title: Neutralizations of IL-17A and IL-21 regulate regulatory T cell/T-helper 17 imbalance via T-helper 17-associated signaling pathway in immune thrombocytopenia.
abstract: OBJECTIVE
  The imbalance of regulatory T cell/T-helper 17 (Treg/Th17) is critical for the pathogenesis of immune thrombocytopenia (ITP) and IL-17A and IL-21 are overexpressed in ITP. The effects and mechanisms of IL-17A and IL-21 in Treg/Th17 imbalance and ITP pathophysiology are not clarified.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells from ITP patients and healthy controls were treated with cytokines or antibodies to increase or neutralize IL-17A or IL-21 levels for 72 h. Treg/Th17 differentiation, apoptosis, proliferation and Th17 differentiation-associated transcriptional factors were analyzed.
  
  
  RESULTS
  Natural Treg/Th17 decreased in newly diagnosed ITP patients and recovered after remission. IL-17A or IL-21 increased Th17, decreased Tregs and downregulated Treg/Th17 in vitro. Conversely, neutralization of IL-17A or IL-21 decreased Th17, increased Tregs and up-regulated Treg/Th17. The reverse effects of IL-17A or IL-21 were mediated by Th17-associated transcriptional factors. IL-17A or IL-21 enhanced STAT-1, STAT-3, STAT-5 or RAR-related orphan receptor C (RORC), whereas anti-IL-17A or anti-IL-21 mAb downregulated STAT-1, STAT-5 or RORC transcripts in ITP PBMCs. Proliferation showed no significant difference. IL-21 inhibited apoptosis in ITP PBMCs.
  
  
  CONCLUSIONS
  IL-17A and IL-21 induce Th17 and inhibit Tregs re-differentiation via Th17-associated signaling pathway in ITP patients in vitro. It highlights the potential value of IL-17A or IL-21 blockade as a novel therapeutic target for ITP.
authors.affiliation: Shandong University, Qilu Hospital, Department of Hematology , Jinan , China daoxinma@hotmail.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Wang
authors.forename: Shuang
authors.initials: S
authors.lastname: Yu
authors.forename: Yu
authors.initials: Y
authors.lastname: Hou
authors.forename: Daoxin
authors.initials: D
authors.lastname: Ma
authors.forename: Ming
authors.initials: M
authors.lastname: Hou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000008:administration & dosage; D017252:CD3 Complex / Q000276:immunology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000008:administration & dosage; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D055815:Young Adult; D000098546:Interleukin-21
chemical_list: D000906:Antibodies; D017252:CD3 Complex; D016207:Cytokines; C508717:IL17A protein, human; D020381:Interleukin-17; D007378:Interleukins; D000098546:Interleukin-21
keywords: T-helper 17; T-helper 17 cytokines; immune thrombocytopenia; regulatory T cell