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Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Autoimmuna sjukdomar, Autoimmunity)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Autoimmuna sjukdomar, Autoimmunity)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2011 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, no 1, 235-245 p.Article in journal (Refereed) Published
Abstract [en]

Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis. To investigate whether the Th reactivity to Candida albicans (C. albicans) and other stimuli was altered, we isolated PBMC from APS-1 patients and matched healthy controls. The Th17 pathway was upregulated in response to C. albicans in APS-1 patients, whereas the IL-22 secretion was reduced. Autoantibodies against IL-22, IL-17A and IL-17F were detected in sera from APS-1 patients by immunoprecipitation. In addition, Aire-deficient (Aire(0/0) ) mice were much more susceptible than Aire(+/+) mice to mucosal candidiasis and C. albicans-induced Th17- and Th1-cell responses were increased in Aire(0/0) mice. Thus an excessive IL-17A reactivity towards C. albicans was observed in APS-1 patients and Aire(0/0) mice.

Place, publisher, year, edition, pages
2011. Vol. 41, no 1, 235-245 p.
Keyword [en]
Autoimmunity, Cytokines, Fungal, T cells
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-140180DOI: 10.1002/eji.200939883ISI: 000285933000024PubMedID: 21182094OAI: oai:DiVA.org:uu-140180DiVA: diva2:383145
Available from: 2011-01-04 Created: 2011-01-04 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Immunological Studies using Human and Canine Model Disorders
Open this publication in new window or tab >>Immunological Studies using Human and Canine Model Disorders
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Immunologiska studier av modellsjukdomar i människa och hund
Abstract [en]

The studies presented in this thesis focus on human and canine models for autoimmune disease, with the main aim to gain new knowledge about disease mechanisms and to further evaluate the dog as a model for autoimmune disease.

Autoimmune Polyendocrine Syndrome type 1 (APS-1) is a hereditary human multiorgan disease caused by mutations in the autoimmune regulator (AIRE) gene. Hallmarks of APS-1 are chronic mucocutaneous candidiasis caused by Candida albicans, together with the autoimmune endocrine disorders hypoparathyroidism and adrenocortical failure. Many human diseases have an equivalent disease in dogs. Because humans share environment, and in part life style with the dogs they provide an interesting model for further genetic studies.

Immune responses to Candida albicans in APS-1 patients displayed an increased secretion of the proinflammatory cytokine IL-17A and similar results were also found in AIRE deficient mice. Anticytokine autoantibodies to IL-17A, IL-17F and IL-22 were detected in APS-1 patients, and a radioligand binding assay for measuring these autoantibodies was developed and evaluated.

In the canine studies we investigated whether canine diabetes mellitus could serve as a model for human autoimmune diabetes mellitus. Furthermore, we investigated type I IFN responses in Nova Scotia duck tolling retriever dogs with a systemic autoimmune disease resembling human SLE.

Four assays were used in search for signs of humoral autoimmunity in diabetic dogs. However, no evidence for a type 1 diabetes-like phenotype in dogs was found. Sera from Nova Scotia duck tolling retrievers suffering from steroid-responsive meningitis arteritis elicited an increased expression of IFN-inducible genes in the canine MDCK cell line. This suggests that these dogs have an IFN signature, as seen in human SLE.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 721
Keyword
Autoimmunity, T cell, T helper cell, B cell, Autoantibodies, Interferon, Interleukin, Dogs, APS-1, Candida albicans, fungus
National Category
Basic Medicine
Research subject
Immunology; Medicine
Identifiers
urn:nbn:se:uu:diva-160550 (URN)978-91-554-8211-4 (ISBN)
Public defence
2011-12-08, Enghoffsalen, Akademiska sjukhuset. Ingång 50, bv, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2011-11-16 Created: 2011-10-25 Last updated: 2011-11-23Bibliographically approved

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Ahlgren, Kerstin M.Gustafsson, JanKämpe, OlleLobell, Anna

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