Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases

Oftedal, Bergithe E.; Hellesen, Alexander; Erichsen, Martina M.; Bratland, Eirik; Vardi, Ayelet; Perheentupa, Jaakko; Kemp, E. Helen; Fiskerstrand, Torunn; Viken, Marte K.; Weetman, Anthony P.; Fleishman, Sarel J.; Banka, Siddharth; Newman, William G.; Sewell, William A.; Sozaeva, Leila; Zayats, Tetyana; Haugarvoll, Kristoffer; Orlova, Elizaveta; Haavik, Jan; Johansson, Stefan; Knappskog, Per M.; Løvås, Kristian; Wolff, Anette S. B.; Abramson, Jakub; Husebye, Eystein S.

doi:10.1016/j.immuni.2015.04.021

Cited by 241 publications

(244 citation statements)

References 47 publications

Supporting

Mentioning

230

Contrasting

Unclassified

Order By: Relevance

“…Mutated AIRE protein with point mutations in the HSR domain (L28P, L29P, W78R, and L93R) are distributed throughout the cytoplasm with some presence in the nucleus but not found in the concentrated specks as WT-AIRE, which is consistent with HSR domain mutations causing drastic decreases in INS-VNTR activation. Our study showed cytoplasm distribution of L28P AIRE in clusters and was not as apparent as previously reported as totally diffuse in the cytoplasm and nucleus (31,32). The discrepancy could be due to the cell type difference and/or fluorescencetagged fusion L28P (7).…”

Section: Mutation In Different Functional Domains Interferes With Airsupporting

confidence: 60%

“…An animal study using a G228W knock-in mouse model has shown that this variant acted in a dominant negative manner to cause a unique autoimmune syndrome (34). A recent report has identified multiple cases and families with non-allelic mutations in AIRE with dominant inheritance (31). They studied the AIRE dominant negative mutations in the PHD1 domain of APS-1 patients.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Functional Domains of Autoimmune Regulator (AIRE) Modulate INS-VNTR Transcription in Human Thymic Epithelial Cells

Sparks

Chen

Breslin

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

INS-VNTR (insulin-variable number of tandem repeats)and AIRE (autoimmune regulator) have been associated with the modulation of insulin gene expression in thymus, which is essential to induce either insulin tolerance or the development of insulin autoimmunity and type 1 diabetes. We sought to analyze whether each functional domain of AIRE is critical for the activation of INS-VNTR in human thymic epithelial cells. Twelve missense or nonsense mutations in AIRE and two chimeric AIRE constructs were generated. A luciferase reporter assay and a pulldown assay using biotinylated INS-class I VNTR probe were performed to examine the transactivation and binding activities of WT, mutant, and chimeric AIREs on the INS-VNTR promoter. Confocal microscopy analysis was performed for WT or mutant AIRE cellular localization. We found that all of the AIRE mutations resulted in loss of transcriptional activation of INS-VNTR except mutant P252L. Using WT/mutant AIRE heterozygous forms to modulate the INS-VNTR target revealed five mutations (R257X, G228W, C311fsX376, L397fsX478, and R433fsX502) that functioned in a dominant negative fashion. The LXXLL-3 motif is identified for the first time to be essential for DNA binding to INS-VNTR, whereas the intact PHD1, PHD2, LXXLL-3, and LXXLL-4 motifs were important for successful transcriptional activation. AIRE nuclear localization in the human thymic epithelial cell line was disrupted by mutations in the homogenously staining region domain and the R257X mutation in the PHD1 domain. This study supports the notion that AIRE mutation could specifically affect human insulin gene expression in thymic epithelial cells through INS-VNTR and subsequently induce either insulin tolerance or autoimmunity. Type 1 diabetes (T1D)2 is defined by absolute loss of insulin secretion due to the autoimmune destruction of insulin-producing ␤ cells in the pancreas. There are a few target autoantigens identified in ␤ cell autoimmune destruction with insulin and pro-insulin auto-antibodies detected in 23 and 34% of T1D patients, respectively (1, 2). The autoimmune polyendocrinopathy type 1 syndrome (APS-1 also known as APECED) is an autosomal recessive, monogenic form of human autoimmunity that is characterized by autoimmune destruction of multiple endocrine organs and defective cell-mediated immunity (3, 4).In 1997 an autoimmune regulator (AIRE) gene, which underlies APS-1, was identified on chromosome 21q22.3 using a positional cloning strategy (5, 6). The specific domains that the AIRE protein contains include (i) the N terminus of a homogenously staining region (HSR) domain and/or caspase recruitment domain (CARD), which is believed to be involved in dimerization and/or caspase recruitment (7, 8), (ii) a nuclear localization signal, (iii) a SAND (Sp100, AIRE-1, NucP41/75, DEAF-1) domain, which is thought to be involved in DNA binding (9), and (iv), two plant homeodomain (PHD) type zinc fingers (10, 11) and four LXXLL motifs (12). The AIRE protein has been shown to activate hundreds of tissue-restricted anti...

show abstract

Section: Mutation In Different Functional Domains Interferes With Airsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Functional Domains of Autoimmune Regulator (AIRE) Modulate INS-VNTR Transcription in Human Thymic Epithelial Cells

