One of the most remarkable characteristics of the immune system is its ability to discriminate between self and non-self antigens. This capacity is mediated by mechanisms of central and peripheral immunologic tolerance, which are essential for the maintenance of immune homeostasis and prevention of devastating autoimmunity. Therefore, in addition to dissecting the functional complexity of the thymus and of the TEC compartment, our lab is also interested in understanding how immunological tolerance to self is established in the thymus, and how breakdown of this process results in autoimmune disorders.
In particular, we focus on a unique subset of medullary thymic epithelial cells (mTECs), which expresses the Autoimmune regulator (AIRE) gene. These AIRE+ mTECs play an indispensable role in the establishment of central immunological tolerance and prevention of autoimmunity. Specifically, their essential role in the induction of self-tolerance is mainly thanks to their amazing and unique capacity to express, and subsequently present, essentially all body antigens, including those whose expression was originally thought to be restricted only to peripheral organs (e.g. insulin, casein, etc.). Such “promiscuous” expression of tissue-restricted-antigen (TRA) genes in the thymus “foreshadows” the self-antigens that T cells would encounter once they reach maturity and are released into the body. Strikingly, AIRE was shown to be responsible for the expression of up to 25% of the genome (Danan M et al, Genome Biology, 2016) . The physiological significance of AIRE in the thymus is best illustrated by mouse models and/or human patients with a dysfunctional Aire gene, which consequently develop a multi-organ autoimmune syndrome characterized by autoantibodies and immune infiltrates directed at multiple peripheral tissues.
In the past decade we have been interested in deciphering the mechanisms underlying the AIRE-driven induction of self-tolerance in the thymus. These included identification of transcriptional machinery controlling AIRE expression in mTECs, identification of key partners of AIRE addressing this specific question by successful identification of several novel physiological partners of Aire, including the lysine deacetylase Sirtuin1 (Sirt1), which is critical for Aire-mediated induction of immunological tolerance (Chuprin A et al, Nature Immunology, 2015; Avin A et al, Nature Communications, 2017). Our studies also brought important insights into transcriptional mechanisms controlling the expression of AIRE itself (Herzig Y et al, Nature Immunology, 2017; Goldfarb Y, et al, J Exp Med, 2022)
In addition to providing a more in-depth comprehension of how immunological tolerance is established on a molecular level, our research has also provided critical insights into the pathogenesis of the breakdown of central tolerance, which ultimately results in organ-specific autoimmunity. Specifically, in close collaboration with the lab of Dr. Husebye we demonstrated that certain mutations in the AIRE gene follow an autosomal dominant-inheritance pattern, and that even mutation in a single allele of the AIRE gene is sufficient to break self-tolerance and cause autoimmunity (Oftedal B et al, Immunity, 2015). More recently, using genetically engineered mouse models, the lab has successfully elucidated the modus operandi by which these dominant-negative AIRE mutations cause breakdown of self-tolerance mechanisms (Goldfarb Y, et al, J Exp Med, 2022).
Furthermore, by studying AIRE deficiency in human patients, the lab has recently discovered a previously unreported autoimmune disorder – autoimmune amelogenesis imperfecta, which is characterized by presence of various autoantibodies (mainly of IgA isotype) against the enamel matrix and subsequent destruction of the enamel layer on permanent teeth (Gruper Y at al, Nature 2023). Importantly, this novel disorder is not restricted only to AIRE-deficient patients, but also occurs in a substantial fraction of celiac children. Most recently, the lab has also identified a novel genetic factor – Ubd - which is highly and specifically expressed in AIRE+ TECs, and was found to play a critical role in the establishment of central tolerance in the thymus (in progress).