Identification and characterization of rare toll-like receptor 3 variants in patients with autoimmune Addison's disease
Identification and characterization of rare toll-like receptor 3 variants in patients with autoimmune Addison's disease
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DOI：
10.1016/j.jtauto.2019.100005
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发表时间：
2019-04-01
影响因子：
3.9
通讯作者：
Bratland, Eirik
中科院分区：
文献类型：
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作者：
Aslaksen, Sigrid;Wolff, Anette B.;Bratland, Eirik
自身免疫性阿狄森病（AAD）是一种典型的器官特异性自身免疫性疾病，其特征是免疫介导的对肾上腺皮质的攻击。与大多数自身免疫性疾病一样，AAD被认为是由遗传和环境因素的组合以及两者之间的相互作用引起的。持续的病毒感染被认为通过引发炎症和自身免疫性破坏而发挥触发作用。无法清除感染可能是由于先天免疫的畸变，包括参与识别保守微生物模式的基因突变。在一项匿名AAD患者的全外显子组测序研究中，我们发现了几种罕见的变异体，这些变异体被预测在编码Toll样受体3（TLR 3）的基因中具有破坏性。TLR 3识别双链RNA，因此是抗病毒防御的主要因素。我们在此报告了AAD患者TLR 3中5种罕见错义变异的发生和功能特征。这些变异中的大多数与一种常见的TLR 3变异一起发生，该TLR 3变异与广泛的免疫病理学相关。在基于细胞的测定中评估了这些变体对TLR 3功能的生物学意义，揭示了三种罕见变体的部分功能丧失效应。此外，在AAD患者中检测到TLR 3-干扰素（IFN）信号通路其他成员的罕见突变。总之，这些发现表明TLR 3和下游信号蛋白在AAD患者亚组的发病机制中的潜在作用。
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.