Human adaptive immunity rescues an inborn error of innate immunity

• Laura Israel ^[1] ; Ying Wang ^[2] ; Katarzyna Bulek ^[3]
  1. [1] French Institute of Health and Medical Research

     French Institute of Health and Medical Research

     París, Francia

     
  2. [2] University of Texas Southwestern Medical Center

     University of Texas Southwestern Medical Center

     Estados Unidos

     
  3. [3] Cleveland Clinic Foundation

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• Localización: Cell, ISSN 0092-8674, Vol. 168, Nº. 5, 2017, págs. 789-800
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • 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.