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).
von Bernuth, H,