MyD88 deficiency (TLR2/4)

Stable Identifier
Homo sapiens
Related Species
Chlamydia trachomatis, Neisseria meningitidis serogroup B
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Myeloid differentiation primary response (MyD88) is an adaptor protein that mediates intracellular signaling pathways evoked by all Toll-like receptors (TLRs) except for TLR3 and by several interleukin-1 receptors (IL-1Rs) (Medzhitov R et al. 1998). Upon ligand binding, TLRs hetero- or homodimerize and recruit MyD88 through their respective TIR domains. Then, MyD88 oligomerizes via its death domain (DD) and TIR domain and interacts with the interleukin-1 receptor-associated kinases (IRAKs) to form the Myddosome complex (MyD88:IRAK4:IRAK1/2) (Motshwene PG et al. 2009; Lin SC et al. 2010). The Myddosome complex transmits the signal leading to activation of transcription factors such as nuclear factor-kappaB (NFkB) and activator protein 1 (AP1).

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.

Literature References
PubMed ID Title Journal Year
15069402 Primary immunodeficiency to pneumococcal infection due to a defect in Toll-like receptor signaling

Devon, RS, Reid, GS, Currie, AJ, MacDonald, KL, Speert, DP, Bharya, S, Davidson, DJ

J. Pediatr. 2004
24316379 Functional assessment of the mutational effects of human IRAK4 and MyD88 genes

Kondo, N, Shirakawa, M, Ohnishi, H, Tochio, H, Kato, Z, Tsutsumi, N, Kubota, K, Yamamoto, T

Mol. Immunol. 2014
18669862 Pyogenic bacterial infections in humans with MyD88 deficiency

Abel, L, Li, X, von Bernuth, H, Jin, Z, Camcioglu, Y, Pascal, M, Sirvent, N, Alsina, L, Guedes, M, Antón, J, Fortuny, C, Ruiz-Ortiz, E, Herrero-Mata, MJ, Vasconcelos, J, Banchereau, J, Mustapha, IB, Yagüe, J, Aróstegui, JI, Janniere, L, Rodrigo, C, Chaussabel, D, Pankla, R, Issekutz, A, Ku, CL, Chrabieh, M, Rodriguez-Gallego, C, Garty, BZ, Puel, A, Chang, HH, Picard, C, Xiao, H, Maródi, L, Juan, M, Ghandil, P, Chapel, H, Vitor, AB, Casanova, JL, Rose, Y

Science 2008
Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
Cross References
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