IFN-γ–Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells (original) (raw)
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Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells
Clinical and Experimental Immunology, 2000
The pathogenesis of pulmonary sarcoidosis has been related to an increased production of Th1-like cytokines. However, cytokine expression in sarcoidosis has not been systematically studied at a singlecell level. We therefore investigated the expression of IL-2, IL-4, IL-13, tumour necrosis factor-alpha (TNF-a ) and interferon-gamma (IFN-g) intracellularly in bronchoalveolar lavage (BAL) and peripheral blood CD3 1 T lymphocytes from patients with pulmonary sarcoidosis (radiologic stage II±III, n 8) and normal controls (n 9) by flow cytometry. In contrast to IL-4 and IL-13, the percentage of T lymphocytes expressing intracellular IL-2 (49´3^21´3% versus 14´5^15´6%), IFN-g (75´5^14´9% versus 32´6^18´7%) and TNF-a (68´3^18´7% versus 36´8^20´8%) was significantly higher in patients with sarcoidosis than in normal controls (each P , 0´005). In contrast to BAL lymphocytes, expression of these cytokines in peripheral blood lymphocytes did not differ between patients with sarcoidosis and normal controls. Close correlations were observed between the percentages of BAL lymphocytes expressing intracellular IL-2, IFN-g and TNF-a , but not for IL-4 or IL-13. Analysis of the expression of these cytokines in T lymphocyte subsets revealed IL-2, IFN-g, and TNF-a in CD4 1 as well as CD8 1 T lymphocytes, suggesting a contribution of TC1 cells to the production of proinflammatory cytokines in sarcoidosis. We conclude that a Th1-like cytokine pattern can be observed in CD4 1 as well as in CD8 1 BAL T lymphocytes in patients with pulmonary sarcoidosis.
Sarcoidosis Th17 Cells are ESAT-6 Antigen Specific but Demonstrate Reduced IFN-γ Expression
Journal of Clinical Immunology, 2012
Rationale-Sarcoidosis is a granulomatous disease of unknown etiology. Many patients with sarcoidosis demonstrate antigen-specific immunity to mycobacterial virulence factors. Th-17 cells are crucial to the immune response in granulomatous inflammation, and have recently been shown to be present in greater numbers in the peripheral blood and bronchoalveolar lavage (BAL) fluid (BALF) of sarcoidosis patients than healthy controls. It is unclear whether Th-17 cells in sarcoidosis are specific for mycobacterial antigens, or whether they have similar functionality to control Th-17 cells. Methods-Flow cytometry was used to determine the numbers of Th-17 cells present in the peripheral blood and BALF of patients with sarcoidosis, the percentage of Th-17 cells that were specific to the mycobacterial virulence factor ESAT-6, and as well as to assess IFN-γ expression in Th-17 cells following polyclonal stimulation.
Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes
The European respiratory journal, 2018
The lung-draining mediastinal lymph nodes (MLNs) are currently widely used to diagnose sarcoidosis. We previously reported that T-helper (Th) 17.1 cells are responsible for the exaggerated interferon-γ production in sarcoidosis lungs. In this study, we aimed to investigate 1) whether Th17.1 cells are also increased in the MLNs of sarcoidosis patients and 2) whether frequencies of the Th17.1 cells at diagnosis may correlate with disease progression.MLN cells from treatment-naive pulmonary sarcoidosis patients (n=17) and healthy controls (n=22) and peripheral blood mononuclear cells (n=34) and bronchoalveolar lavage fluid (BALF) (n=36) from sarcoidosis patients were examined for CD4 T-cell subset proportions using flow cytometry.Higher proportions of Th17.1 cells were detected in sarcoidosis MLNs than in control MLNs. Higher Th17.1 cell proportions were found in sarcoidosis BALF compared with MLNs and peripheral blood. Furthermore, BALF Th17.1 cell proportions were significantly highe...
