Breakdown of Immune Tolerance in AIRE-Deficient Rats Induces a Severe Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy–like Autoimmune Disease

Ossart, Jason; Moreau, Anne; Autrusseau, Elodie; Ménoret, Séverine; Martin, Jérôme C.; Besnard, Marine; Ouisse, Laure-Hélène; Tesson, Laurent; Flippe, Léa; Kisand, Kai; Peterson, Pärt; Hubert, François-Xavier; Anegón, Ignacio; Josien, Régis; Guillonneau, Carole

doi:10.4049/jimmunol.1701318

Cited by 26 publications

(34 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, experimental transfer of autoantibody-containing AIRE-deficient serum in mice is not sufficient to promote autoimmunity ( 41 , 42 ). Serum transfer experiments in the recently developed AIRE-deficient rat model, which harbors a broader spectrum of autoantibodies relative to AIRE-deficient mice, may help further elucidate the potential direct role of autoantibodies in autoimmune tissue destruction ( 61 , 62 ).…”

Section: Pathogenesis Of Aire Deficiencymentioning

confidence: 99%

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

2021

View full text Add to dashboard Cite

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.

show abstract

Section: Pathogenesis Of Aire Deficiencymentioning

confidence: 99%

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

2021

View full text Add to dashboard Cite

show abstract

“…negative selection) or directing them toward the Treg lineage (10)(11)(12). Accordingly, mutations in Aire result in a defect in central tolerance in humans as well as in mice and rats affecting both of these arms of central tolerance (10,13,14). In addition to the well-characterized role in ectopic antigen expression, Aire has been proposed to control a number of other functions including regulation of thymic chemokines (15)(16)(17) and mTEC maturation (18).…”

Section: Central Tolerance Induction and Mtec Differentiationmentioning

confidence: 99%

Post-Aire Medullary Thymic Epithelial Cells and Hassall’s Corpuscles as Inducers of Tonic Pro-Inflammatory Microenvironment

et al. 2021

Self Cite

View full text Add to dashboard Cite

While there is convincing evidence on the role of Aire-positive medullary thymic epithelial cells (mTEC) in the induction of central tolerance, the nature and function of post-Aire mTECs and Hassall’s corpuscles have remained enigmatic. Here we summarize the existing data on these late stages of mTEC differentiation with special focus on their potential to contribute to central tolerance induction by triggering the unique pro-inflammatory microenvironment in the thymus. In order to complement the existing evidence that has been obtained from mouse models, we performed proteomic analysis on microdissected samples from human thymic medullary areas at different differentiation stages. The analysis confirms that at the post-Aire stages, the mTECs lose their nuclei but maintain machinery required for translation and exocytosis and also upregulate proteins specific to keratinocyte differentiation and cornification. In addition, at the late stages of differentiation, the human mTECs display a distinct pro-inflammatory signature, including upregulation of the potent endogenous TLR4 agonist S100A8/S100A9. Collectively, the study suggests a novel mechanism by which the post-Aire mTECs and Hassall’s corpuscles contribute to the thymic microenvironment with potential cues on the induction of central tolerance.

show abstract

“…Patients with the autoimmune polyendocrinopathy-candidiasis-ectodermaldystrophy syndrome have genetic defects in AIRE. Aire KO rats show signs of generalized autoimmunity and clinical signs of disease that are much more pronounced than in Aire KO mice and closer to manifestations in humans (Ossart et al, 2018).…”

Section: Immune and Hematological Systemsmentioning

confidence: 71%

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

et al. 2021

Self Cite

View full text Add to dashboard Cite

The rat has been extensively used as a small animal model. Many genetically engineered rat models have emerged in the last two decades, and the advent of gene-specific nucleases has accelerated their generation in recent years. This review covers the techniques and advances used to generate genetically engineered rat lines and their application to the development of rat models more broadly, such as conditional knockouts and reporter gene strains. In addition, genome-editing techniques that remain to be explored in the rat are discussed. The review also focuses more particularly on two areas in which extensive work has been done: human genetic diseases and immune system analysis. Models are thoroughly described in these two areas and highlight the competitive advantages of rat models over available corresponding mouse versions. The objective of this review is to provide a comprehensive description of the advantages and potential of rat models for addressing specific scientific questions and to characterize the best genome-engineering tools for developing new projects.

show abstract

Breakdown of Immune Tolerance in AIRE-Deficient Rats Induces a Severe Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy–like Autoimmune Disease

Cited by 26 publications

References 47 publications

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Post-Aire Medullary Thymic Epithelial Cells and Hassall’s Corpuscles as Inducers of Tonic Pro-Inflammatory Microenvironment

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

Contact Info

Product

Resources

About