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.

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

“…TLR3 variant L412F has been associated with a wide range of autoimmune diseases including Addison disease and hypothyroidism [ 39 ]. TLR3 rare variants resulting in partial loss of function and occurring together with the common variant L412F, or with another rare variant, have been identified in Addison disease [ 40 ]. Persistent viral infections in a background of defective innate immunity lead to overexpression of HLA allotypes prone to present autoantigen.…”

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

“…TLR3 rare variants resulting in partial loss of function and occurring together with the common variant L412F, or with another rare variant, have been identified in Addison’s disease [40]. Persistent viral infections in a background of defective innate immunity lead to overexpression of HLA haplotypes prone to present autoantigen.…”

Coexistence of Congenital Adrenal Hyperplasia and Autoimmune Addison's Disease

“…A whole-exome sequencing study involving 142 AAD patients (5) revealed a patient with a rare homozygous mutation in exon 2 of HSD3B2 [frequency ~0.00003 in the Genome Aggregation Database (gnomAD)] at nucleotide position 15 (NM_000198.3:c.15C>A), resulting in the exchange of the cysteine codon to a premature stop codon (p.Cys5Ter). Subsequent screening of the Norwegian Addison Registry identified the patient harboring the mutation, a 55-year-old female with AAD, premature ovarian insufficiency and vitamin B12 deficiency, accompanied by 21OH- and parietal cell autoantibodies (Figure 2A).…”