Diseases associated with the TLR signaling cascade

Stable Identifier
Homo sapiens
Defects in Toll-like Receptor Cascades
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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
23622315 Mendelian predisposition to herpes simplex encephalitis

Abel, L, Zhang, SY, Casanova, JL

Handb Clin Neurol 2013
22610250 Genetic variation in Toll-like receptors and disease susceptibility

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

Nat. Immunol. 2012
16176658 Heritable defects of the human TLR signalling pathways

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

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

Puel, A, Picard, C, Casanova, JL

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