The susceptibility of Aire−/− mice to experimental myasthenia gravis involves alterations in regulatory T cells

Aricha, Revital; Feferman, Tali; Scott, Hamish S.; Souroujon, Miriam C.; Berrih‐Aknin, Sonia; Fuchs, Sara

doi:10.1016/j.jaut.2010.09.007

Cited by 36 publications

(19 citation statements)

References 50 publications

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“…Aging AIRE −/− mice have a similar phenotype to BAFF transgenic mice [115, 116] . As shown recently, AIRE −/− mice are also susceptible to the induction of EAMG [117], and this appears to be age related. Susceptibility is associated with lower expression of AChR in the thymus and, presumably, a failure to eliminate AChR-reactive T cells; that is, a failure of central tolerance.…”

Section: Baff Productionmentioning

confidence: 65%

B-Cell-Activating Factor and Autoimmune Myasthenia Gravis

Ragheb

Lisak

2011

Autoimmune Diseases

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BAFF is a potent B-cell survival factor, and it plays an essential role in B-cell homeostasis and B-cell function in the periphery. Both normal and autoreactive B cells are BAFF dependent; however, excess BAFF promotes the survival, growth, and maturation of autoreactive B cells. When overexpressed, BAFF protects B cells from apoptosis, thereby contributing to autoimmunity. Three independent studies have shown higher BAFF levels in the circulation of MG patients. BAFF may play an important role in the pathogenesis of MG. BAFF antagonists may well provide new treatment options for MG patients, particularly those patients with thymic lymphoid follicular hyperplasia.

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Section: Baff Productionmentioning

confidence: 65%

B-Cell-Activating Factor and Autoimmune Myasthenia Gravis

Ragheb

Lisak

2011

Autoimmune Diseases

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“…These processes require expression of Aire [39,40]. In human, Aire mutation results in loss of immune tolerance and development of autoimmune disease, and likewise in Aire − / − mice tolerance is compromised and Treg populations are significantly reduced, leading to profound autoimmunity [41,42]. Our data showed that Foxa1 and Foxa2 are required for normal Aire + mTEC differentiation.…”

Section: Discussionmentioning

confidence: 85%

Foxa1 and Foxa2 in thymic epithelial cells (TEC) regulate medullary TEC and regulatory T-cell maturation

Lau

Yánez

Solanki

et al. 2018

Journal of Autoimmunity

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The Foxa1 and Foxa2 transcription factors are essential for mouse development. Here we show that they are expressed in thymic epithelial cells (TEC) where they regulate TEC development and function, with important consequences for T-cell development. TEC are essential for T-cell differentiation, lineage decisions and repertoire selection. Conditional deletion of Foxa1 and Foxa2 from murine TEC led to a smaller thymus with a greater proportion of TEC and a greater ratio of medullary to cortical TEC. Cell-surface MHCI expression was increased on cortical TEC in the conditional Foxa1Foxa2 knockout thymus, and MHCII expression was reduced on both cortical and medullary TEC populations. These changes in TEC differentiation and MHC expression led to a significant reduction in thymocyte numbers, reduced positive selection of CD4+CD8+ cells to the CD4 lineage, and increased CD8 cell differentiation. Conditional deletion of Foxa1 and Foxa2 from TEC also caused an increase in the medullary TEC population, and increased expression of Aire, but lower cell surface MHCII expression on Aire-expressing mTEC, and increased production of regulatory T-cells. Thus, Foxa1 and Foxa2 in TEC promote positive selection of CD4SP T-cells and modulate regulatory T-cell production and activity, of importance to autoimmunity.

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“…AIRE knockout mice are susceptible to EAMG and have a lower expression of CD4 + FOXP3 + cells in thymus compared to wildtype mice [82]. Study on human MG showed that AIRE is expressed poorly in thymoma epithelial cells but thymomas from MG (+) and MG (-) patients exhibited similar levels of AIRE RNA.…”

Section: Relationships Of Tregs and Aire In Mgmentioning

confidence: 99%

The role of T regulatory cells in immunopathogenesis of myasthenia gravis: implications for therapeutics

Alahgholi-Hajibehzad

Kasapoğlu

Jafari

et al. 2015

Expert Review of Clinical Immunology

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T regulatory cells (Tregs) are crucial for the development of self-tolerance and are the major focus in many studies interpreting the pathogenesis of myasthenia gravis (MG), an autoimmune-based disease. In normal conditions, Tregs regulate the immune responses, while impaired regulatory function of these cells can lead to autoimmunity. Recent studies have confirmed that the thymic and peripheral blood CD4(+)CD25(+) Tregs of MG are defective in functions and/or in numbers, which are associated with disease severity; approaches to correct the defects of these Tregs may be promising in the treatment of MG. This review discusses recent studies on characteristics, quantitative and qualitative changes of Tregs and possible mechanisms that are involved in the impairment of these cells in MG pathogenesis. In addition, new approaches inducing Treg generation that are currently being investigated as therapies for MG, will be discussed as well as proposed approaches for future therapies.

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The susceptibility of Aire−/− mice to experimental myasthenia gravis involves alterations in regulatory T cells

Cited by 36 publications

References 50 publications

B-Cell-Activating Factor and Autoimmune Myasthenia Gravis

B-Cell-Activating Factor and Autoimmune Myasthenia Gravis

Foxa1 and Foxa2 in thymic epithelial cells (TEC) regulate medullary TEC and regulatory T-cell maturation

The role of T regulatory cells in immunopathogenesis of myasthenia gravis: implications for therapeutics

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