AIRE gene polymorphisms in systemic sclerosis associated with autoimmune thyroiditis

Ferrera, Francesca; Rizzi, Marta; Sprecacenere, B.; Balestra, P; Sessarego, Marta; Carlo, Aldo Di; Filaci, Gilberto; Gabrielli, Armando; Ravazzolo, Roberto; Indiveri, Francesco

doi:10.1016/j.clim.2006.09.013

Cited by 38 publications

(32 citation statements)

References 23 publications

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“…Furthermore, by sequencing of the AIRE gene in an additional 25 patients with AAD, no non-synonymous polymorphisms, except possibly the Val301Met transition, seem to have pronounced impact on the risk of developing ADD. In a previous study by Ferrera et al, 30 this mutation was found in a female patient with systemic sclerosis who was affected by autoimmune thyroiditis. The same SNP was also found in a few patients with alopecia, however in the same frequencies as in healthy controls.…”

Section: Discussionmentioning

confidence: 74%

“…A role for the intronic variant G11107A in the risk of developing systemic sclerosis in combination with thyroiditis was recently suggested. 30 However, few subjects were included in the study and the results need to be replicated before a firm conclusion could be drawn. The Ser278Arg mutation was found to be associated with alopecia in a recent study on 202 patients and 175 controls.…”

Section: Discussionmentioning

confidence: 99%

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AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

et al. 2008

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Autoimmune Addison's disease (AAD) is often associated with other components in autoimmune polyendocrine syndromes (APS). Whereas APS I is caused by mutations in the AIRE gene, the susceptibility genes for AAD and APS II are unclear. In the present study, we investigated whether polymorphisms or copy number variations in the AIRE gene were associated with AAD and APS II. First, nine SNPs in the AIRE gene were analyzed in 311 patients with AAD and APS II and 521 healthy controls, identifying no associated risk. Second, in a subgroup of 25 of these patients, AIRE sequencing revealed three novel polymorphisms. Finally, the AIRE copy number was determined by duplex quantitative PCR in 14 patients with APS I, 161 patients with AAD and APS II and in 39 healthy subjects. In two Scandinavian APS I patients previously reported to be homozygous for common AIRE mutations, we identified large deletions of the AIRE gene covering at least exon 2 to exon 8. We conclude that polymorphisms in the AIRE gene are not associated with AAD and APS II. We further suggest that DNA analysis of the parents of patients found to be homozygous for mutations in AIRE, always should be performed.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

et al. 2008

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“…On this basis, we decided to analyze SNPs of AIRE gene in order to verify whether peculiar polymorphic genotypes could protect or predispose to the development of melanoma. Among all the AIRE SNPs already identified, five SNPs were selected following two main criteria consisting in their presence at elevated frequency in the European population (rs878081, rs1055311, rs1800520, rs1800525 and rs1800522) [34] and in the already demonstrated association with human autoimmune diseases (rs1800520 and rs1800525 linked to alopecia aerata and systemic sclerosis associated with autoimmune thyroiditis, respectively) [35,36]. Indeed, we reasoned that an AIRE polymorphic genotype potentially predisposing to an autoimmune disease could also be responsible for a lower level of TRAs transcription in the thymus, including that of tumor-specific antigens, subsequently resulting in a less effective negative selection of autoantigen (and tumor antigen)-specific T lymphocytes and to a potentially lower susceptibility to tumor development.…”

Section: Discussionmentioning

confidence: 99%

The role of AIRE polymorphisms in melanoma

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Ferrera

Pastorino

et al. 2010

Clinical Immunology

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Polymorphisms of AIRE, a transcription factor that up-regulates intrathymic expression of tissue-specific antigens including melanoma-associated antigens (MAAs), may variably affect the selection of MAAs-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to melanoma. We found that AIRE single nucleotide polymorphisms (SNPs) rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients, independently from sex, age and stages of melanoma. The presence of these SNPs was associated with increased frequency of two T-cell clonotypes specific for MAGE-1 linking their protective effect to selection/expansion of MAA-specific T cells. Interestingly, mRNA transcribed on the rs1800520 SNP showed increased free energy than the wild type suggesting that its reduced stability may be responsible for the different activity of the polymorphic AIRE molecule. This finding may contribute at identifying subjects with increased risk of developing melanoma or patients with melanoma that may take benefit from immunotherapy.

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“…Certain heterozygous members of this kindred manifested only autoimmune thyroiditis, which is not a major clinical feature of APS 1 (11). Although some studies have demonstrated that Aire mutation carriers may be found in autoimmune disease cohorts (38), further study is needed to determine the exact contribution of Aire variants to autoimmune diseases with features distinct from APS 1. In addition, it may be possible that isolated kindreds with evidence of autosomal dominant autoimmunity harbor an Aire allele similar to G228W.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire

et al. 2008

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Homozygous loss-of-function mutations in AIRE cause autoimmune polyglandular syndrome type 1 (APS 1), which manifests in a classic triad of hypoparathyroidism, adrenal insufficiency, and candidiasis. Interestingly, a kindred with a specific G228W AIRE variant presented with an autosomal dominant autoimmune phenotype distinct from APS 1. We utilized a novel G228W-knockin mouse model to show that this variant acted in a dominant-negative manner to cause a unique autoimmunity syndrome. In addition, the expression of a large number of Aire-regulated thymic antigens was partially inhibited in these animals, demonstrating the importance of quantitative changes in thymic antigen expression in determining organ-specific autoimmunity. Furthermore, the dominant-negative effect of the G228W variant was exerted through recruitment of WT Aire away from active sites of transcription in the nucleus of medullary thymic epithelial cells in vivo. Together, these results may demonstrate a mechanism by which autoimmune predisposition to phenotypes distinct from APS 1 can be mediated in a dominant-negative fashion by Aire.

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AIRE gene polymorphisms in systemic sclerosis associated with autoimmune thyroiditis

Cited by 38 publications

References 23 publications

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

The role of AIRE polymorphisms in melanoma

Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire

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