title: Defect of regulatory T cells in patients with Omenn syndrome.
abstract: BACKGROUND
  Omenn syndrome (OS) is an autosomal-recessive disorder characterized by severe immunodeficiency and T-cell-mediated autoimmunity. The disease is caused by hypomorphic mutations in recombination-activating genes that hamper the process of Variable (V) Diversity (D) Joining (J) recombination, leading to the generation of autoreactive T cells. We have previously shown that in OS the expression of autoimmune regulator, a key factor governing central tolerance, is markedly reduced.
  
  
  OBJECTIVE
  Here, we have addressed the role of peripheral tolerance in the disease pathogenesis.
  
  
  METHODS
  We have analyzed forkhead box protein P3 (FOXP3) expression in peripheral blood T cells of 4 patients with OS and in lymphoid organs of 8 patients with OS and have tested the suppressive activity of sorted CD4(+) CD25(high) peripheral blood T cells in 2 of these patients.
  
  
  RESULTS
  We have observed that CD4(+)CD25(high)T cells isolated ex vivo from patients with OS failed to suppress proliferation of autologous or allogenic CD4(+) responder T cells. Moreover, despite individual variability in the fraction of circulating FOXP3(+) CD4 cells in patients with OS, the immunohistochemical analysis of FOXP3 expression in lymph nodes and thymus of patients with OS demonstrated a severe reduction of this cell subset compared with control tissues.
  
  
  CONCLUSIONS
  Overall, these results suggest a defect of regulatory T cells in OS leading to a breakdown of peripheral tolerance, which may actively concur to the development of autoimmune manifestations in the disease.
authors.affiliation: Fondazione Humanitas per la Ricerca, Rozzano (MI), Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.forename: Daniele
authors.initials: D
authors.lastname: Moratto
authors.forename: Cristina
authors.initials: C
authors.lastname: Sobacchi
authors.forename: Veronica
authors.initials: V
authors.lastname: Marrella
authors.forename: Laura
authors.initials: L
authors.lastname: Imperatori
authors.forename: Donatella
authors.initials: D
authors.lastname: Vairo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Silvia
authors.initials: S
authors.lastname: Giliani
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Fulvio
authors.initials: F
authors.lastname: Porta
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
mesh_terms: D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology*; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D053645:Interleukin-2 Receptor alpha Subunit; C064658:RAG-1 protein