Diseases associated with the TLR signaling cascade

Stable Identifier
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
22610250 Genetic variation in Toll-like receptors and disease susceptibility

Netea, MG, Wijmenga, C, O'Neill, LA

Nat. Immunol. 2012
23622315 Mendelian predisposition to herpes simplex encephalitis

Zhang, SY, Abel, L, Casanova, JL

Handb Clin Neurol 2013
16176658 Heritable defects of the human TLR signalling pathways

Puel, A, Yang, K, Ku, CL, von Bernuth, H, Bustamante, J, Santos, OF, Lawrence, T, Chang, HH, Al-Mousa, H, Picard, C, Casanova, JL

J. Endotoxin Res. 2005
21734245 Infectious diseases in patients with IRAK-4, MyD88, NEMO, or I?B? deficiency

Picard, C, Casanova, JL, Puel, A

Clin. Microbiol. Rev. 2011
Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
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