Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity

Laura Israel, Ying Wang, Katarzyna Bulek, Erika Della Mina, Zhao Zhang, Vincent Pedergnana, Maya Chrabieh, Nicole A. Lemmens, Vanessa Sancho-Shimizu, Marc Descatoire, Théo Lasseau, Elisabeth Israelsson, Lazaro Lorenzo, Ling Yun, Aziz Belkadi, Andrew Moran, Leonard E. Weisman, François Vandenesch, Frederic Batteux, Sandra WellerMichael Levin, Jethro Herberg, Avinash Abhyankar, Carolina Prando, Yuval Itan, Willem J.B. van Wamel, Capucine Picard, Laurent Abel, Damien Chaussabel, Xiaoxia Li, Bruce Beutler, Peter D. Arkwright, Jean Laurent Casanova, Anne Puel

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)789-800.e10
Issue number5
StatePublished - Feb 23 2017


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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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