Functional characterization of genetic risk factors in autoimmune Addison’s disease

Abstract

Autoimmune diseases occur when the immune system attacks and damages the body’s own tissue. Why people develop these diseases, and how the autoimmune reaction develops are unanswered questions. Autoimmune Addison's disease (AAD) is an organ-specific autoimmune disorder characterized by an immunological attack of the adrenal cortex. The complex genetic architecture underlying AAD has not been entirely established, and the overall aim of this project was therefore to identify and functionally characterize genetic risk factors in AAD. We discovered several rare and damaging inborn errors of antiviral immunity in AAD patients. Among them, variants in the gene encoding Toll-like receptor 3 (TLR3), which recognizes double-stranded RNAs (dsRNAs) upon viral infection. Functional characterization of the TLR3 variants revealed a partial loss of function effect on the receptor’s signaling activity, leading to impaired interferon (IFN) responses ex vivo. Next, we identified a homozygous stop-gain variant in the gene encoding 3βhydroxysteroid dehydrogenase type 2 (3βHSD2), causing a rare form of congenital adrenal hyperplasia (CAH). The mutation was carried by an AAD patient with circulating antibodies against the major AAD autoantigen 21-hydroxylase (21OH). To our knowledge, this combination represents a novel disease etiology. Finally, we wanted to identify HLA-specific immunodominant epitopes of 21OH, targeted by autoreactive T cells. We discovered a new immunodominant epitope, ARLELFVVL (21OH434-442), presented by HLA-C*0701. This is the first HLAC*0701 restricted epitope described for a self-antigen in an autoimmune disease. We also confirmed the presence of autoreactive CD8+ T cells responses to the previously proposed epitope LLNATIAEV (21OH342-350), restricted to HLA-A2. Altogether, the work in this doctoral dissertation has provided new insights into why certain individuals might be more genetically susceptible to develop AAD, and partly how the autoimmune reaction progresses