The prediction value of Treg cell subtype alterations for glucocorticoid treatment in newly diagnosed primary immune thrombocytopenia patients

Cheng, Luya; Liu, Chanjuan; Li, Feng; Wu, Boting; Min, Zhihui; Chen, Pu; Zhan, Yanxia; Ke, Yang; Hua, Fanli; Yuan, Ling; Sun, Lihua; Chen, Hao; Ji, Lili; Cheng, Yunfeng

doi:10.1016/j.thromres.2019.07.001

Cited by 21 publications

(13 citation statements)

References 27 publications

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“…Indeed, high‐dose Dex treatment has been reported to restore a normal Th1/Th2 ratio, reduce Th17 cells, and increase the number of Tregs 23 . A subset of CD45RA – FoxP3 hi Tregs with high IL‐10 expression has also been correlated with greater sensitivity to corticosteroid treatment 24 . Corticosteroids can also upregulate IL‐10 expression in other cell types, including CD8 + T cells 25,26 and B cells 27 .…”

Section: Resultsmentioning

confidence: 99%

IL‐10 and IL‐17 expression by CD4+ T cells is altered in corticosteroid refractory immune thrombocytopenia (ITP)

Stimpson

Lait

Schewitz-Bowers

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Corticosteroids remain the first-line treatment for patients with immune thrombocytopenia (ITP). However, 20% to 30% of patients do not respond to treatment at tolerable doses. This variation in corticosteroid efficacy is replicated in other autoimmune diseases and may have an adaptive immune basis. Objective: To test the hypothesis that CD4 + T-cell responses to corticosteroids are different in patients with clinically defined corticosteroid refractory ITP. Methods: In this prospective cohort study, CD4 + T cells from patients with ITP were cultured in the presence or absence of dexamethasone (Dex). Intracellular cytokine expression was then quantified by flow cytometry and compared with patients' clinical response to corticosteroid treatment. A control cohort of patients with autoimmune uveitis was also studied to evaluate whether our findings were limited to ITP or are potentially generalizable across autoimmune diseases. Results: The ratio of interleukin (IL)-10 to IL-17 expression following CD4 + T cell culture with Dex was able to discriminate between ITP patients with a clinically defined complete (n = 33), partial (n = 12) or nonresponse (n = 11) to corticosteroid treatment (P = .002). These findings were replicated in patients with autoimmune uveitis (complete response n = 14, nonresponse n = 22; P = .01). Conclusions: There is a relative abrogation of IL-10 and persistence of IL-17 expression in the CD4 + T cells of patients who clinically fail corticosteroid therapy. This observation has potential to inform both our mechanistic understanding of the action of corticosteroids in the treatment of ITP, and as a biomarker for steroid refractory disease, with potential application across a range of hematological and nonhematological conditions.

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Section: Resultsmentioning

confidence: 99%

IL‐10 and IL‐17 expression by CD4+ T cells is altered in corticosteroid refractory immune thrombocytopenia (ITP)

Stimpson

Lait

Schewitz-Bowers

et al. 2020

Journal of Thrombosis and Haemostasis

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“…Antibodies against self‐platelet antigens produced by autoreactive B cells are considered the primary immunologic defect in ITP 3,4 . In addition, considerable abnormalities of the immune cells have been identified in ITP, such as skewed Th1/Th2 ratio (Th1 polarization), 3 numerically and functionally impaired regulatory T cells (Tregs), 5,6 elevated frequency of Th17 cells, 7 and enhanced antigen presentation by dendritic cells 8 . T‐cell‐mediated cytotoxicity has also been shown to directly destroy platelets in a substantial subset of ITP patients 9 …”

Section: Introductionmentioning

confidence: 99%

Decreased levels of immune-regulatory cytokines in patients with immune thrombocytopenia and long-lasting overexpression of these cytokines in the splenectomized patients

