Epipolymorphisms associated with the clinical outcome of autoimmune arthritis affect CD4+ T cell activation pathways
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE89253 | GEO | 2016/10/28
SECONDARY ACCESSION(S): PRJNA350837
REPOSITORIES: GEO
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Project description:Multifactorial diseases, including autoimmune juvenile idiopathic arthritis (JIA), result from a complex interplay between genetics and environment. Epigenetic mechanisms are believed to integrate such gene-environment interactions, fine-tuning gene expression and possibly contributing to immune system dysregulation. Although anti-TNF therapy has strongly increased JIA remission rates, it is not curative and up to 80% of patients flare upon treatment withdrawal. Thus, a crucial unmet medical and scientific need is to understand the immunological mechanisms associated with remission or flare to inform clinical decisions. Here, we explored the CD4+ T cell DNA methylome of 68 poly-articular and extended oligo-articular JIA patients, before and after anti-TNF therapy withdrawal, to identify features associated with maintenance of inactive disease (ID). Individual CpG sites were clustered in coherent modules without a priori knowledge of their function through network analysis. The methylation level of several CpG modules, specifically those enriched in CpG sites belonging to genes that mediate T cell activation, uniquely correlated with clinical activity. Differences in DNA methylation were already detectable at the time of therapy discontinuation, suggesting epigenetic predisposition. RNA profiling also detected differences in T cell activation markers, including HLA-DR, but, overall, its sensitivity was lower than epigenetic profiling. Changes to the T cell activation signature at the protein level were detectable by flow cytometry, confirming the biological relevance of the observed alterations in methylation. Our work proposes, for the first time, epigenetic discrimination between clinical activity states, and reveals T cell-related biological functions tied to, and possibly predicting and/or causing, clinical outcome.
2016-10-28 | GSE89251 | GEO
Project description:Multifactorial diseases, including autoimmune juvenile idiopathic arthritis (JIA), result from a complex interplay between genetics and environment. Epigenetic mechanisms are believed to integrate such gene-environment interactions, fine-tuning gene expression, and possibly contributing to immune system dysregulation. Although anti-TNF therapy has strongly increased JIA remission rates, it is not curative and up to 80% of patients flare upon treatment withdrawal. Thus, a crucial unmet medical and scientific need is to understand the immunological mechanisms associated with remission or flare to inform clinical decisions. Here, we explored the CD4+ T-cell DNA methylome of 68 poly-articular and extended oligo-articular JIA patients, before and after anti-TNF therapy withdrawal, to identify features associated with maintenance of inactive disease. Individual CpG sites were clustered in coherent modules without a priori knowledge of their function through network analysis. The methylation level of several CpG modules, specifically those enriched in CpG sites belonging to genes that mediate T-cell activation, uniquely correlated with clinical activity. Differences in DNA methylation were already detectable at the time of therapy discontinuation, suggesting epigenetic predisposition. RNA profiling also detected differences in T-cell activation markers (including HLA-DR) but, overall, its sensitivity was lower than epigenetic profiling. Changes to the T-cell activation signature at the protein level were detectable by flow cytometry, confirming the biological relevance of the observed alterations in methylation. Our work proposes epigenetic discrimination between clinical activity states, and reveals T-cell-related biological functions tied to, and possibly predicting or causing, clinical outcome.
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Project description:Multifactorial diseases, including autoimmune juvenile idiopathic arthritis (JIA), result from a complex interplay between genetics and environment. Epigenetic mechanisms are believed to integrate such gene-environment interactions, fine-tuning gene expression and possibly contributing to immune system dysregulation. Although anti-TNF therapy has strongly increased JIA remission rates, it is not curative and up to 80% of patients flare upon treatment withdrawal. Thus, a crucial unmet medical and scientific need is to understand the immunological mechanisms associated with remission or flare to inform clinical decisions. Here, we explored the CD4+ T cell DNA methylome of 68 poly-articular and extended oligo-articular JIA patients, before and after anti-TNF therapy withdrawal, to identify features associated with maintenance of inactive disease (ID). Individual CpG sites were clustered in coherent modules without a priori knowledge of their function through network analysis. The methylation level of several CpG modules, specifically those enriched in CpG sites belonging to genes that mediate T cell activation, uniquely correlated with clinical activity. Differences in DNA methylation were already detectable at the time of therapy discontinuation, suggesting epigenetic predisposition. RNA profiling also detected differences in T cell activation markers, including HLA-DR, but, overall, its sensitivity was lower than epigenetic profiling. Changes to the T cell activation signature at the protein level were detectable by flow cytometry, confirming the biological relevance of the observed alterations in methylation. Our work proposes, for the first time, epigenetic discrimination between clinical activity states, and reveals T cell-related biological functions tied to, and possibly predicting and/or causing, clinical outcome.
