Diseases associated with the TLR signaling cascade

Toll like receptors (TLRs) are sensors of the innate immune system that detect danger signals derived from pathogens (pathogen-associated molecular patterns - PAMP) or damaged cells (damage-associated molecular patterns - DAMP) (Pasare C and Medzhitov R 2005; Barton GM and Kagan JC 2009; Kawai T and Akira S 2010). Signaling by these sensors promotes the activation and nuclear translocation of transcription factors (IRFs, NFkB and AP1). The transcription factors induce secretion of inflammatory cytokines such as IL-6, TNF and pro-IL1beta that direct the adaptive immune response. Inherited or acquired abnormalities in TLR-mediated processes may lead to increased susceptibility to infection, excessive inflammation, autoimmunity and malignancy (Picard C et al. 2010; Netea MG et al. 2012; Varettoni M et al. 2013). Here we describe four primary immunodeficiency (PID) disorders associated with defective TLR-mediated responses. First, MyD88 or IRAK4 deficiency is characterized with a greater susceptibility to pyogenic bacteria in affected patients (Picard C et al. 2003; von Bernuth H et al. 2008). Second, defects in the TLR3 signaling pathway are associated with a greater susceptibility to herpes simplex virus encephalitis (Zhang SY et al. 2013). Third, imunodeficiencies due to defects in NFkB signaling components are linked to impaired TLR-mediated responses (Courtois G et al. 2003; Fusco F et al. 2004). Finally, events are annotated showing constitutive activation of a somatically mutated MyD88 gene which results in malignancy (Varettoni M et al. 2013).

Toll 样受体（TLRs）是先天免疫系统的感应器，能够探测源自病原体（病原体相关分子模式 - PAMP）或受损细胞（损伤相关分子模式 - DAMP）的危险信号（Pasare C 和 Medzhitov R，2005；Barton GM 和 Kagan JC，2009；Kawai T 和 Akira S，2010）。这些传感器的信号传导促进了转录因子（IRFs、NFkB 和 AP1）的激活和核转位。转录因子诱导分泌炎症细胞因子，如 IL-6、TNF 和前 IL1beta，这些因子指导适应性免疫反应。TLR 介导过程中遗传性或获得性的异常可能导致感染易感性增加、炎症过度、自身免疫和恶性肿瘤（Picard C 等，2010；Netea MG 等，2012；Varettoni M 等，2013）。在此，我们描述了四种与缺陷的 TLR 介导反应相关的原发性免疫缺陷（PID）疾病。首先，MyD88 或 IRAK4 缺陷的特征是受影响患者对化脓性细菌的易感性增加（Picard C 等，2003；von Bernuth H 等，2008）。其次，TLR3 信号通路缺陷与单纯疱疹病毒脑炎的易感性增加相关（Zhang SY 等，2013）。第三，由于 NFkB 信号传导组件缺陷导致的免疫缺陷与受损的 TLR 介导反应相关（Courtois G 等，2003；Fusco F 等，2004）。最后，标注了体细胞突变 MyD88 基因的持续激活事件，这导致恶性肿瘤（Varettoni M 等，2013）。