title: Intrathymic restriction and peripheral expansion of the T-cell repertoire in Omenn syndrome.
abstract: Mutations in the human RAG genes that impair, but do not abolish, recombination activity lead to Omenn syndrome, a severe primary immune deficiency that is associated with clinical and pathological features of graft-versus-host disease and oligoclonal expansion of activated, autologous T cells. We have analyzed the mechanisms accounting for peripheral oligoclonality of the T-cell repertoire. Predominance of few T-cell receptor clonotypes (both within TCRAB- and within TCRGD-expressing lymphocytes) is already detectable in the thymus and is further selected for in the periphery, with a different distribution of clonotypes in different tissues. These data indicate that oligoclonality of the T-cell repertoire in Omenn syndrome is due both to intrathymic restriction and to peripheral expansion. Moreover, the RAG genes defect that causes Omenn syndrome directly affects early stages of V(D)J recombination, but does not alter the process of double-strand-break DNA repair, including N and P nucleotide insertion.
authors.affiliation: Terzo Servizio Analisi, Spedali Civili, the Institute of Chemistry, the Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Signorini
authors.forename: L
authors.initials: L
authors.lastname: Imberti
authors.forename: S
authors.initials: S
authors.lastname: Pirovano
authors.forename: A
authors.initials: A
authors.lastname: Villa
authors.forename: F
authors.initials: F
authors.lastname: Facchetti
authors.forename: M
authors.initials: M
authors.lastname: Ungari
authors.forename: F
authors.initials: F
authors.lastname: Bozzi
authors.forename: A
authors.initials: A
authors.lastname: Albertini
authors.forename: A G
authors.initials: AG
authors.lastname: Ugazio
authors.forename: P
authors.initials: P
authors.lastname: Vezzoni
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; D011948:Receptors, Antigen, T-Cell; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein