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T cell receptor-V? repertoires in lung and blood CD4+ and CD8+ T cells of pulmonary sarcoidosis patients.

ABSTRACT: BACKGROUND: Sarcoidosis patients have accumulations of activated CD4+ T cells in affected organs, such as the lungs. T cell receptor (TCR) V?-chain usage has been incompletely characterized in these patients. METHODS: We surveyed the TCR V? usage in CD4+ and CD8+ T cells in bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC) from 15 HLA-typed Scandinavian sarcoidosis patients. In addition, PBMC from 9 healthy volunteers and BAL cells from three of them were examined. Using 21 V? family-specific antibodies, we covered approximately 70% of all V? chains. RESULTS: In BAL T cells from sarcoidosis patients, we identified 16 CD4+ T cell expansions in 271 analyses (5.9%) and 21 CD8+ expansions in 240 analyses (8.7%). In PBMC we found 9 CD4+ expansions in 276 analyses (3.3%) and 12 CD8+ expansions out of 263 analyses (4.6%). Consistent with previous studies we found V?8 and V?16 expansions in sarcoidosis patients' lungs. In addition, we found lung restricted V?22 expansions in three HLA DRB1 03+ patients. However, we found no statistically significant difference in frequency of expansions between patients and healthy controls. CONCLUSIONS: The identified T cell expansions in present study indicate specific antigen recognition in the lungs of sarcoidosis patients.

SUBMITTER: Ahlgren KM

PROVIDER: S-EPMC3997965 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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T cell receptor-Vβ repertoires in lung and blood CD4+ and CD8+ T cells of pulmonary sarcoidosis patients.

Ahlgren Kerstin M KM Ruckdeschel Tina T Eklund Anders A Wahlström Jan J Grunewald Johan J

BMC pulmonary medicine 20140322

<h4>Background</h4>Sarcoidosis patients have accumulations of activated CD4+ T cells in affected organs, such as the lungs. T cell receptor (TCR) Vβ-chain usage has been incompletely characterized in these patients.<h4>Methods</h4>We surveyed the TCR Vβ usage in CD4+ and CD8+ T cells in bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC) from 15 HLA-typed Scandinavian sarcoidosis patients. In addition, PBMC from 9 healthy volunteers and BAL cells from three of them w ...[more]

PMID: 24656074

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Project description:RationaleNew approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations.ObjectivesTo determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases.MethodsWe compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations.Measurements and main resultsAn Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls.ConclusionsTuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.

Project description:BackgroundSarcoidosis is a granulomatous systemic disease of unknown etiology. Mononuclear cells such as macrophages or lymphocytes in lung tissue and hilar or mediastinal lymph nodes have been recognized to play an essential role in granuloma formation in pulmonary sarcoidosis. Peripheral blood mononuclear cells (PBMCs) consist of several immunocompetent cells and have been shown to play a mechanistic role in the pathogenesis of sarcoidosis. However, the genetic modifications that occur in bulk PBMCs of sarcoidosis remain to be elucidated.PurposeThis study aimed to explore the pathobiological markers of sarcoidosis in PBMCs by comparing the transcriptional signature of PBMCs from patients with pulmonary sarcoidosis with those of healthy controls by RNA sequencing.MethodsPBMC samples were collected from subjects with pulmonary sarcoidosis with no steroid/immunosuppressant drugs (n = 8) and healthy controls (n = 11) from August 2020 to April 2021, and RNA sequencing was performed with the PBMC samples.ResultsPrincipal component analysis using RNA sequencing datasets comparing pulmonary sarcoidosis with healthy controls revealed that the two groups appeared to be differentiated, in which 270 differentially expressed genes were found in PBMCs between sarcoidosis and healthy controls. Enrichment analysis for gene ontology suggested that some biological processes related to the pathobiology of sarcoidosis, such as cellular response to interleukin (IL)-1 and IFN-γ, regulation of IL-6 production, IL-8 secretion, regulation of mononuclear cell migration, and response to lipopolysaccharide, were involved. Enrichment analysis of the KEGG pathway indicated the involvement of tumor necrosis factor (TNF), toll-like receptor signaling, IL-17 signaling pathways, phagosomes, and ribosomes. Most of the genes involved in TNF and IL-17 signaling pathways and phagosomes were upregulated, while most of the ribosome-related genes were downregulated.ConclusionThe present study demonstrated that bulk gene expression patterns in PBMCs were different between patients with pulmonary sarcoidosis and healthy controls. The changes in the gene expression pattern of PBMCs could reflect the existence of sarcoidosis lesions and influence granuloma formation in sarcoidosis. These new findings are important to strengthen our understanding of the etiology and pathobiology of sarcoidosis and indicate a potential therapeutic target for sarcoidosis.

Project description:BackgroundNarcolepsy Type I (NT1) is a rare, life-long sleep disorder arising as a consequence of the extensive destruction of orexin-producing hypothalamic neurons. The mechanisms involved in the destruction of orexin neurons are not yet elucidated but the association of narcolepsy with environmental triggers and genetic susceptibility (strong association with the HLA, TCRs and other immunologically-relevant loci) implicates an immuno-pathological process. Several studies in animal models and on human samples have suggested that T-cells are the main pathogenic culprits.MethodsRNA sequencing was performed on four CD4 and CD8 T-cell subsets (naive, effector, effector memory and central memory) sorted by flow cytometry from peripheral blood mononuclear cells (PBMCs) of NT1 patients and HLA-matched healthy donors as well as (age- and sex-) matched individuals suffering from other sleep disorders (OSD). The RNAseq analysis was conducted by comparing the transcriptome of NT1 patients to that of healthy donors and other sleep disorder patients (collectively referred to as the non-narcolepsy controls) in order to identify NT1-specific genes and pathways.ResultsWe determined NT1-specific differentially expressed genes, several of which are involved in tubulin arrangement found in CD4 (TBCB, CCT5, EML4, TPGS1, TPGS2) and CD8 (TTLL7) T cell subsets, which play a role in the immune synapse formation and TCR signaling. Furthermore, we identified genes (GZMB, LTB in CD4 T-cells and NLRP3, TRADD, IL6, CXCR1, FOXO3, FOXP3 in CD8 T-cells) and pathways involved in various aspects of inflammation and inflammatory response. More specifically, the inflammatory profile was identified in the "naive" subset of CD4 and CD8 T-cell.ConclusionWe identified NT1-specific differentially expressed genes, providing a cell-type and subset specific catalog describing their functions in T-cells as well as their potential involvement in NT1. Several genes and pathways identified are involved in the formation of the immune synapse and TCR activation as well as inflammation and the inflammatory response. An inflammatory transcriptomic profile was detected in both "naive" CD4 and CD8 T-cell subsets suggesting their possible involvement in the development or progression of the narcoleptic process.

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T cell receptor-V? repertoires in lung and blood CD4+ and CD8+ T cells of pulmonary sarcoidosis patients.

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T cell receptor-Vβ repertoires in lung and blood CD4+ and CD8+ T cells of pulmonary sarcoidosis patients.

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