title: Novel primary immunodeficiencies revealed by the investigation of paediatric infectious diseases.
abstract: Human primary immunodeficiencies impairing myeloid and/or lymphoid cellular responses to activating receptors other than antigen receptors have recently been described in children with various infectious diseases. Germline mutations in NEMO and IKBA impair NF-kappaB-mediated signalling, at least in response to the stimulation of TLRs, IL-1Rs and TNFRs, and confer a broad predisposition to infections. Mutations in IRAK4 selectively impair TLRs other than TLR3 and most IL-1R responses, and confer a predisposition to pyogenic bacterial diseases, including invasive pneumococcal disease in particular. Mutations in TLR3 and UNC93B1 impair TLR3 responses and confer a predisposition to herpes simplex encephalitis. Mutations in STAT1 impair IFN-gamma and/or IFN-alpha/beta responses and predispose subjects to mycobacterial and viral diseases, respectively. Mutations in IFNGR1 and IFNGR2 impair IFN-gamma responses and confer a predisposition to mycobacterial diseases. Mutations in IL12B and IL12RB1 impair IL-12 and IL-23 responses and predispose subjects to infections caused by mycobacteria and Salmonella. Finally, mutations in TYK2 and STAT3 mostly impair IL-6R responses, conferring a predisposition to staphylococcal disease in particular. The infectious phenotypes associated with these novel leukocyte activation deficiencies are therefore collectively diverse, tightly dependent on the morbid gene and affected pathway, and individually narrow, often restricted to one or a few infectious diseases.
authors: Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM-U550, Paris 75015, France, EU.
authors: Jacinta
authors: J
authors: Bustamante
authors: Stéphanie
authors: S
authors: Boisson-Dupuis
authors: Emmanuelle
authors: E
authors: Jouanguy
authors: Capucine
authors: C
authors: Picard
authors: Anne
authors: A
authors: Puel
authors: Laurent
authors: L
authors: Abel
authors: Jean-Laurent
authors: JL
authors: Casanova
mesh_terms: D002648:Child; D016207:Cytokines / Q000378:metabolism; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000276:immunology; D018095:Germ-Line Mutation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D007239:Infections / Q000235:genetics* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D050794:STAT1 Transcription Factor; D051193:Toll-Like Receptors