Sparks

Chen

Breslin

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Elles se caractérisent par une divergence des profils auto-immuns retrouvés chez les patients. Ainsi, lorsque la mutation est hétérozygote, les patients présentent un retard dans l'apparition des signes cliniques caractéristiques du syndrome et une pénétrance incomplète [31]. Si les mutations dans le gène Aire sont associées à des profils d'auto-immunité, il apparaît aussi qu'en l'absence de mutations identifiées, une faible expression de la protéine soit également associée à des perturbations du système immunitaire.…”

Section: Liens Entre Faible Expression De Aire Et Auto-immunitéunclassified

Prédisposition aux pathologies auto-immmunes

2017

View full text Add to dashboard Cite

> Les maladies auto-immunes sont un groupe d'environ 80 pathologies différentes affectant 5 à 8 % de la population. Elles sont dues à un dysfonctionnement du système immunitaire au niveau de la tolérance thymique. Le thymus est le site d'éducation des lymphocytes T. Cet apprentissage repose sur des interactions entre les lymphocytes T et les cellules épithéliales thymiques (CET) qui expriment les protéines spécifiques de tissus périphériques. Ce mécanisme complexe est appelé tolérance centrale. Les maladies autoimmunes présentent, pour la majorité d'entre elles, une forte prévalence féminine. La comparaison des transcriptomes thymiques de femmes et d'hommes met en évidence des différences d'expression des protéines spécifiques de tissus périphériques. Dans le thymus, l'expression de ces protéines est contrôlée par le modulateur de transcription AIRE (autoimmune regulator). Une analyse translationnelle de la relation entre le sexe, les hormones et AIRE, dans des modèles cellulaires humains et murins, montre qu'après la puberté, ce facteur est moins exprimé chez la femme que chez l'homme. Les estrogènes induisent une augmentation du nombre de sites de méthylation au niveau du promoteur de Aire réprimant ainsi son expression. À partir de la puberté, les femmes auraient une efficacité diminuée du processus de tolérance centrale, ce qui entraînerait un accroissement des cellules autoréactives et de leur susceptibilité aux maladies auto-immunes. Ces observations nous amènent à nous interroger sur les effets d'une exposition croissante aux perturbateurs endocriniens, molécules estrogen-like qui, en diminuant l'expression de AIRE, conduiraient à une augmentation de la fréquence des maladies auto-immunes. < Maladies auto-immunes : une forte prévalence féminineLes maladies auto-immunes touchent 5 à 8 % de la population en Europe Occidentale et aux États-Unis. Elles comprennent 70 à 80 pathologies différentes, comme la polyarthrite rhumatoïde, le lupus érythémateux disséminé, la sclérose en plaque, le diabète de type 1, le psoriasis, la maladie de Crohn et la myasthé-nie grave. Bien qu'elles présentent une grande disparité en ce qui concerne les organes ou systèmes ciblés, les auto-anticorps sériques produits et la réponse aux traitements, une caractéris-tique épidémiologique commune a été mise en évidence pour un grand nombre de ces pathologies : une forte prévalence féminine [1] (Tableau I). Cette prédominance féminine connue depuis des décennies demeure inexpliquée bien que de nombreuses hypothèses aient été émises impliquant l'environnement hormonal, le microchimérisme foetal, l'inactivation et/ou des anomalies du chromosome X. Le système immunitaire a pour fonction de protéger l'organisme contre des infections à travers des réponses innées et/ou adaptatives. Toutefois, il est clairement établi que les maladies autoimmunes se développent suite à une rupture dans les mécanismes de tolérance centrale ou périphérique du système immunitaire. Dans chacune de ces pathologies, une inflammation chronique ou périodique contribu...

show abstract

“…APS-1 is a rare, recessive monogenic disease that is caused by mutations in the autoimmune regulator (AIRE) gene, characterised by the presence of two of the three main components: PAI, hypoparathyroidism and chronic mucocutaneous candidiasis, which has been reviewed elsewhere (20). Recently, several monoallelic mutations in AIRE's PHD1-domain were found to be associated with a milder form of APS-1 masquerading sometimes as APS-2, often with vitiligo and pernicious anaemia as disease components (21). Isolated PAI and APS-2 share the same…”

Section: Incidence and Prevalencementioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Epidemiology, quality of life and complications of primary adrenal insufficiency: a review

Bensing

Hulting

Husebye

et al. 2016

European Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

In this article, we review published studies covering epidemiology, natural course and mortality in primary adrenal insufficiency (PAI) or Addison's disease. Autoimmune PAI is a rare disease with a prevalence of 100-220 per million inhabitants. It occurs as part of an autoimmune polyendocrine syndrome in more than half of the cases. The patients experience impaired quality of life, reduced parity and increased risk of preterm delivery. Following a conventional glucocorticoid replacement regimen leads to a reduction in bone mineral density and an increase in the prevalence of fractures. Registry studies indicate increased mortality, especially evident in patients diagnosed with PAI at a young age and in patients with the rare disease autoimmune polyendocrine syndrome type-1. Most notably, unnecessary deaths still occur because of adrenal crises. All these data imply the need to improve the therapy and care of patients with PAI.

show abstract

Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases

Cited by 241 publications

References 47 publications

Functional Domains of Autoimmune Regulator (AIRE) Modulate INS-VNTR Transcription in Human Thymic Epithelial Cells

Functional Domains of Autoimmune Regulator (AIRE) Modulate INS-VNTR Transcription in Human Thymic Epithelial Cells

Prédisposition aux pathologies auto-immmunes

MANAGEMENT OF ENDOCRINE DISEASE: Epidemiology, quality of life and complications of primary adrenal insufficiency: a review

Contact Info

Product

Resources

About