The Roles of T Helper 1, T Helper 17 and Regulatory T Cells in the Pathogenesis of Sarcoidosis
Iranian journal of allergy, asthma, and immunology, 2016
Sarcoidosis is a systemic granulomatous disorder of unidentified etiology, with a heterogeneous clinical presentation. It is characterized by a reduced delayed-type hypersensitivity to tuberculin and common antigens. The balance between Th1, Th17 and Regulatory T(Treg) cells controls T-cell proliferation and activation.The Th17/Treg ratio in the peripheral blood and bronchoalveolar lavage fluidis increased in patients with active sarcoidosis. Amplified IL-17A expression in granulomas and the presence of IL-17A+, IL-17A+IL-4+ and IL-17A+IFN-γ+ memory T helper cells in the circulation and BAL indicate Th17 cell involvement in granuloma induction and/or maintenance in sarcoidosis. Sarcoidosis should therefore be considered as a Th1/Th17 multisystem disorder and anti-IL-17/Th17 approaches that control and reduce IL-17Amay be an option, therefore, for the treatment of sarcoidosis.Here we provide a short overview as to the role of Th17 cells as critical cells in the pathogenesis of sarcoi...
Thorax, 1984
Different lymphocyte subpopulations have been evaluated in bronchoalveolar fluid and blood obtained from six patients with active and six with inactive pulmonary sarcoidosis and from six normal subjects by means of two recently described monoclonal antibodies, 5/9 and MLR4. The percentages of OKT4 positive (helper) and OKT8 positive (suppressor) T cells were also determined. Patients with active sarcoidosis had significantly higher proportions of 5/9 positive T cells in the bronchoalveolar fluid than patients with inactive disease (p < 0.01) or normal subjects (p < 0.001). In contrast, the proportions of 5/9 positive blood T cells were similar in the three groups studied. Patients with active sarcoidosis had also a greater proportion proportion of MLR4 positive T lymphocytes in bronchoalveolar fluid than patients with inactive disease or normal subjects (p < 0*01 for each comparison), but similar proportions of MLR4 positive blood T cells were found in each group. The ratio of 5/9 positive to MLR4 positive T cells was higher in the bronchoalveolar fluid (but not in the blood) in patients with either active or inactive sarcoidosis than in normal subjects. These observations suggest that the MLR4 negative fraction rather than the MLR4 positive fraction of the 5/9 positive T cells is preferentially expanded in the lungs of patients with pulmonary sarcoidosis and may indicate a secondary role for the MLR4 positive T cells in producing lung injury in this disorder. Comparisons of the OKT4 positive and 5/9 positive T cells showed that in patients with active disease most of the lung T lymphocytes expressed both the OKT4 and the 5/9 surface antigens, so the 5/9 monoclonal antibody may be considered a good marker of activity in this disorder. Pulmonary sarcoidosis may be characterised by the preferential expansion of helper T cell subsets at sites of disease activity. Sarcoidosis is a generalised disorder of unknown aetiology characterised by non-caseating granulomas in the affected organs'-5 and by polyclonal hypergammaglobulinaemia.6'3 Recent studies on pulmonary sarcoidosis have shown that in patients with active disease (high intensity alveolitis) both granuloma formation and immunoglobulin production appear to be modulated by activated T lymphocytes.'2-5 Patients with high intensity
American Journal of Respiratory and Critical Care Medicine, 2000
In previous reports of studies of Scandinavian sarcoidosis patients, we have described a strong association between lung-restricted expansions of T cells expressing T-cell receptor (TCR) AV2S3 and the human leukocyte antigen (HLA)-DRB1*0301 (DR17) and-DRB3*0101 alleles, suggesting the presence of a specific antigen in sarcoidosis. In the present study, the degree of lung-accumulated TCR AV2S3 ϩ T cells was related to clinical data in 51 HLA-DRB1*0301/DRB3*0101-positive Scandinavian patients with pulmonary sarcoidosis. Significantly more AV2S3 ϩ lung T cells (median: 30.0% of CD4 ϩ cells in bronchoalveolar lavage fluid [BALF]) were found accumulated in patients with a short (Ͻ 2 yr) than with a long (Ͼ 2 yr) (median: 18.6%) disease duration (p ϭ 0.003). A strong positive association was also found between lung-restricted AV2S3 ϩ T cells and both the CD4 ϩ-to-CD8 ϩ cell ratio (p ϭ 7 ϫ 10 Ϫ 6) in BALF and with an acute disease onset (p ϭ 0.018). Negative associations were found between both the interval from disease onset to bronchoalveolar lavage (p ϭ 0.0001) and the age of the patient (p ϭ 0.002). Our findings strongly link lung-accumulated AV2S3 ϩ T cells to the acute inflammatory response in sarcoidosis. Moreover, the association of these cells with a good prognosis indicates that AV2S3 ϩ T cells may have a protective role against a presumed sarcoidosis antigen. Grunewald J, Berlin M, Olerup O, Eklund A. Lung T-helper cells expressing T-cell receptor AV2S3 associate with clinical features of pulmonary sarcoidosis.
