Three human primary immunodeficiencies associated with impaired TLR signalling were described. A
Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), either X-linked recessive or autosomal dominant, is caused by hypomorphic mutations in NEMO or hypermorphic mutation in IKBA, respectively, both involved in nuclear factor-kappaB (NF-kappaB) activation. These patients present with abnormal development of ectoderm-derived structures and suffer from a broad spectrum of infectious diseases. In vitro studies of the patients’ cells showed an impaired, but not abolished, NF-kappaB activation in response to a large set of stimuli, including TLR agonists.
Autosomal recessive amorphic mutations in IRAK4 have been reported, presenting no developmental defect and a more restricted spectrum of infectious diseases, mostly caused by pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive. In vitro studies carried out with these patients’ cells showed a specific impairment of the Toll-interleukin-1 receptor (TIR)-interleukin-1 receptor associated kinase (IRAK) signalling pathway.
NF-kappaB- and mitogen activated protein kinase (MAPK) pathways are impaired in response to all TIR agonists tested.
TLRs could play a critical role in host defence against pyogenic bacteria, but may be dispensable or redundant for immunity to most other infectious agents in humans.
References
Puel A, Yang K, Ku CL, von Bernuth H, Bustamante J, Santos OF, Lawrence T, Chang HH, Al-Mousa H, Picard C, Casanova JL. Heritable defects of the human TLR signalling pathways. J Endotoxin Res. 2005;11(4):220-4. PMID: 16176658
Ku CL, Yang K, Bustamante J, Puel A, von Bernuth H, Santos OF, Lawrence T, Chang HH, Al-Mousa H, Picard C, Casanova JL. Inherited disorders of human Toll-like receptor signaling: immunological implications. Immunol Rev. 2005 Feb;203:10-20. PMID: 15661018