2016-10-28 | GSE89252 | GEO
Project description:Epipolymorphisms associated with the clinical outcome of autoimmune arthritis affect CD4+ T cell activation pathways
| PRJNA350837 | ENA
Project description:HIV infection is characterized by a brisk immune activation that plays an important role in the CD4 depletion and immune dysfunction of patients with AIDS. The mechanism underlying this activation is poorly understood. In the current study, we tested the hypothesis that this activation is the net product of two distinct pathways: the inflammatory response to HIV infection and the homeostatic response to CD4 T cell depletion. Using ex vivo BrdU incorporation of PBMCs from 284 patients with different stages of HIV infection, we found that CD4 proliferation was better predicted by the combination of CD4 depletion and HIV viral load (R(2) = 0.375, P < 0.001) than by either parameter alone (CD4 T cell counts, R(2) = 0.202, P < 0.001; HIV viremia, R(2) = 0.302, P < 0.001). Interestingly, CD8 T cell proliferation could be predicted by HIV RNA levels alone (R(2) = 0.334, P < 0.001) and this predictive value increased only slightly (R(2) = 0.346, P < 0.001) when CD4 T cell depletion was taken into account. Consistent with the hypothesis that CD4 T cell proliferation is driven by IL-7 as a homeostatic response to CD4 T cell depletion, levels of phosphorylated STAT-5 were found to be elevated in naive subsets of CD4 and CD8 T cells from patients with HIV infection and in the central memory subset of CD4 T cells. Taken together these data demonstrate that at least two different pathways lead to immune activation of T cells in patients with HIV infection and these pathways differentially influence CD4 and CD8 T cell subsets.
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Project description:Rheumatoid arthritis (RA) is an autoimmune disease that is related to the induction of T helper (Th)17 cells, which secrete interleukin-17, and activation of the signal transducer and activator of transcription (STAT) 3. The expression of high-temperature requirement protein A (HtrA) 2, a serine protease involved in apoptosis, was decreased in RA patients nonresponsive to drug treatment of RA. The aim of this study was to determine whether overexpression of HtrA2 has a therapeutic effect on RA. Th17 differentiation, osteoclastogenesis, and lymphocyte activation are increased in motor neuron degeneration (mnd)2 mice, which lack HtrA2 activity because of a missense mutation (Ser276Cys) in the protease domain of HtrA2. The inhibitor of HtrA2 also increased Th17 differentiation. On the other hand, HtrA2 induced cleavage of STAT3 and overexpression of HtrA2 attenuated CIA in a mouse model. HtrA2 overexpression inhibited plaque development as well as the differentiation of Th17 in ApoE-/- mice after immunization with proteoglycans to induce a hyperlipidemia-based RA animal model. The therapeutic function of HtrA2 in inflammatory diseases is linked with Th17 development and the STAT3 pathway in splenocytes. These results suggest that HtrA2 participates in immunomodulatory activity where the upregulation of HtrA2 may shed light on therapeutic approaches to RA and hyperlipidemia.
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Project description:Long intergenic noncoding RNAs (lincRNAs) are a class of independently transcribed molecules longer than 200 nucleotides that do not overlap known protein-coding genes. LincRNAs have diverse roles in gene expression and participate in a spectrum of biological processes. Dysregulation of lincRNA expression can abrogate cellular homeostasis, cell differentiation, and development and can also deregulate the immune and nervous systems. A growing body of literature indicates their important and multifaceted roles in the pathogenesis of several different diseases. Furthermore, certain lincRNAs can be considered potential therapeutic targets and valuable diagnostic or prognostic biomarkers capable of predicting the onset of a disease, its degree of activity, or the progression phase. In this review, we discuss possible mechanisms and molecular functions of lincRNAs in the pathogenesis of selected autoimmune and neurodegenerative disorders: multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This summary can provide new ideas for future research, diagnosis, and treatment of these highly prevalent and devastating diseases.
