title: Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity.
abstract: The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Israel
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44106, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Della Mina
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Pedergnana
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Chrabieh
authors.affiliation: Medical Microbiology and Infectious Diseases, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Lemmens
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; Department of Virology, Imperial College London, Norfolk Place, London W21 PG, UK; Section for Paediatrics, Department of Medicine, Imperial College London, London W21 PG, UK.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Sancho-Shimizu
authors.affiliation: INSERM U1151-CNRS UMR 8253, Paris Descartes University, Necker-Enfants Malades Medical School-Broussais, 75014 Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Descatoire
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Théo
authors.initials: T
authors.lastname: Lasseau
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Israelsson
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Lazaro
authors.initials: L
authors.lastname: Lorenzo
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Ling
authors.initials: L
authors.lastname: Yun
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: Greater Manchester Immunology Service, Manchester Royal Infirmary, Manchester, M13 9WL, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Moran
authors.affiliation: Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Leonard E
authors.initials: LE
authors.lastname: Weisman
authors.affiliation: French National Reference Center for Staphylococci, Hospices Civils of Lyon, 69677 Bron Cedex, France.
authors.forename: François
authors.initials: F
authors.lastname: Vandenesch
authors.affiliation: Department of Biological Immunology, Cochin Hospital, 75679 Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Batteux
authors.affiliation: INSERM U1151-CNRS UMR 8253, Paris Descartes University, Necker-Enfants Malades Medical School-Broussais, 75014 Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Weller
authors.affiliation: Section for Paediatrics, Department of Medicine, Imperial College London, London W21 PG, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.affiliation: Section for Paediatrics, Department of Medicine, Imperial College London, London W21 PG, UK.
authors.forename: Jethro
authors.initials: J
authors.lastname: Herberg
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Prando
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: Medical Microbiology and Infectious Diseases, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Willem J B
authors.initials: WJB
authors.lastname: van Wamel
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; Pediatric Hematology-Immunology Unit, Assistance Publique Hôpitaux de Paris, Necker Hospital, 75015 Paris, France; Study Center for Primary Immunodeficiencies, AP-HP, Necker Hospital, 75015 Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44106, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: University of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WL, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Pediatric Hematology-Immunology Unit, Assistance Publique Hôpitaux de Paris, Necker Hospital, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: jean-laurent.casanova@rockefeller.edu.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Electronic address: anne.puel@inserm.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
mesh_terms: D056704:Adaptive Immunity; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D002648:Child; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D009000:Monocytes / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010375:Pedigree; D010586:Phagocytes / Q000378:metabolism; D017354:Point Mutation; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D013682:Teichoic Acids / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D020033:Protein Isoforms; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495342:TLR2 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; C009900:lipoteichoic acid
keywords: LTA; TIRAP; anti-LTA antibodies; incomplete clinical penetrance; lipoteichoic acid; primary immunodeficiency; staphylococcus aureus; toll-like receptors