Sun

et al. 2021

Journal of Leukocyte Biology

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Immune thrombocytopenia (ITP) is an autoimmune‐mediated disease characterized by decreased platelet counts. Cytokines play important roles in modulating the immune response and are involved in the pathogenesis of many autoimmune diseases. This study aimed at exploring the serum levels of a core set of cytokines that exert immune‐regulatory functions in newly diagnosed ITP patients (both before and after treatment) and splenectomized ITP patients. Using the Bio‐Plex suspension array system and ELISA, the serum levels of IL‐10, IL‐21, IL‐27, IL‐33, IL‐35, IL‐37, and TGF‐β1 were detected. The data showed that the serum levels of the immune regulatory cytokines IL‐10, IL‐35, and TGF‐β1 were significantly lower in newly diagnosed ITP patients. Decreased cytokine levels could be improved in patients with a complete response or a response after steroid‐based treatment(s). The serum concentrations of TGF‐β1 were positively correlated with the platelet counts both before and after treatment. All the detected immune‐regulatory cytokines, except IL‐37, showed significantly higher levels in splenectomized ITP patients than pretreatment ITP patients and healthy controls. In conclusion, these data suggest that lower levels of immune‐regulatory cytokines are involved in the pathogenesis of ITP and that there is a long‐lasting overexpression of immune‐regulatory cytokines in ITP patients with splenectomy.

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“…Foxp3, a transcription factor of Treg cells, is critical for maintaining its differentiated phenotype and function. Treg cells inhibit the expression of IL-17 by secreting IL-10 and TGF-β, which plays an immunosuppressive role [19]. Studies have demonstrated that the imbalance of Treg/Th17 cells is involved in ITP pathogenesis and inhibition of Th17 cell differentiation can ameliorate ITP [4,[20][21][22].…”

Section: Discussionmentioning

confidence: 99%

Decreasing lncRNA PVT1 causes Treg/Th17 imbalance via NOTCH signaling in immune thrombocytopenia

Yu¹,

Zhang²,

Jiang

et al. 2021

Hematology

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Objectives: Immune thrombocytopenia (ITP) is an autoimmune disease. T helper cell 17 (Th17) cells are increased in peripheral blood of ITP patients. NOTCH signaling is involved in Th17 cell differentiation and function. Besides, lncRNA Plasmacytoma variant translocation 1 (PVT1) was decreased in experimental autoimmune encephalomyelitis, and overexpressing PVT1 inhibited Th17 cell differentiation. Here, we aimed to investigate the effect of lncRNA PVT1 on ITP and its related mechanism. Methods: The number of Th17 cells and Treg cells was carried out using flow cytometry. PVT1 levels were detected by quantitative real-time PCR. Interleukin-17 (IL-17) levels and transforming growth factor-β (TGF-β) levels were detected by enzyme-linked immunosorbent assay. Protein levels of retinoid acid-related orphan receptor γ t (RORγt), forkhead box P3 (Foxp3), and NOTCH1 were carried out by western blot. NOTCH1 ubiquitylation was detected by ubiquitination assay. Results: PVT1 was down-regulated and Th17 cells were up-regulated in ITP patients. Overexpression of PVT1 decreased the number of Th17 cells, and also decreased the levels of IL-17, RORγt, and NOTCH1. Besides, PVT1 could bind to NOTCH1 and mediated NOTCH1 degradation by increasing its ubiquitination. Additionally, excessive expression of PVT1 could increase the levels of PVT1, reduce the amount of Th17 cells, as well as the levels of IL-17, RORγt, and NOTCH1, while co-overexpressing NOTCH1 reversed the results. Conclusion: PVT1 was down-regulated in ITP patients. Overexpressing PVT1 might reduce Th17 cell differentiation by down-regulating NOTCH1, and further alleviated the development of ITP.

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The prediction value of Treg cell subtype alterations for glucocorticoid treatment in newly diagnosed primary immune thrombocytopenia patients

Cited by 21 publications

References 27 publications

IL‐10 and IL‐17 expression by CD4+ T cells is altered in corticosteroid refractory immune thrombocytopenia (ITP)

IL‐10 and IL‐17 expression by CD4+ T cells is altered in corticosteroid refractory immune thrombocytopenia (ITP)

Decreased levels of immune-regulatory cytokines in patients with immune thrombocytopenia and long-lasting overexpression of these cytokines in the splenectomized patients

Decreasing lncRNA PVT1 causes Treg/Th17 imbalance via NOTCH signaling in immune thrombocytopenia

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