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Project description:Obstructive chronic lung allograft dysfunction (BOS) is the major limiting factor for lung transplantation (LTx) outcome. PTPN22 is described as the hallmark autoimmunity gene, and one specific single nucleotide polymorphism (SNP), rs2476601, is associated with multiple autoimmune diseases, impaired T cell regulation, and autoantibody formation. Taking into consideration the contribution of autoimmunity to LTx outcome, we hypothesized that polymorphisms in the PTPN22 gene could be associated with BOS incidence. We selected six SNPs within PTPN22 and analyzed both patient and donor genotypes on BOS development post-LTx. A total of 144 patients and matched donors were included, and individual SNPs and haplotype configurations were analyzed. We found a significant association between patients carrying the heterozygous configuration of rs2476601 and a higher risk for BOS development (p = 0.005, OR: 4.400, 95%CI: 1.563-12.390). Kaplan-Meier analysis showed that heterozygous patients exhibit a lower BOS-free survival compared to patients homozygous for rs2476601 (p = 0.0047). One haplotype, which solely contained the heterozygous risk variant, was associated with BOS development (p = 0.015, OR: 7.029, 95%CI: 1.352-36.543). Our results show that LTx patients heterozygous for rs2476601 are more susceptible for BOS development and indicate a deleterious effect of the autoimmune-related risk factor of PTPN22 in patients on LTx outcome.
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Project description:INTRODUCTION: Genetic and disease-related factors give rise to a wide spectrum of glucocorticoid (GC) sensitivity in rheumatoid arthritis (RA). In clinical practice, GC treatment is not adapted to these differences in GC sensitivity. In vitro assessment of GC sensitivity before the start of therapy could allow more individualized GC therapy. The aim of the study was to investigate the association between in vitro and in vivo GC sensitivity in RA. METHODS: Thirty-eight early and 37 established RA patients were prospectively studied. In vitro GC sensitivity was assessed with dexamethasone-induced effects on interleukin-2 (IL-2) and glucocorticoid-induced leucine zipper (GILZ) messenger RNA expression in peripheral blood mononuclear cells (PBMCs). A whole-cell dexamethasone-binding assay was used to measure number and affinity (1/KD) of glucocorticoid receptors (GRs). RESULTS: GR number was positively correlated with improvement in DAS. IL-2-EC?? and GILZ-EC?? values both had weak near-significant correlations with clinical improvement in DAS in intramuscularly treated patients only. HAQ responders had lower GILZ-EC?? values and higher GR number and KD. CONCLUSIONS: Baseline cellular in vitro glucocorticoid sensitivity is modestly associated with in vivo improvement in DAS and HAQ-DI score after GC bridging therapy in RA. Further studies are needed to evaluate whether in vitro GC sensitivity may support the development of tailor-made GC therapy in RA.
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Project description:Methotrexate (MTX) is a standard, first-line therapy for rheumatoid arthritis (RA); however, its precise mechanisms of action other than antifolate activity are largely unknown. We performed DNA microarray analyses of CD4+ T cells in patients with RA before and after MTX treatment and found that TP63 was the most significantly downregulated gene after MTX treatment. TAp63, an isoform of TP63, was highly expressed in human IL-17-producing Th (Th17) cells and was suppressed by MTX in vitro. Murine TAp63 was expressed at high levels in Th cells and at lower levels in thymus-derived Treg cells. Importantly, TAp63 knockdown in murine Th17 cells ameliorated the adoptive transfer arthritis model. RNA-Seq analyses of human Th17 cells overexpressing TAp63 and those with TAp63 knockdown identified FOXP3 as a possible TAp63 target gene. TAp63 knockdown in CD4+ T cells cultured under Th17 conditions with low-dose IL-6 increased Foxp3 expression, suggesting that TAp63 balances Th17 cells and Treg cells. Mechanistically, TAp63 knockdown in murine induced Treg (iTreg) cells promoted hypomethylation of conserved noncoding sequence 2 (CNS2) of the Foxp3 gene and enhanced the suppressive function of iTreg cells. Reporter analyses revealed that TAp63 suppressed the activation of the Foxp3 CNS2 enhancer. Collectively, TAp63 suppresses Foxp3 expression and exacerbates autoimmune arthritis.
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