title: A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire(-/-) mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus. We have explored reasons for the difference between the comparatively mild phenotype of Aire-deficient mice and human APECED patients. We provide evidence that, unlike in the Aire(-/-) mice, in the patients a key mediator of active tolerance, the CD4(+)CD25(+) regulatory T (Treg) cell subset is impaired. This was shown by significantly decreased expression of FOXP3 mRNA and protein, decreased function, and alterations in TCR repertoire. Also, in the normal human thymus a concentric accumulation of AIRE(+) cells was seen around thymic Hassall's corpuscles, suggesting that in the patients these cells may be involved in the observed Treg cell failure. In Aire(-/-) mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process. Our results suggest that a Treg cell defect is involved in the pathogenesis of APECED and emphasize the importance of active tolerance mechanisms in preventing human autoimmunity.
authors.affiliation: Department of Immunology, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Eliisa
authors.initials: E
authors.lastname: Kekäläinen
authors.forename: Heli
authors.initials: H
authors.lastname: Tuovinen
authors.forename: Joonas
authors.initials: J
authors.lastname: Joensuu
authors.forename: Mikhail
authors.initials: M
authors.lastname: Gylling
authors.forename: Rauli
authors.initials: R
authors.lastname: Franssila
authors.forename: Nora
authors.initials: N
authors.lastname: Pöntynen
authors.forename: Kimmo
authors.initials: K
authors.lastname: Talvensaari
authors.forename: Jaakko
authors.initials: J
authors.lastname: Perheentupa
authors.forename: Aaro
authors.initials: A
authors.lastname: Miettinen
authors.forename: T Petteri
authors.initials: TP
authors.lastname: Arstila
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000096927:AIRE Protein
chemical_list: D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D000096927:AIRE Protein; C418974:FOXP3 protein, human