Projection of an Immunological Self Shadow Within the Thymus by the Aire Protein

Anderson, Mark S.; Venanzi, Emily S.; Klein, Ludger; Chen, Zhibin; Berzins, Stuart P.; Turley, Shannon J.; Boehmer, Harald von; Bronson, Roderick T.; Dierich, Andrée; Benoist, Christophe; Mathis, Diane

doi:10.1126/science.1075958

Cited by 2,157 publications

(2,319 citation statements)

References 35 publications

Supporting

Mentioning

2,185

Contrasting

Unclassified

Order By: Relevance

“…However, the most under-expressed genes (214 genes) may have more in common in terms of their regulation. For example, a good number of them (Gatm, Ambp, Gal, Chgb, Pap, Tff2, Aldh1a1, Ins2, Camp, S100a9, S100a8, Ltf) are believed to be AIRE-regulated [43,44]. All but one (S100a9) had their expression up-regulated by treatment and half of them significantly, although the expression of Aire was not changed (p=0.93).…”

Section: Discussionmentioning

confidence: 99%

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Creusot

Yaghoubi²,

Kodama

et al. 2008

Clinical Immunology

View full text Add to dashboard Cite

A deficit in IL-4 production has been previously reported in both diabetic human patients and nonobese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-wk old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/ IL-4) into 12-wk old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Creusot

Yaghoubi²,

Kodama

et al. 2008

Clinical Immunology

View full text Add to dashboard Cite

show abstract

“…Homozygous loss of AIRE function in the thymus causes the debilitating autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED) syndrome in humans [19], characterised by multiple-organ autoimmune responses involving mostly endocrine glands and including high risk of type 1 diabetes [20]. In mice, targeted Aire disruption leads to a marked decrease in self-antigen expression, almost eliminating the 'promiscuous' gene expression pattern [21]. These mice, like APECED patients, have multiple autoimmune responses directed against various organs [22].…”

Section: Introductionmentioning

confidence: 99%

“…These mice, like APECED patients, have multiple autoimmune responses directed against various organs [22]. A considerable amount of work has been done on this transcription factor, demonstrating its essential role for this process and its implications for autoimmune disease [19,[21][22][23]. However, it is not known whether gene-specific regulatory mechanisms of this thymic 'promiscuous' gene expression exist.…”

Section: Introductionmentioning

confidence: 99%

“…The problem is that tissue-specific antigens are expressed in only a small fraction of mTECs (1-3% for insulin) that have not, until now, been used in isolation, to study regulatory mechanisms specific to the gene of interest [21]. Single-cell PCR has been used [25,26], but its results are qualitative rather than quantitative; for physiological regulation studies a stable cultured cell line would be ideal.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Levi

Polychronakos

2009

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis The expression of tissue-specific selfantigens in the thymus is essential for self-tolerance. Genetic susceptibility to type 1 diabetes correlates inversely with thymic insulin expression and, in mice, lowered levels of this expression result in T cell responses against insulin. This study was undertaken to examine whether thymic insulin expression is regulated by the same metabolic stimuli as in beta cells or by different inputs, possibly of an immune nature. Methods Ins2 mRNA changes in mouse thymus were evaluated in vivo, following intraperitoneal glucose injection. We also examined the effect of a high glucose concentration on Ins2 mRNA in clones of insulin-expressing medullary thymus epithelial cell lines (mTECs). The same in vitro system was used to evaluate the effect of IFN-γ and cell-tocell contact with thymocytes in co-culture. Results Ins2 mRNA was significantly increased in the pancreas following a glucose load, but remained unchanged in the thymus. Furthermore, stimulation of insulin-expressing mTECs in vitro with IFN-γ, a cytokine involved in T cell negative selection, decreased levels of insulin expression even though expression of Aire was increased. Last, coculture of mTECs with thymocytes resulted in an upregulation of both Aire and insulin expression. Conclusions/interpretation We conclude that regulation of insulin transcription in the thymus is not dependent on metabolic stimuli but it may, instead, be under the control of cytokines and cell-to-cell interactions with lymphoid cells. That this regulation is not always coordinated with that of Aire, a non-specific master switch, suggests insulinspecific mechanisms.

show abstract

“…The Autoimmune Regulator ( AIRE) gene is the disease-causing gene [3,4]. AIRE acts as a transcriptional regulator and is almost exclusively expressed in the thymus [5] where it orchestrates the process of negative selection of self-reactive T cells and contributes to the development of regulatory T cells (Tregs) [6,7]. All patients present autoantibodies against autoantigens expressed in the affected tissue [8] and/or against immune mediators such as interferon-omega (ω) and interleukin (IL)-22 [9,10].…”

mentioning

confidence: 99%

Oral microbiota in autoimmune polyendocrine syndrome type 1

Bruserud

Siddiqui

Marthinussen

et al. 2018

Journal of Oral Microbiology

View full text Add to dashboard Cite

Background: Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare, childhood onset disease caused by mutations in the Autoimmune Regulator gene. The phenotypic expression is highly variable and includes disease manifestations in the oral cavity, including mucocutaneous candidiasis. Increasing evidence suggests a potential role of the skin, oral and gut microbiotas in the pathogenesis of autoimmunity. To date, no information exists regarding the oral microbiota in APS-1. Objective: To assess the bacterial microbiota of whole saliva in APS-1 patients by using high throughput sequencing. Design: Whole unstimulated saliva was collected from 10 APS-1 patients and 17 healthy controls and examined by high throughput sequencing of the hypervariable region V1-V2 of 16S rRNA using the 454 GS Junior system. Metastats (http://cbcb.umd.edu/software/metastats) was used to analyse the pyrosequencing reads. Results: A reduction in the total number of bacterial genera and species was detected in APS-1 compared to healthy controls. The proportion of the major phyla Firmicutes was higher (60% vs 41%, p = 0.002) and Bacteroidetes lower (15% vs 28%, p = 0.007) in APS-1 compared to healthy controls. On the genus level, Streptococcus and Gemella were prevalent in APS-1. Conclusion: Our findings indicate a significantly altered oral microbiota in APS-1.

show abstract

Projection of an Immunological Self Shadow Within the Thymus by the Aire Protein

Cited by 2,157 publications

References 35 publications

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Oral microbiota in autoimmune polyendocrine syndrome type 1

Contact Info

Product

Resources

About