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Heritable defects of the human TLR signalling pathways

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France, puel{at}necker.fr

Kun Yang

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France, French-Chinese Laboratory of Genetics and Life Sciences, Rui-Jin Hospital, Shanghai University, Shanghai, China

Cheng-Lung Ku

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France

Horst von Bernuth

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France

Jacinta Bustamante

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France

Orchidée Filipe Santos

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France

Tatiana Lawrence

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France

Huey-Hsuan Chang

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France

Hamoud Al-Mousa

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France, Pediatric Hematology-Immunology Unit, Necker Hospital, Paris, France

Capucine Picard

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France, Pediatric Hematology-Immunology Unit, Necker Hospital, Paris, France

Jean-Laurent Casanova

Laboratory of Human Genetics of Infectious Diseases, University of Paris-INSERM U550, Necker Medical School, Paris, France, Pediatric Hematology-Immunology Unit, Necker Hospital, Paris, France

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-B (NF-B) 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-B 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-B- 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.

Key Words: Human TLR signalling • heritable defects • NEMO • IKBA • IRAK4 • anhidrotic ectodermal dysplasia

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