title: Casitas B lineage lymphoma b is a key regulator of peripheral tolerance in systemic lupus erythematosus.
abstract: OBJECTIVE
  To analyze whether the expression and modulation of T cell receptor (TCR) signaling is dependent on Casitas B lineage lymphoma b (Cbl-b) in T cells from patients with systemic lupus erythematosus (SLE) upon stimulation with a tolerogenic substance.
  
  
  METHODS
  Peripheral blood mononuclear cells were obtained from 20 patients with SLE (active disease or in remission) and 20 healthy controls. Levels of Cbl-b expression were measured using reverse transcription-polymerase chain reaction and Western blotting in peripheral CD4+ T cells from SLE patients and healthy controls upon anergy induction. Cell proliferation was measured using the carboxyfluorescein diacetate succinimidyl ester dilution method. Cytokine production was analyzed by luminometry, and surface expression of activation markers was assessed by flow cytometry. Transfection assays were performed to induce overexpression of Cbl-b, and phosphorylation of TCR-associated kinases was evaluated.
  
  
  RESULTS
  CD4+ T cells from SLE patients displayed resistance to anergy (as evidenced by increased cell proliferation, interleukin-2 production, and expression of activation and costimulatory markers), and this was associated with altered Cbl-b expression. Upon ionomycin treatment, primary T cells showed enhanced MAPK activity and decreased Akt phosphorylation, which was representative of the anergic state. In T cells from lupus patients, Cbl-b overexpression led to increased expression of phosphorylated MAPK, thus indicating the reversibility of anergy resistance.
  
  
  CONCLUSIONS
  These findings suggest that abnormal peripheral tolerance in SLE is caused by a deficiency in Cbl-b, and that this ubiquitin ligase plays a key role in regulating TCR signaling during the induction of peripheral tolerance.
authors.affiliation: Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
authors.forename: Diana
authors.initials: D
authors.lastname: Gómez-Martín
authors.forename: María
authors.initials: M
authors.lastname: Ibarra-Sánchez
authors.forename: Jorge
authors.initials: J
authors.lastname: Romo-Tena
authors.forename: José
authors.initials: J
authors.lastname: Cruz-Ruíz
authors.forename: José
authors.initials: J
authors.lastname: Esparza-López
authors.forename: Miguel
authors.initials: M
authors.lastname: Galindo-Campos
authors.forename: Mariana
authors.initials: M
authors.lastname: Díaz-Zamudio
authors.forename: Jorge
authors.initials: J
authors.lastname: Alcocer-Varela
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D017635:Clonal Anergy; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D061166:Peripheral Tolerance / Q000276:immunology*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl