title: AIRE deficiency in thymus of 2 patients with Omenn syndrome.
abstract: Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restricted receptor repertoire. Loss of central tolerance in genetically determined autoimmune diseases, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is associated with defective expression by medullary thymic epithelial cells of AIRE, the transcription activator that induces thymic expression of tissue-specific antigens. Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-beta receptor mRNAs, while mRNAs of the self-antigens insulin, cytochrome P450 1a2, and fatty acid-binding protein were undetectable in thymi from immunodeficiency patients. These results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development and suggest that in Omenn syndrome, the few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.
authors.affiliation: 1Istituto di Medicina Molecolare Angelo Nocivelli, Clinica Pediatrica, University of Brescia, Brescia, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cavadini
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Stefania
authors.initials: S
authors.lastname: Fontana
authors.forename: Seiho
authors.initials: S
authors.lastname: Nagafuchi
authors.forename: Evelina
authors.initials: E
authors.lastname: Mazzolari
authors.forename: Anna
authors.initials: A
authors.lastname: Sediva
authors.forename: Veronica
authors.initials: V
authors.lastname: Marrella
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007223:Infant; D053259:Lymphotoxin beta Receptor; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency*; D000096927:AIRE Protein
chemical_list: D053259:Lymphotoxin beta Receptor; D018124:Receptors, Tumor Necrosis Factor; D014157:Transcription Factors; D000096927:AIRE Protein; C505697:LTBR protein, human