title: Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines.
abstract: Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A-producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.
authors.affiliation: Molecular Pathology Group, Institute of General and Molecular Pathology, University of Tartu, 50411 Tartu, Estonia. kai.kisand@ut.ee
authors.forename: Kai
authors.initials: K
authors.lastname: Kisand
authors.forename: Anette S
authors.initials: AS
authors.lastname: Bøe Wolff
authors.forename: Katarina Trebusak
authors.initials: KT
authors.lastname: Podkrajsek
authors.forename: Liina
authors.initials: L
authors.lastname: Tserel
authors.forename: Maire
authors.initials: M
authors.lastname: Link
authors.forename: Kalle V
authors.initials: KV
authors.lastname: Kisand
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ersvaer
authors.forename: Jaakko
authors.initials: J
authors.lastname: Perheentupa
authors.forename: Martina Moter
authors.initials: MM
authors.lastname: Erichsen
authors.forename: Nina
authors.initials: N
authors.lastname: Bratanic
authors.forename: Antonella
authors.initials: A
authors.lastname: Meloni
authors.forename: Filomena
authors.initials: F
authors.lastname: Cetani
authors.forename: Roberto
authors.initials: R
authors.lastname: Perniola
authors.forename: Berrin
authors.initials: B
authors.lastname: Ergun-Longmire
authors.forename: Noel
authors.initials: N
authors.lastname: Maclaren
authors.forename: Kai J E
authors.initials: KJ
authors.lastname: Krohn
authors.forename: Mikulás
authors.initials: M
authors.lastname: Pura
authors.forename: Berthold
authors.initials: B
authors.lastname: Schalke
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Leite
authors.forename: Tadej
authors.initials: T
authors.lastname: Battelino
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.forename: Nick
authors.initials: N
authors.lastname: Willcox
authors.forename: Anthony
authors.initials: A
authors.lastname: Meager
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D002178:Candidiasis, Chronic Mucocutaneous / Q000276:immunology*; D002454:Cell Differentiation; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology; D009154:Mutation; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology*; D011565:Psoriasis / Q000097:blood / Q000276:immunology; D017634:Self Tolerance; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013945:Thymoma / Q000276:immunology*; D013953:Thymus Neoplasms / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22