Cytokine mRNA gene expression in active and nonactive pulmonary sarcoidosis
European Respiratory Journal, 1997
Sarcoidosis is a multisystem granulomatous disease associated with the expansion and activation of CD4+ T-lymphocytes and macrophages. To investigate the immunopathology of active and nonactive pulmonary sarcoidosis, we have examined the expression of cytokine gene transcripts in bronchoalveolar lavage cells from 15 patients with active pulmonary sarcoidosis, eight patients with nonactive pulmonary sarcoidosis, and nine normal controls. Using in situ hybridization, the percentage of cells expressing messenger ribonucleic acid (mRNA) for interleukin (IL)-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 and interferon-γ (IFNγ) were compared in the groups studied. In individuals with active sarcoidosis, there were significantly greater proportions of cells expressing mRNA for IL-2, IL-10, IL-12 and IFN-γ than in subjects with nonactive disease and normal controls (p<0.01). There was no significant difference in the percentage of positive cells expressing IL-10 and IL-12 mRNA in the nonactive group compared to the normal controls (p>0.05). No significant differences in the percentages of IL-3, IL-4 and IL-5 mRNA positive cells were observed between active and nonactive sarcoidosis patients and normal controls (p>0.05). These results demonstrate that there is a preferential expression of T-helper type 1 cytokines in pulmonary sarcoidosis, and that cytokines related to macrophage activation are the most prominent. In addition, these data implicate an elevated expression of interleukin-2,-10 and-12 and interferon-γ in active compared to nonactive sarcoidosis.
Sarcoidosis is a Th1/Th17 multisystem disorder
Thorax, 2011
Background and aims Sarcoidosis is characterised by a compartmentalisation of CD4 + T helper 1 (Th1) lymphocytes and activated macrophages in involved organs, including the lung. Recently, Th17 effector CD4 + T cells have been claimed to be involved in the pathogenesis of granuloma formation. The objective of this study was to investigate the involvement of Th17 cells in the pathogenesis of sarcoidosis. Methods Peripheral and pulmonary Th17 cells were evaluated by flow cytometry, real-time PCR, immunohistochemistry analyses and functional assays in patients with sarcoidosis in different phases of the disease and in control subjects. Results Th17 cells were detected both in the peripheral blood (4.7262.27% of CD4 + T cells) and in the bronchoalveolar lavage (BAL) (8.8162.25% of CD4 + T lymphocytes) of patients with sarcoidosis and T cell alveolitis. Immunohistochemical analysis of lung and lymph node specimens showed that interleukin 17 (IL-17) + /CD4 + T cells infiltrate sarcoid tissues surrounding the central core of the granuloma. IL-17 was expressed by macrophages infiltrating sarcoid tissue and/or forming the granuloma core (7.8862.40% of alveolar macrophages). Analysis of some lung specimens highlighted the persistence of IL-17 + /CD4 + T cells in relapsed patients and their absence in the recovered cases. Migratory assays demonstrated the ability of the Th17 cell to respond to the chemotactic stimulus CCL20dthat is, the CCR6 ligand (74.868.5 vs 7.662.8 migrating BAL lymphocytes/high-powered field, with and without CCL20, respectively). Conclusions Th17 cells participate in the alveolitic/ granuloma phase and also to the progression towards the fibrotic phase of the disease. The recruitment of this cell subset may be driven by CCL20 chemokine.
Clonal analysis of lung and blood T cells in patients with sarcoidosis
Thorax, 1994
Background -Sarcoidosis is a disease characterised by clinical "anergy" to delayed type hypersensitivity antigens and the formation of non-caseating granulomas, which frequently manifests in the lungs as a T lymphocyte/mononuclear cell alveolitis. Although there is an increased proportion of T cells in bronchoalveolar lavage (BAL) samples from these patients, and these T cells often show evidence of activation and spontaneous secretion of cytokines such as interleukin 2 (IL-2) and interferon gamma (IFNy) -a pattern similar to delayed type hypersensitivity reactionsit is unclear whether both cytokines are produced by the majority of T cells derived from the lungs of patients with sarcoidosis or whether unique subpopulations of T cells produce each cytokine.