Genome-wide DNA methylation analysis of normal and adult primary refractory immune thrombocytopenia samples
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PROVIDER: PRJNA846063 | ENA |
REPOSITORIES: ENA
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Project description:Purpose:we'd like to provide the first DNA methylation profiling for ITP. Methods:Peripheral blood CD4+ T lymphocytes samples were collected from 4 primary refractory ITP cases and 4 age-matched healthy controls, and DNA methylome profiling was performed using Illumina Human Methylation850K. Results:The DNA methylome profiling identified a total of 260 differentially methylated CpG sites mapping to 72 hypermethylated and 64 hypomethylated genes. Conclusions:we performed genome-wide DNA methylation profiling of primary refractory ITP and healthy controls, and identified a set of differentially methylated genes and pathways.
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Project description:Immune thrombocytopenia (ITP) is an acquired autoimmune disease triggered by abnormal T cell immunity, especially the impairment of regulatory T (Treg) cells and helper T (Th) cell subsets. Decitabine, a hypomethylating agent promoting cell differentiation at low dose, has been demonstrated the function of increasing the number of mature polyploidy megakaryocytes in ITP as well as Treg cells in allogeneic transplantation. Recently, our clinical study proved that decitabine was effective and safe in the management of adult ITP patients, and nearly half showed sustained responses. However, whether low-dose decitabine has the potential in restoring immune tolerance in ITP is unknown. In our in vitro studies, we identified that low-dose decitabine could promote the generation and differentiation and enhance the immunosuppressive function of Treg cells. Furthermore, low-dose decitabine alleviated thrombocytopenia and regained the balance of Treg/Th cell subsets in active murine models of ITP. For patients who received low-dose decitabine therapy and showed responses, the quantity and function of Treg cells were substantially improved, whereas Th1 and Th17 cells were depressed compared with the pretreatment levels. Finally, immunophenotyping and next-generation RNA sequencing analysis showed that low-dose decitabine restored T cell homeostasis and decreased the level of proinflammatory cytokines along with the downregulation of STAT3 and Akt in refractory ITP patients. Therefore, our data reveal the immunomodulatory effect of decitabine and provide unique insights into the sustained response achieved by decitabine in the management of ITP patients.
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Project description:Immune thrombocytopenia (ITP) is an autoimmune disease characterized by enhanced platelet clearance and defective platelet production. Diagnosis by exclusion and “trial-error” treatment strategies are common practice, and despite the advancement conferred by Thrombopoietin receptor agonists (TPO-RA´s), many patients remain refractory. While the existence of different pathophysiological entities is acknowledged, we are still far from stratifying and understanding ITP, a necessary step in order to provide personalized treatment options. We propose that the platelet proteome may give diagnostic and prognostic insights into the disease. As a proof of principle, we aimed to dissect the potential platelet proteome dynamics in the so-called passive and active pre-clinical ITP mouse models. To do that, we obtained the platelet proteome at the thrombocytopenic stage and upon platelet count recovery (reached naturally or upon IVIg-treatment, depending on the model). While most of the proteomic alterations were common to both ITP models, there were model-specific protein dynamics. Interestingly, we observed that not all proteomic alterations were restored when the platelet count has returned to normal. We discuss the biological processes associated with the proteome dynamics observed. Our results show that profiling the platelet proteome may have great potential to improve the management of ITP in humans.
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Project description:Dabie bandavirus, also termed as severe fever with thrombocytopenia syndrome virus (SFTSV), was first isolated in China in 2010. At this time, the virus was found to have spread to South Korea, Japan, and other countries. A high case fatality rate is reported for SFTS, ranging from 12–50% within various sources. Several omics for clinical studies among SFTS patients as well as studies of cultured SFTSV have attempted to characterize the relevant molecular biology and epidemiology of the disease. However, a global serum proteomics analysis among SFTS patients has not yet been reported to date. Thrombocytopenia and multiple organ failure are the major immediate causes of death among SFTS patients. In this study, serum proteomic changes related to thrombocytopenia, abnormal immune response, and inflammatory activation were documented in SFTS patients. These findings provide useful information forunderstanding the clinical manifestations of SFTS.
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Project description:Chronic primary immune thrombocytopenia (ITP) can today benefit from multiple therapeutic approaches with proven clinical efficacy, including rituximab, thrombopoietin receptor agonists (TPO-RA), and splenectomy. However, some ITP patients are unresponsive to multiple lines of therapy with prolonged and severe thrombocytopenia. The diagnosis of refractory ITP is mainly performed by exclusion of other disorders and is based on the clinician's expertise. However, it significantly increases the risk of drug-related toxicity and of bleedings, including life-threatening events. The management of refractory ITP remains a major clinical challenge. Here, we provide an overview of the currently available treatment options, and we discuss the emerging rationale of new therapeutic approaches and their strategic combination. Particularly, combination strategies may target multiple pathogenetic mechanisms and trigger additive or synergistic effects. A series of best practices arising both from published studies and from real-life clinical experience is also included, aiming to optimize the management of refractory ITP.
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