all subjects and concentrations were higher in patients with sarcoidosis compared with controls (115.5 ± 79.6 pg mol−1 versus 82.3 ± 16.2 pg mol−1, p = 0.048). There was no difference in EBC ACE activity, which was only detectable in 3/20 healthy controls and 2/16 patients (p = 0.91). EBC markers of granulomatous inflammation are detectable at greater levels in patients with sarcoidosis compared to healthy controls subjects. Larger studies and development of sensitive assays are warranted to examine the disease correlates and predictive utility of these markers.Journal of Breath Research 10/2013; 7(4):046003. · 3.59 Impact Factor
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ABSTRACT: Cytokines appear to play a key role in some inflammatory reactions affecting the interactions among pro- and anti-inflammatory mechanisms that result in several diseases such as coal workers' pneumoconiosis (CWP). In this study, to determine the cytokine gene profiles of Turkish coal miners, we performed genotyping analysis to investigate the polymorphisms of CWP-related pro-inflammatory (TNFA, IL1A, IL1B, and IL6) and anti-inflammatory cytokines (IL-1RN and TGFB1). An additional goal was to observe whether these cytokine gene polymorphisms influence the development risk and severity of. Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. TNFA (-238) gene polymorphism principally affected CWP development and severity (OR = 3.47: 95% CI, 1.12-10.77 and OR = 4.30: 95% CI, 1.25-14.74, respectively) and also risk of CWP (OR = 3.79: 95% CI, 1.37-10.46). The TNFA (-308) variant was associated with a risk for the CWP severity (OR = 2.84: 95% CI, 1.08-7.39). A protective effect of IL6 was found on the development (OR = 0.48: 95% CI, 0.21-0.93) and severity of CWP (OR = 0.37: 95% CI, 0.15-0.91). We suggest that TNFA (-238) variant may be a risk factor in both development and the severity of CWP, while TNFA (-308) variant seems to be important only in disease severity. On the other hand, IL6 variant may have a protective effect on the development and disease severity.American Journal of Industrial Medicine 10/2008; 51(10):741-7. DOI:10.1002/ajim.20632 · 1.59 Impact Factor
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ABSTRACT: This review discusses the immunology of chronic beryllium disease. It addresses the importance of the interaction between class II molecules and the T cells that recognize beryllium, along with the subsequent immune response that results in sensitization and disease, and genetic factors leading to variation in this response. HLA-DPB1 with a glutamic acid at amino acid position 69 (Glu69) confers increased risk of beryllium sensitization and is not specific for chronic beryllium disease. The degree of negative surface charge of the molecule may increase risk of chronic beryllium disease but not sensitization. In the absence of Glu69, HLA-DRB1 alleles may function in beryllium presentation, increasing the risk of chronic beryllium disease. The T-cell response as assessed by the beryllium lymphocyte proliferation test is dependent on central memory T-cells, while Th1 cytokine secretion leading to granulomatous inflammation and chronic beryllium disease is dependent on the activity of effector memory T cells. Polymorphisms in cytokine genes, such as the TGF-beta1 gene, also affect the risk of chronic beryllium disease and more severe disease. The current diagnostic criteria for sensitization and chronic beryllium disease rely on the beryllium lymphocyte proliferation test. By understanding the novel immunologic mechanisms and genetic factors associated with sensitization and chronic beryllium disease, we may improve our ability to detect beryllium health effects with new diagnostics, and hopefully refine therapies for disease.Current Opinion in Allergy and Clinical Immunology 05/2008; 8(2):126-34. DOI:10.1097/ACI.0b013e3282f824a4 · 3.66 Impact Factor