title: Reduced central tolerance in Omenn syndrome leads to immature self-reactive oligoclonal T cells.
abstract: BACKGROUND
  Omenn syndrome (OS) is characterized by a peculiar severe T-cell immune deficiency associated with autoimmunelike manifestations. Dysregulations of the central and peripheral immune tolerance, mediated by the protein autoimmune regulator (AIRE) and regulatory T cells, respectively, were proposed as possible mechanisms of this aberrant inflammatory process.
  
  
  OBJECTIVE
  We studied mechanisms of central and peripheral tolerance in patients with OS and also examined the gene expression profile associated with OS features.
  
  
  METHODS
  T-cell receptor diversity, DNA rearrangement, and the expression of AIRE and forkhead box P3 mRNA as well as the expression of regulatory T cells in cells obtained from patients with OS were studied. Characterization of gene expression in these cells was carried out by using the TaqMan Low-Density Array.
  
  
  RESULTS
  Transcript expression of peripheral blood AIRE but not forkhead box P3 was reduced in patients with OS. The expression of natural killer T and regulatory T cells was normal, although the latter showed an abnormal CD4-negative population. Patients with OS have oligoclonal T cells with limited DNA recombination activity, including the presence of early but not late T-cell maturation events, regardless of the genetic defect underlying the syndrome. The transcriptional profile associated with OS features reveals significant changes in 25.5% of the tested genes compared with normal control.
  
  
  CONCLUSIONS
  Our findings suggest that T-cell oligoclonal expansion in OS emanates from an incomplete block before the maturation stage of negative selection, which may explain escape of autoreactive T cells from the thymus. Dysregulated genes in patients with OS are closely involved with self-tolerance and autoimmunity.
authors.affiliation: Cancer Research Center, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv, Israel. rsomech@hotmail.com
authors.forename: Raz
authors.initials: R
authors.lastname: Somech
authors.forename: Amos J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Atar
authors.initials: A
authors.lastname: Lev
authors.forename: Ilan
authors.initials: I
authors.lastname: Dalal
authors.forename: Zvi
authors.initials: Z
authors.lastname: Spirer
authors.forename: Itamar
authors.initials: I
authors.lastname: Goldstein
authors.forename: Meital
authors.initials: M
authors.lastname: Nagar
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
mesh_terms: D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D015329:Gene Rearrangement, T-Lymphocyte; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000096927:AIRE Protein
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D000096927:AIRE Protein; C418974:FOXP3 protein, human