Division of Immunology & Allergy, Canadian Centre for Primary Immunodeficiency, Department of Pediatrics, The Hospital for Sick Children & The University of Toronto, Ontario, Canada.
Autoimmun Rev. 2012 Mar;11(5):341-7. doi: 10.1016/j.autrev.2011.10.007. Epub 2011 Oct 17.
Toll-like receptors, a major component of the innate immune system, play an important role in the initial response against pathogens. Genetic abnormalities in some receptors like TLR2, TLR3 and TLR4 have been associated with susceptibility to fungal and viral infections while other aberrations in TLR genes such as TLR3, TLR7 and TLR9 may predispose to autoimmunity. Recently we have shown an association of a TLR3 receptor variant, L412F, to susceptibility to chronic candidiasis, recurrent viral and bacterial infections and autoimmunity. We investigated here the biological implications of this TLR3 mutant.
To study the functional impact of the L412F variant of TLR3 we tested patients' peripheral blood mononuclear cells (PBMCs) as well as fibroblasts for secretion of cytokines in response to TLR3 ligand, candida or cytomegalovirus (CMV). In addition, the P2.1 cell line was used as a model for the TLR3 WT and L412F variant receptors function.
Patient's cells carrying the L412F variant showed reduced IFNγ as well as TNFα secretion in response to stimulation with the TLR3 ligand, CMV or Candida albicans. Fibroblasts with the L412F variant showed decreased secretion of IFNλ in response to stimulation with both polyinosine ploycytidylic acid (Poly I:C) and CMV and P2.1 cells transfected with the L412F variant showed reduced secretion of IFN-β in comparison to cells transfected with the wild type receptor.
We have shown here aberrant biological responses mediated by the TLR3 variant receptor, L412F, which may explain in part susceptibility of patients to chronic candidiasis, viral infections and autoimmunity.
Toll 样受体是先天免疫系统的主要组成部分，在对抗病原体的初始反应中发挥重要作用。某些受体（如 TLR2、TLR3 和 TLR4）的遗传异常与真菌和病毒感染易感性有关，而 TLR 基因（如 TLR3、TLR7 和 TLR9）的其他异常可能导致自身免疫。最近，我们发现 TLR3 受体变异体 L412F 与慢性念珠菌病、复发性病毒和细菌感染以及自身免疫易感性有关。在这里，我们研究了这种 TLR3 突变体的生物学意义。
为了研究 TLR3 L412F 变体的功能影响，我们测试了患者的外周血单核细胞（PBMC）以及成纤维细胞对 TLR3 配体、念珠菌或巨细胞病毒（CMV）刺激后的细胞因子分泌情况。此外，还使用 P2.1 细胞系作为 TLR3 WT 和 L412F 变体受体功能的模型。
携带 L412F 变体的患者细胞在受到 TLR3 配体、CMV 或白色念珠菌刺激后，IFNγ和 TNFα的分泌减少。携带 L412F 变体的成纤维细胞在受到 Poly I:C 和 CMV 刺激后 IFNλ的分泌减少，而转染 L412F 变体的 P2.1 细胞与转染野生型受体的细胞相比，IFN-β的分泌减少。
我们在这里显示了 TLR3 变体受体 L412F 介导的异常生物学反应，这可能部分解释了患者对慢性念珠菌病、病毒感染和自身免疫易感性的原因。
