title: Abnormalities of quantities and functions of linker for activations of T cells in severe aplastic anemia.
abstract: OBJECTIVE
  Severe aplastic anemia (SAA) is a rare immune-regulated disease characterized by severe pancytopenia and bone marrow failure, caused by destruction of hematopoietic cells by the activated T lymphocytes. Linker for activation of T cells (LAT), a transmembrane adaptor protein, plays a key role in T-cell and mast cell functions. However, it remains unclear how LAT may change in patients with SAA. This study aims at understanding the role of lymphocyte LAT in SAA.
  
  
  METHODS
  The expression of LAT, related signaling molecules, and T-cell effector molecules was determined by flow cytometry. LAT mRNA was evaluated by quantitative real-time PCR. Cytokine production by cultured T cells was determined by ELISA.
  
  
  RESULTS
  Patients with SAA had an increased levels of LAT and both total phosphorylated LAT and of the related molecule (ZAP-70) in circulating T cells compared with normal controls. In patients with SAA, the expression of LAT was positively associated with the expression of perforin and granzyme B in CD8(+) T cells. Inhibition of LAT expression in T cells from patients with SAA decreased the activation of the CD4(+) and CD8(+) T-cell subsets. Overexpression of LAT in T cells from normal controls increased the activation of CD4(+) and CD8(+) T-cell subsets with increased apoptosis of K562 cells in coculture.
  
  
  CONCLUSIONS
  Our findings demonstrate that dysregulation of LAT expression and activation may contribute to over-function of T cells, imbalance of Th1/Th2 subsets and thus lead to hematopoiesis failure in SAA. Immunosuppressive therapy dramatically reduced the expression of LAT making it an attractive therapeutic target in SAA.
authors.affiliation: The Department of Hematology, The General Hospital of Tianjin Medical University, Tianjin, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Sheng
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.forename: Rong
authors.initials: R
authors.lastname: Fu
authors.forename: Huaquan
authors.initials: H
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Qu
authors.forename: Erbao
authors.initials: E
authors.lastname: Ruan
authors.forename: Guojin
authors.initials: G
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Jia
authors.initials: J
authors.lastname: Song
authors.forename: Limin
authors.initials: L
authors.lastname: Xing
authors.forename: Jing
authors.initials: J
authors.lastname: Guan
authors.forename: Lijuan
authors.initials: L
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Zonghong
authors.initials: Z
authors.lastname: Shao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D005260:Female; D005786:Gene Expression Regulation; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D020014:K562 Cells; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D054353:Perforin / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics* / Q000276:immunology; D012720:Severity of Illness Index; D015398:Signal Transduction; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007166:Immunosuppressive Agents; C110810:LAT protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D054353:Perforin; D051746:ZAP-70 Protein-Tyrosine Kinase; D053804:Granzymes
keywords: T lymphocytes; linker for activation of T cells; severe aplastic anemia