type: misc

label: url

en: 胸腺における制御性T細胞分化

ja: 胸腺における制御性T細胞分化

en: Journal of Clinical and Experimental Medicine

ja: 医学のあゆみ


en: AIRE - The Autoimmune Regulator

ja: AIRE - The Autoimmune Regulator

en: eLS

ja: eLS


en: AIRE遺伝子と多腺性自己免疫症候群

ja: AIRE遺伝子と多腺性自己免疫症候群

en: The Medical Frontline

ja: 最新医学


en: Switching on the Aire conditioner

ja: Switching on the Aire conditioner

en: Aire has been cloned as the gene responsible for a hereditary type of organ-specific autoimmune disease. Aire controls the expression of a wide array of tissue-restricted Ags by medullary thymic epithelial cells (mTECs), thereby leading to clonal deletion and Treg-cell production, and ultimately to the establishment of self-tolerance. However, relatively little is known about the mechanism responsible for the control of Aire expression itself. In this issue of the European Journal of Immunology, Haljasorg et al. [Eur. J. Immunol. 2015. 45: 3246-3256] have reported the presence of an enhancer element for Aire that binds with NF-κB components downstream of the TNF receptor family member, RANK (receptor activator of NF-κB). The results suggest that RANK has a dual mode of action in Aire expression: one involving the promotion of mTEC differentiation and the other involving activation of the molecular switch for Aire within mature mTECs.

en: European Journal of Immunology

ja: European Journal of Immunology


en: Mechanisms underlying the establishment of T-cell tolerance in the thymus

ja: T細胞の中枢免疫トレランスの機序

en: 月刊臨床免疫・アレルギー科

ja: 月刊臨床免疫・アレルギー科


en: AIRE遺伝子を導入したHeLa細胞における細胞周期依存的なAIREタンパク質のリン酸化

en: Seikagaku

ja: 生化学


en: Which model better fits the role of Aire in the establishment of self-tolerance: the transcription model or the maturation model?

en: The discovery of Aire-dependent transcriptional control of many tissue-restricted self-antigen (TRA) genes in thymic epithelial cells in the medulla (medullary thymic epithelial cells, mTECs) has raised the intriguing question of how the single Aire gene can influence the transcription of such a large number of TRA genes within mTECs. From a mechanistic viewpoint, there are two possible models to explain the function of Aire in this action. In the first model, TRAs are considered to be the direct target genes of Aire's transcriptional activity. In this scenario, the lack of Aire protein within cells would result in the defective TRA gene expression, while the maturation program of mTECs would be unaffected in principle. The second model hypothesizes that Aire is necessary for the maturation program of mTECs. In this case, we assume that the mTEC compartment does not mature normally in the absence of Aire. If acquisition of the properties of TRA gene expression depends on the maturation status of mTECs, a defect of such an Aire-dependent maturation program in Aire-deficient mTECs can also result in impaired TRA gene expression. In this brief review, we will focus on these two contrasting models for the roles of Aire in controlling the expression of TRAs within mTECs.

en: Frontiers in Immunology

ja: Frontiers in Immunology


en: Contrasting models for the roles of Aire in the differentiation program of epithelial cells in the thymic medulla

en: The current prevailing view regarding the role of Aire in self-tolerance is that it is involved in the transcriptional control of many tissue-restricted self-antigen genes in thymic epithelial cells in the medulla (mTECs); however, accumulating evidence also suggests that Aire has other roles, e.g. in mTEC differentiation, and furthermore that Aire can either promote or inhibit the mTEC differentiation program, i.e. Aire does not play a neutral role in mTEC differentiation. This review discusses when and how Aire plays an important role in controlling the organization of mTECs required for the expression of self-antigen genes.


en: The role of autoimmune regulator (Aire) in the development of the immune system

en: AIRE is the gene responsible for a rather rare hereditary type of autoimmune disease. The mechanism underlying the autoimmune pathogenesis caused by AIRE deficiency is a focus of intense research because it could provide clues to the fundamental question of how the immune system discriminates between self and non-self within the thymic microenvironment.

en: Microbes and Infection

ja: Microbes and Infection


en: Autoimmune regulator functions in autoimmunity control.

