RESEARCH INTERESTS
Autoimmunity
The Su research group is interested in understanding the genetics of autoimmune diseases using both mouse models and patient samples. Our work is highly translational and aims to have direct relevance to human disease. One of our approaches is to study rare Mendelian autoimmunity syndromes in order to determine the contributions of a particular gene to developing autoimmunity. We have focused on Autoimmune Polyendocrinopathy Syndrome Type 1 (APS1 or APECED), a rare condition due to mutations in the Autoimmune Regulator (Aire) gene. We are interested in how Aire promotes tolerance and have utilized both APS1 mouse models and patient samples to understand the disease mechanisms underlying this condition. A model for how Aire functions to prevent autoimmune disease is shown below (Figure 1, from Su and Anderson, Pediatric Research, 2009).
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Aire enforces T cell tolerance toward self-antigens. In the normal thymus, Aire in medullary thymic epithelial cells (mTECs) promotes expression of tissue-specific self-antigens (ovals). T cells developing in the thymus that recognize these antigens undergo negative selection or are diverted to the regulatory T cell (Treg) lineage. See our review on Aire function: Anderson and Su, Nat Rev Imm (2016)
Loss of Aire function results in decrease self-antigen expression and defective negative selection of self-reactive T cells. In patients, two null Aire mutations result in Autoimmune Polyendocrinopathy Syndrome (APS) 1 or APECED, a multi-organ autoimmune disease. We and others have demonstrated that dominant Aire mutations can also underlie other forms of autoimmune disease (Su et al, J Clin Invest, 2008).
Aire deficiency predisposes to peripheral nervous system (PNS) autoimmunity. We identified myelin protein zero (MPZ or P0) as a PNS-specific Aire-regulated antigen expressed in the thymus. Aire deficiency allows escape of P0 specific T cells to escape negative selection to cause PNS autoimmunity. We discovered that autoimmune-prone NOD mice with a dominant Aire G228W mutation develop spontaneous PNS autoimmunity that resembles features of Guillain Barre Syndrome and its chronic counterpart CIDP (chronic inflammatory demyelinating polyneuropathy). APS1 patients have also been reported to develop CIDP, suggesting that Aire deficiency also predisposes to PNS autoimmunity in humans. See our review on CIDP pathogenesis: Wolbert et al, JCI Insight, 2020
Androgen upregulation of Aire results in more efficient negative selection of self-reactive T cells. Sex differences in multiple autoimmune diseases have been well-described. We recently reported that increased androgens may protect against autoimmune disease through upregulation of Aire. See our review on this subject: Wilkinson et all
Cancer
Our recent studies have shown that in the course of preventing autoimmunity, Aire also prevents effective anti-tumor immunity. Furthermore, we have shown that administration of biologic inhibitors can transiently break Aire-mediated central tolerance. These findings have the potential for enhancing the efficacy of current cancer immunotherapy strategies. A model for how Aire functions to restrict anti-cancer immunity is shown below (Figure 2, from Su and Anderson, Oncoimmunology, 2014).​
Aire deficiency allows escape of self/melanoma-reactive T cells from thymic deletion. Aire normally upregulates mTEC expression of TRP-1, a self-antigen that is also expressed by melanoma cancer cells. In Aire deficiency, lack of TRP-1 expression allows escape of TRP-1-reactive T cells from negative selection, which enhances anti-melanoma immunity
We recently reported that anti-RANKL antibody (a treatment that blocks the development of Aire+ mTECs) enhances anti-melanoma immunity. Moreover, anti-RANKL antibody and checkpoint inhibitors have additive effects in immune rejection of melanoma. See our review on anti-RANKL and cancer immunotherapies: Su and Anderson, Cancer Immunology Research, 2019
Checkpoint inhibitor immunotherapy
While checkpoint inhibitor immunotherapy has revolutionized treatments for cancer, their utility is limited by the development of immune related adverse events (IRAEs) resembling autoimmune disease. Our lab is investigating the mechanisms of IRAEs in order to understand how these unwanted side effects can be prevented and treated without adversely affecting anti-cancer immunity.
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