MyD88 deficiency (TLR5)

Stable Identifier
Homo sapiens
Related Species
Escherichia coli
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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 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 invasive pneumococcal disease manifested in infancy and early childhood. Patients with MyD88-deficiency show delayed or weak signs of inflammatory responses (Picard C et al. 2010; Picard C et al. 2011).

Functional assessment of MyD88 deficiency revealed that cytokine responses were abolished in patient-derived blood cells upon stimulation with bacterial flagellin, which is recognized by TLR5 (von Bernuth et al. 2008). An NFkB luciferase reporter gene assay using human embryonic kidney 293 (HEK293T) cells showed that MyD88 variants, S34Y, E52del, E53X, L93P, R98C, and R196C, were compromised in the 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 in the endosome, 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
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
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