Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines.
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.
Kisand
Kai
K
Molecular Pathology Group, Institute of General and Molecular Pathology, University of Tartu, 50411 Tartu, Estonia. kai.kisand@ut.ee
Bøe Wolff
Anette S
AS
Podkrajsek
Katarina Trebusak
KT
Tserel
Liina
L
Link
Maire
M
Kisand
Kalle V
KV
Ersvaer
Elisabeth
E
Perheentupa
Jaakko
J
Erichsen
Martina Moter
MM
Bratanic
Nina
N
Meloni
Antonella
A
Cetani
Filomena
F
Perniola
Roberto
R
Ergun-Longmire
Berrin
B
Maclaren
Noel
N
Krohn
Kai J E
KJ
Pura
Mikulás
M
Schalke
Berthold
B
Ströbel
Philipp
P
Leite
Maria Isabel
MI
Battelino
Tadej
T
Husebye
Eystein S
ES
Peterson
Pärt
P
Willcox
Nick
N
Meager
Anthony
A
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
D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22