A highly conserved NF‐κB‐responsive enhancer is critical for thymic expression of Aire in mice

Haljasorg, Uku; Bichele, Rudolf; Saare, Mario; Guha, Mithu; Maslovskaja, Julia; Kõnd, Karin; Remm, Anu; Pihlap, Maire; Tomson, Laura; Kisand, Kai; Laan, Martti; Peterson, Pärt

doi:10.1002/eji.201545928

Cited by 55 publications

(49 citation statements)

References 50 publications

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“…Mice deficient in the non-canonical NF-κB family member NF-κB2 p52 have a defect in Aire expression in mTECs, which is associated with impaired central tolerance 94 . Although this phenotype may also involve defects in mTEC differentiation, this early study is corroborated by more recent studies demonstrating that the Aire gene contains a conserved non-coding sequence that binds and responds to non-canonical and canonical NF-κB family members and is required for Aire gene expression and immune tolerance 95,96 .…”

Section: Role In Immune Regulationmentioning

confidence: 58%

The non-canonical NF-κB pathway in immunity and inflammation

2017

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The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies.

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Section: Role In Immune Regulationmentioning

confidence: 58%

The non-canonical NF-κB pathway in immunity and inflammation

2017

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“…Identified regulators include enhancer elements that contain NF-κB response elements (8,9); transcription factors, including activator protein-1 (AP-1), specificity protein 1 (Sp1), nuclear factor Y (NF-Y), and ETS family transcription factors (10); histone modifications (9); and DNA methylation (11). Dragin et al report that direct binding of estrogen/ER complexes to the AIRE promoter is unlikely, as predicted estrogen response elements are lacking at this site.…”

Section: Estrogen-mediated Aire Downregulationmentioning

confidence: 99%

Estrogen turns down “the AIRE”

Bakhru¹,

Su²

2016

Journal of Clinical Investigation

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C o m m e n t a r yAutoimmune disease: sex-dependent differencesThe incidence of autoimmune disease is increasing worldwide; therefore, the need to understand the basis of autoimmunity has taken on a new urgency. Progress in identifying genetic contributors to autoimmunity has been made through the study of monogenic autoimmune diseases. Such an approach has identified critical immuneregulatory genes, such as the autoimmune regulator (AIRE), which encodes a nuclear protein that functions as a key regulator of thymic central tolerance (reviewed in ref. 1). AIRE enforces self tolerance by promoting the promiscuous expression of tissue self-antigens (TSAs) within medullary thymic epithelial cells (mTECs), a nonhematopoietic, stromal cell population (Figure 1A). Presentation of these TSAs within the thymus results in negative selection of bone marrow-derived T cells, which recognize these TSAs with high affinity. In addition to eliminating autoreactive T cell clones within the thymus, AIRE also maintains self tolerance by diverting autoreactive T cells into the Treg lineage. AIRE is important for preventing autoimmune disease, as individuals with a complete loss of AIRE function develop the multiorgan autoimmune disease autoimmune polyendocrinopathy syndrome type 1 (APS1, which is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED]). While genetics are a major factor that determines autoimmune disease predisposition, it is clear that sex also plays a defining role in disease development. The incidence of autoimmunity is skewed toward females for many autoimmune diseases, including Sjögren's disease, systemic lupus erythematosus (SLE), and autoimmune thyroid disease (reviewed in ref. 2). Remarkably, over 80% of those affected with these conditions are female, illustrating the strong influence of sex in disease predisposition. Multiple factors likely underlie this sex bias, including the distinct sex hormone profiles in females versus males. Accumulating evidence suggests that male androgen hormones are immune suppressive, while female estrogen hormones are immune activating. For instance, androgen increases the differentiation of immunoregulatory CD4+ T cells (3), whereas estrogen enhances survival of T cells in patients with autoimmunity (4). Thus, there is a plethora of evidence that sex hormones directly modulate T cells in the periphery.Early clues that sex hormones may also modulate thymic stromal populations, such as mTECs, came from elegant studies that utilized bone marrow chimeras (5, 6). These studies showed that thymic epithelial cells express estrogen receptor (ER) and androgen receptor (AR) and that expression of these hormone receptors in the stromal compartment is required for altering bone marrow-derived T cell subsets in the thymus (5, 6). In this issue, Dragin et al. confirm that sex hormones indeed act on receptors on thymic stromal cells to impinge upon T cell development within the thymus. Furthermore, this study demonstrates that sex hormones regulate AIRE expre...

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“…MiR-181 enhances cell proliferation in medullary thymic epithelial cells via regulating TGF-β signaling 18 and is involved in the positive and negative selection of T-cells 19 . MiR-342-3p is a well-known regulator of the NF-κB pathway 20 , whose activation was shown to be necessary for the thymic expression of Aire in mice 21,22 .…”

Section: Resultsmentioning

confidence: 99%

Minipuberty and Sexual Dimorphism in the Infant Human Thymus

Moreira-Filho

Bando

Bertonha

et al. 2018

Sci Rep

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AIRE expression in thymus is downregulated by estrogen after puberty, what probably renders women more susceptible to autoimmune disorders. Here we investigated the effects of minipuberty on male and female infant human thymic tissue in order to verify if this initial transient increase in sex hormones - along the first six months of life - could affect thymic transcriptional network regulation and AIRE expression. Gene co-expression network analysis for differentially expressed genes and miRNA-target analysis revealed sex differences in thymic tissue during minipuberty, but such differences were not detected in the thymic tissue of infants aged 7–18 months, i.e. the non-puberty group. AIRE expression was essentially the same in both sexes in minipuberty and in non-puberty groups, as assessed by genomic and immunohistochemical assays. However, AIRE-interactors networks showed several differences in all groups regarding gene-gene expression correlation. Therefore, minipuberty and genomic mechanisms interact in shaping thymic sexual dimorphism along the first six months of life.

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A highly conserved NF‐κB‐responsive enhancer is critical for thymic expression of Aire in mice

Cited by 55 publications

References 50 publications

The non-canonical NF-κB pathway in immunity and inflammation

The non-canonical NF-κB pathway in immunity and inflammation

Estrogen turns down “the AIRE”

Minipuberty and Sexual Dimorphism in the Infant Human Thymus

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