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Cell. 2017 Feb 23;168(5):789-800.e10. doi: 10.1016/j.cell.2017.01.039.

Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity.

Author information

1
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
2
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA.
3
Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44106, USA.
4
Medical Microbiology and Infectious Diseases, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
5
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.
6
INSERM U1151-CNRS UMR 8253, Paris Descartes University, Necker-Enfants Malades Medical School-Broussais, 75014 Paris, France.
7
Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
8
Greater Manchester Immunology Service, Manchester Royal Infirmary, Manchester, M13 9WL, UK.
9
Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
10
French National Reference Center for Staphylococci, Hospices Civils of Lyon, 69677 Bron Cedex, France.
11
Department of Biological Immunology, Cochin Hospital, 75679 Paris, France.
12
Section for Paediatrics, Department of Medicine, Imperial College London, London W21 PG, UK.
13
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
14
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.
15
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.
16
University of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WL, UK.
17
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.
18
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.

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.

KEYWORDS:

LTA; TIRAP; anti-LTA antibodies; incomplete clinical penetrance; lipoteichoic acid; primary immunodeficiency; staphylococcus aureus; toll-like receptors

Comment in

PMID:
28235196
PMCID:
PMC5328639
DOI:
10.1016/j.cell.2017.01.039
[Indexed for MEDLINE]
Free PMC Article

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