title: Heritable defects of the human TLR signalling pathways.
abstract: Recently, three human primary immunodeficiencies associated with impaired TLR signalling were described. 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. More recently, patients with 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. These data, therefore, suggest that TLRs 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.
authors.affiliation: University of Paris-INSERM U550, Necker Medical School, Paris, France. puel@necker.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Ku
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Orchidée Filipe
authors.initials: OF
authors.lastname: Santos
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lawrence
authors.forename: Huey-Hsuan
authors.initials: HH
authors.lastname: Chang
authors.forename: Hamoud
authors.initials: H
authors.lastname: Al-Mousa
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000276:immunology*; D040181:Genetic Diseases, X-Linked / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000502:physiology*; D018448:Models, Immunological; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors
chemical_list: D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors