Identification and characterization of rare toll-like receptor 3 variants in patients with autoimmune Addison's disease

Abstract Autoimmune Addison's disease (AAD) is a classic organ-specific autoimmune disease characterized by an immune-mediated attack on the adrenal cortex. As most autoimmune diseases, AAD is believed to be caused by a combination of genetic and environmental factors, and probably interactions between the two. Persistent viral infections have been suggested to play a triggering role, by invoking inflammation and autoimmune destruction. The inability of clearing infections can be due to aberrations in innate immunity, including mutations in genes involved in the recognition of conserved microbial patterns. In a whole exome sequencing study of anonymized AAD patients, we discovered several rare variants predicted to be damaging in the gene encoding Toll-like receptor 3 (TLR3). TLR3 recognizes double stranded RNAs, and is therefore a major factor in antiviral defense. We here report the occurrence and functional characterization of five rare missense variants in TLR3 of patients with AAD. Most of these variants occurred together with a common TLR3 variant that has been associated with a wide range of immunopathologies. The biological implications of these variants on TLR3 function were evaluated in a cell-based assay, revealing a partial loss-of-function effect of three of the rare variants. In addition, rare mutations in other members of the TLR3-interferon (IFN) signaling pathway were detected in the AAD patients. Together, these findings indicate a potential role for TLR3 and downstream signaling proteins in the pathogenesis in a subset of AAD patients.