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Loss of BTK function causes X-linked agammaglobulinemia (XLA), a rare primary immunode?ciency disease with severe defects in early B-cell development resulting in an almost complete absence of peripheral B cells and severely reduced serum levels of immunoglobulins of all classes (Väliaho J et al. 2006). Affected individuals suffer from recurrent bacterial and enteroviral infections. It remains unclear whether XLA patients have normal or impared TLR signaling functions. LPS-stimulated monocytes from XLA patients were found to produce reduced amounts of TNFalpha (Horwood NJ et al. 2003), These data contradict a study that showed enhanced amounts of TNFalpha and IL6 comparing to control cells, starting at 6 hours and extending for 48 hours (Marron TU et al. 2012). The other group reported similar expression TNFalpha upon TLR4 triggering, compared with healthy control cells (Perez de Diego R et al. 2006). Thus, the effect of BTK deficiency on TLR-mediated inflammation needs to be further clarified.
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 interaction 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 IRAK4-deficient 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-4-deficient patients may control viral infections by TLR7-9-independent production of IFNs such as IRAK4-independent 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.
Studies have identified patients with autosomal recessive (AR) form of MyD88 deficiency caused by homozygous or compound heterozygous mutations in MYD88 gene leading to abolished protein production (von Bernuth et al. 2008). AR MyD88 deficiency is a type of a primary immunodeficiency characterized by greater susceptibility to pyogenic bacteria (such as Streptococcus pneumoniae, Staphylococcus aureus or Pseudomonas aeruginosa) manifested in infancy and early childhood. Patients with MyD88 deficiency show delayed or weak signs of inflammation (Picard C et al. 2010; Picard C et al. 2011).
Functional assessment of MyD88 deficiency revealed that cytokine responses were impaired in patient-derived blood cells upon stimulation with the agonists of TLR2 and TLR4 (PAM2CSK4 and LPS respectively), although some were produced in response to LPS. (von Bernuth et al. 2008). NFkB luciferase reporter gene assays using human embryonic kidney 293 (HEK293T) cells showed that MyD88 variants, S34Y, E52del, E53X, L93P, R98C, and R196C, were compromised in their ability to enhance NFkB activation (Yamamoto T et al. 2014). The molecular basis for the observed functional effects (reported for selected mutations) probably faulty Myddosome formation due to impaired MyD88 oligomerization and/or interaction with IRAK4 (George J et al. 2011; Nagpal K et al. 2011; Yamamoto T et al. 2014).
While MyD88-deficiency might be expected to perturb MyD88?IRAK4 dependent TLR7 and TLR8 signaling events associated with the sensing viral infections, patients with MyD88 and IRAK4 deficiencies have so far not been reported to be susceptible to viral infection.