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Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Autoimmuna sjukdomar (Kämpe))
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2006 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 27, no 2, 96-104 p.Article in journal (Refereed) Published
Abstract [en]

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, or APS1), is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. The three main components of APECED are chronic mucocuteaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. However, several additional endocrine or other autoimmune disease components, or ectodermal dystrophies form the individually variable clinical picture of APECED. An important feature of APECED is a spectrum of well-characterized circulating autoantibodies, reacting against tissue-specific autoantigens. Aire deficient mice develop some characteristics of APECED phenotype. In order to investigate whether the Aire deficient mice produce autoantibodies similar to human APECED, we studied the reactivity of Aire mouse sera against mouse homologues of 11 human APECED antigens. None of the APECED antigens indicated elevated reactivity in the Aire knock-out mouse sera, implying the absence of APECED associated autoantibodies in Aire deficient mice. These findings were supported by the failure of the autoantigens to activate mouse T-cells. Furthermore, Aire knock-out mice did not express increased levels of anti-nuclear antibodies compared to wt mice. This study indicates that spontaneous induction of tissue-specific autoantibodies similar to APECED does not occur in the rodent model suggesting differences in the immunopathogenic mechanisms between mice and men.

Place, publisher, year, edition, pages
2006. Vol. 27, no 2, 96-104 p.
Keyword [en]
APS1, Autoantigen, Autoimmune regulator, Knock-out mouse
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-98037DOI: 10.1016/j.jaut.2006.06.001ISI: 000241661500004PubMedID: 16820279OAI: oai:DiVA.org:uu-98037DiVA: diva2:173201
Available from: 2009-02-11 Created: 2009-02-11 Last updated: 2011-05-18Bibliographically approved
In thesis
1. Molecular Targets in Autoimmune Polyendocrine Syndrome Type1 and Their Clinical Implications
Open this publication in new window or tab >>Molecular Targets in Autoimmune Polyendocrine Syndrome Type1 and Their Clinical Implications
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Autoimmune diseases occur when the immune system attacks and destroys healthy body tissue. Autoimmunity is known to cause a wide range of disorders, and is suspected to be responsible for many more. Most autoimmune disorders are chronic and cause severe morbidity for the patients, and are also costly for society. A majority of these disorders are today considered as complex diseases with incompletely known etiology. Hence, model systems for studying the pathogenesis of autoimmunity are important to unravel its causes.

Autoimmune Polyendocrine Syndrome Type 1 (APS-1), (OMIM 240300), is a rare autoimmune disorder. Patients with APS-1 progressively develop multiple organ-specific autoimmune lesions involving both endocrine and non endocrine tissues. Typical autoimmune disease components in APS-1 are hypoparathyroidism, Addison’s disease, vitiligo, alopecia and type 1 diabetes. The gene preventing APS-1 has been identified and designated Autoimmune Regulator (AIRE). It has been shown that mutations of AIRE cause loss of tolerance to self-structures, resulting in organ-specific autoimmunity.

Although APS-1 is a rare syndrome occurring mainly in genetically isolated populations, the disease components of APS-1 are, in isolated forms, not unusual in the general population and affect many patients. Hence, APS-1 is an attractive model disease for studies of molecular mechanisms underlying organ-specific autoimmunity.

This thesis concerns investigations in which two novel autoantigens are identified in APS-1 and used in serological diagnosis of the disease. NALP5, is identified as a parathyroid autoantigen - an important finding since autoimmune hypoparathyroidism is one of the cardinal symptoms of APS-1. Additionally, KCNRG is identified as a bronchial autoantigen in APS-1 patients with respiratory symptoms. Finally, studies that compare the immune response in APS-1 patients and the mouse model for APS-1 are presented.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 417
autoimmunity, autoantibodies, endocrinology, parathyroid, hypoparathyroidism, Addison's disease, pulmonary symptoms, NALP, NALP5, NLR, KCNRG
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-9549 (URN)978-91-554-7403-4 (ISBN)
Public defence
2009-03-05, Enghoffsalen, Enterence 50, Akademiska Sjukhuset, Uppsala University Hospital, SE75185, 09:15 (English)
Available from: 2009-02-11 Created: 2009-02-11 Last updated: 2009-04-17Bibliographically approved

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