en: Mutation of the autoimmune regulator (AIRE) gene is responsible for the development of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), an organ-specific autoimmune disease with monogenic autosomal recessive inheritance. AIRE is strongly expressed in thymic epithelial cells (TECs), and its structural features suggest that it probably acts as a transcriptional regulator. The role of Aire in the elimination of autoreactive T cells (i.e., negative selection) has been well demonstrated with the use of transgenic mouse models, although how Aire regulates this process in TECs has yet to be determined. Aire also regulates other features of autoimmunity, such as target-organ specificity of autoimmune destruction, suggesting that an understanding of the relationship between AIRE gene malfunction and the breakdown of self-tolerance promises to help unravel the pathogenesis of not only APECED but also other types of autoimmune diseases. Owing to this unique tolerogenic function of Aire, the cellular origin and developmental process of Aire-expressing TECs is now becoming an interesting field for intense research.

en: Expert Review of Clinical Immunology

ja: Expert Review of Clinical Immunology


en: NF-κB activation pathway in thymic epithelial cells controls establishment of self-tolerance

en: Inflammation and Regeneration

ja: Inflammation and Regeneration


en: Transcriptional regulation in thymic epithelial cells for the establishment of self tolerance

en: Thymic epithelial cells (TECs) play pivotal roles in the establishment of self tolerance through critical dialogue with developing thymocytes. Unique actions of two transcriptional regulators within TECs, NF-kappaB-inducing kinase (NIK) and an autoimmune regulator (AIRE), for the establishment of self tolerance have recently been highlighted by studies using a strain of mouse bearing a natural mutation of the NIK gene (aly mice) and gene-targeted mice, respectively. Previous studies have demonstrated essential roles of NIK downstream of the lymphotoxin-beta receptor (LTbetaR), which is essential for the development of secondary lymphoid organs; aly mice lack all lymph nodes and Peyer's patches because of the defective LTbetaR signaling. Additional roles of NIK in thymic organogenesis downstream of LTPR, mainly through the developmental regulation of TECs, have now emerged, although the corresponding ligand(s) for LTbetaR participating in this action have not been fully characterized. In contrast, AIRE, a gene responsible for the development of an organ-specific autoimmune disease that demonstrates monogenic autosomal recessive inheritance, contributes to the establishment of self tolerance probably by controlling the expression of self antigens through yet undetermined molecular mechanisms. Thus, it is highly likely that a group of genes control self tolerance within TECs through unique and coordinated actions, and that an understanding of this process would help to unravel the pathogenesis of autoimmune disease.

en: Archivum Immunologiae et Therapiae Experimentalis


en: Role of TNF ligand and receptor family in the lymphoid organogenesis defined by gene targeting

en: The molecular basis of lymphoid organogenesis has recently been elucidated using gene-targeted mice. Mice deficient in lymphotoxin-alpha (LT alpha) lack lymph nodes and Peyer's patches. The action of LT alpha in lymphoid organogenesis is mediated mostly by the membrane form of LT by a mechanism independent of TNF receptor I (TNFR-I) or II (TNFR-II). Additionally, follicular dendritic cell (FDC) clusters or germinal centers fail to develop in the spleen of LT alpha-deficient mice. Mice deficient in either TNFR-I or LT beta R also fail to develop splenic FDC clusters and germinal centers, indicating that signaling through both TNFR-I and LT beta R is required for the development of these structures. The mechanisms underlying the defective lymphoid organogenesis in LT alpha-deficient mice, together with a natural mutant strain, alymphoplasia (aly) mice, which manifest a quite similar phenotype to LT alpha-deficient mice, were investigated by generating aggregation chimeras. These studies demonstrate that LT alpha and the aly gene product together control lymphoid organogenesis with a close mechanistic relationship in their biochemical pathways through governing distinct cellular compartments; the former acting as a circulating ligand and the latter as a LT beta R-signaling molecule expressed by the stroma of the lymphoid organs.

en: The Journal of Medical Investigation : JMI


en: Lymphotoxin-alpha deficient and TNF receptor-I-deficient mice define developmental and functional characteristics of germinal centers

en: Immunological Reviews

ja: Immunological Reviews