Aire knockdown in medullary thymic epithelial cells affects Aire protein, deregulates cell adhesion genes and decreases thymocyte interaction

Pezzi, Nicole; Assis, Amanda Freire; Cotrim-Sousa, Larissa; Lopes, Gabriel S; Mosella, Maritza; Lima, Djalma Sousa; Bombonato-Prado, Karina Fittipaldi; Passos, Geraldo Aleixo Silva

doi:10.1016/j.molimm.2016.08.003

Cited by 27 publications

(65 citation statements)

References 66 publications

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“…The mTECs using Aire control do not only express PTAs but also molecules involved in cell–cell interaction processes and some important adhesion molecules . In turn, the expression of these genes is dependent on the levels of the AIRE protein, so that studies using the small interfering RNA (siRNA) technique allowed the demonstration that the reduction of Aire leads to a concomitant reduction not only in PTAs but also in the adhesion capacity of mTECs to thymocytes . The molecules most affected by the reduction in the Aire levels provoked by siRNA are integrins, claudins and adhesion or co‐stimulatory molecules as CD80 .…”

Section: Aire Controlling Mtec‐thymocyte Adhesionmentioning

confidence: 99%

“…As discussed above, the absence of Aire in mTECs in vitro modulates various genes encoding proteins involved in cell adhesion and migration such as laminin, intercellular adhesion molecule 1 and vascular cell adhesion molecule 4. Functionally, Aire deficiency reduced the adhesion of thymocytes to mTECs that can modulate thymocyte migration and differentiation, contributing to abnormal tolerance or the breakdown of tolerance …”

Section: T‐cell Differentiation Negative Selection and Central Tolermentioning

confidence: 99%

“…57 The molecules most affected by the reduction in the Aire levels provoked by siRNA are integrins, claudins and adhesion or co-stimulatory molecules as CD80. 57 These findings were of great importance because mTEC-thymocyte adhesion is a crucial process for the negative selection of autoreactive thymocytes and induction of immunological tolerance.…”

Section: Role Of Aire Beyond the Control Of Pta Expressionmentioning

confidence: 99%

“…Functionally, Aire deficiency reduced the adhesion of thymocytes to mTECs that can modulate thymocyte migration and differentiation, contributing to abnormal tolerance or the breakdown of tolerance. 57 In addition to the indirect control of adhesion, migration and egress of thymocytes, Aire can modulate DC migration and localization though the expression of XCL1. Aire À/À mice showed diminished mTEC expression of XCL1 and DC accumulation in the medulla, which could, in turn, disturb antigen transfer between mTEC and DCs.…”

Section: T-cell Differentiation Negative Selection and Central Tolermentioning

confidence: 99%

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Update on Aire and thymic negative selection

et al. 2017

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SummaryTwenty years ago, the autoimmune regulator (Aire) gene was associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and was cloned and sequenced. Its importance goes beyond its abstract link with human autoimmune disease. Aire identification opened new perspectives to better understand the molecular basis of central tolerance and self-non-self distinction, the main properties of the immune system. Since 1997, a growing number of immunologists and molecular geneticists have made important discoveries about the function of Aire, which is essentially a pleiotropic gene. Aire is one of the functional markers in medullary thymic epithelial cells (mTECs), controlling their differentiation and expression of peripheral tissue antigens (PTAs), mTEC-thymocyte adhesion and the expression of microRNAs, among other functions. With Aire, the immunological tolerance became even more apparent from the molecular genetics point of view. Currently, mTECs represent the most unusual cells because they express almost the entire functional genome but still maintain their identity. Due to the enormous diversity of PTAs, this uncommon gene expression pattern was termed promiscuous gene expression, the interpretation of which is essentially immunological -i.e. it is related to self-representation in the thymus. Therefore, this knowledge is strongly linked to the negative selection of autoreactive thymocytes. In this update, we focus on the most relevant results of Aire as a transcriptional and post-transcriptional controller of PTAs in mTECs, its mechanism of action, and its influence on the negative selection of autoreactive thymocytes as the bases of the induction of central tolerance and prevention of autoimmune diseases.

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Section: Aire Controlling Mtec‐thymocyte Adhesionmentioning

confidence: 99%

Section: T‐cell Differentiation Negative Selection and Central Tolermentioning

confidence: 99%

Section: Role Of Aire Beyond the Control Of Pta Expressionmentioning

confidence: 99%

Section: T-cell Differentiation Negative Selection and Central Tolermentioning

confidence: 99%

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Update on Aire and thymic negative selection

et al. 2017

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“…▪ Avaliar a interação entre os lncRNAs e os seus mRNAs alvos (interação RNA-RNA). As mTECs 3.10 foram estabelecidas a partir do timo de camundongos recém-nascidos da linhagem C57BL/6 e fenotipadas como células Epcam + Ly51 -UEA1 + CD80 + MHC-II + e que expressam o gene Autoimmune regulator (Aire) (Macedo et al, 2009, Pezzi et al, 2016 (KONG et al, 2007;KANG et al, 2017). Os valores desse score variam de 0 a 1.…”

Section: Objetivos Específicosunclassified