Diseases associated with the TLR signaling cascade

European Bioinformatics Institute, New York University Langone Medical Center, Ontario Institute for Cancer Research, Oregon Health and Science University. The contents of this document may be freely copied and distributed in any media, provided the authors, plus the institutions, are credited, as stated under the terms of Creative Commons Attribution 4.0 International (CC BY 4.0) License. For more information see our license. This is just an excerpt of a full-length report for this pathway. To access the complete report, please download it at the Reactome Textbook. 17/11/2022


Diseases associated with the TLR signaling cascade ↗ Stable identifier: R-HSA-5602358
Diseases: primary immunodeficiency disease 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 TLRmediated 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). Abel, L., Zhang, SY., Casanova, JL. (2013). Mendelian predisposition to herpes simplex encephalitis. Handb Clin Neurol, 112, 1091-7. ↗ Netea, MG., O'Neill, LA., Wijmenga, C. (2012. Genetic variation in Toll-like receptors and disease susceptibility. Nat. Immunol.,13, Puel, A., Chang, HH., Picard, C., von Bernuth, H., Bustamante, J., Ku, CL. et al. (2005). Heritable defects of the human TLR signalling pathways. J. Endotoxin Res.,11, (Picard C et al. 2003;Ku CL et al. 2007;Picard C et al. 2010;Picard C et al. 2011). Leukocytes derived from IRAK4-deficient patients display a lack of production of inflammatory cytokines such as TNF alpha, IL-6 and IL-1 beta by whole blood or a lack of CD62 ligand (CD62L) shedding from granulocytes following activation with the most TLR agonists including those of TLR1/2 (Pam3CSK4), TLR2/6 (Pam2CSK4) and TLR4 (LPS) (Picard C et al. 2003;McDonald DR et al. 2006;Ku CL et al. 2007). However, LPS-induced TLR4-mediated production of some cytokines (IL8 and MIP-1beta) was reduced but not abolished (Ku CL et al. 2007). LPS-stimulated induction of type I IFN via

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MyD88-IRAK4 independent signaling axis was normal or weakly affected suggesting that TLR4 could induce some responses in IRAK4 deficient patients (Yang K et al. 2005).
Patients with AR IRAK4 deficiency were found to bear homozygous or compound heterozygous mutations in the IRAK4 gene (Picard C et al. 2003;Ku CL et al. 2007;McDonald DR et al. 2006). Here we describe selected mutations, that have been functionally characterized. Cell-based assay as well as in vitro protein-interaction analyses with IRAK4 variants showed that the loss-of-function of defective IRAK4 is caused by either loss of protein production (reported for IRAK4 Q293X and E402X) or an impaired interhttps://reactome.org action with MyD88 as shown for missence mutation IRAK4 R12C (Ku CL et al. 2007;Yamamoto T et al. 2014).
Besides defective TLR2/4 mediated signaling, the Reactome module describes the impact of functional deficiency of IRAK4 on TLR5 pathways. The module does not include defective TLR7, TLR8 and TLR9 signaling events, which are associated mostly with viral infections, although studies using patient-derived blood cells showed abolished cytokine production by peripheral blood mononuclear cells (PBMCs) and lack of CD62 ligand (CD62L) shedding from granulocytes in response to TLR7-9 agonists (McDonald DR et al. 2006;von Bernuth H et al. 2006;Ku CL et al. 2007). In addition to the TLR-NFkB signaling axis, endosomic TLR7-9 activates IFN-alpha/beta and IFN-gamma responses and these are also impaired in IRAK4deficient PBMC (Yang K et al. 2005). Nevertheless, IFN-alpha/beta and -gamma production in IRAK-4-deficient blood cells in response to 9 of 11 viruses was normal or weakly affected, suggesting that IRAK-4deficient patients may control viral infections by TLR7-9-independent production of IFNs such as IRAK4independent antiviral RIGI and MDA5 pathways (Yang K et al. 2005). So it is not yet possible to annotate a definitive molecular pathway between IRAK-4 deficiency and changes in TLR7-9 signaling.
However, IFN-alpha/beta and IFN-gamma production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells, suggesting that IRAK-4-deficient patients may control viral infections by TLR7-9-independent production of IFNs (Yang K et al. 2005). So it is not yet possible to annotate a definitive molecular pathway between IRAK-4 deficiency and changes in TLR7-9 signaling.

Literature references
Abel   Abel, L., Li, X., von Bernuth, H., Jin, Z., Camcioglu, Y., Pascal, M. et al. (2008). Pyogenic bacterial infections in humans with MyD88 deficiency. Science, 321, 691-6. ↗   IKBKG is encoded by an X-linked gene. Null alleles of the gene are lethal in hemizygous males, whereas hypomorphic alleles typically result in the impaired NFkB signaling in patients with a broad spectrum of clinical phenotypes in terms of both developmental defects and immunodeficiency (Döffinger R et al. 2001;Hanson EP et al. 2008). Several categories of mutations affecting IKBKG have been reported in humans (Döffinger R et al. 2001;Vinolo E et al. 2006;Fusko F et al. 2008). The first category of these muta-