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.

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Keywords anti-LTA antibodies, incomplete clinical penetrance, lipoteichoic acid, LTA, primary immunodeficiency, staphylococcus aureus, TIRAP, toll-like receptors
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Journal Cell
Israel, L. (Laura), Wang, Y. (Ying), Bulek, K. (Katarzyna), Della Mina, E. (Erika), Zhang, Z. (Zhao), Pedergnana, V. (Vincent), … Puel, A. (Anne). (2017). Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity. Cell, 168(5), 789–800.e10. doi:10.1016/j.cell.2017.01.039