Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines
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Open Access
- 1 February 2010
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 207 (2), 299-308
- https://doi.org/10.1084/jem.20091669
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.Keywords
This publication has 42 references indexed in Scilit:
- Human Dectin-1 Deficiency and Mucocutaneous Fungal InfectionsThe New England Journal of Medicine, 2009
- A HomozygousCARD9Mutation in a Family with Susceptibility to Fungal InfectionsThe New England Journal of Medicine, 2009
- Thymic self-reactivity selects natural interleukin 17–producing T cells that can regulate peripheral inflammationNature Immunology, 2009
- Hidden talents of natural killers: NK cells in innate and adaptive immunityEMBO Reports, 2009
- Transcriptional regulation by AIRE: molecular mechanisms of central toleranceNature Reviews Immunology, 2008
- AIRE regulates T-cell-independent B-cell responses through BAFFProceedings of the National Academy of Sciences of the United States of America, 2008
- Critical immunological pathways are downregulated in APECED patient dendritic cellsJournal of Molecular Medicine, 2008
- Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3 The Journal of Experimental Medicine, 2008
- Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndromeNature, 2008
- Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptidesThe Journal of Experimental Medicine, 2006