TY - JOUR
T1 - Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity
AU - Israel, Laura
AU - Wang, Ying
AU - Bulek, Katarzyna
AU - Della Mina, Erika
AU - Zhang, Zhao
AU - Pedergnana, Vincent
AU - Chrabieh, Maya
AU - Lemmens, Nicole A.
AU - Sancho-Shimizu, Vanessa
AU - Descatoire, Marc
AU - Lasseau, Théo
AU - Israelsson, Elisabeth
AU - Lorenzo, Lazaro
AU - Yun, Ling
AU - Belkadi, Aziz
AU - Moran, Andrew
AU - Weisman, Leonard E.
AU - Vandenesch, François
AU - Batteux, Frederic
AU - Weller, Sandra
AU - Levin, Michael
AU - Herberg, Jethro
AU - Abhyankar, Avinash
AU - Prando, Carolina
AU - Itan, Yuval
AU - van Wamel, Willem J.B.
AU - Picard, Capucine
AU - Abel, Laurent
AU - Chaussabel, Damien
AU - Li, Xiaoxia
AU - Beutler, Bruce
AU - Arkwright, Peter D.
AU - Casanova, Jean Laurent
AU - Puel, Anne
PY - 2017/2/23
Y1 - 2017/2/23
N2 - 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.
AB - 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.
KW - LTA
KW - TIRAP
KW - anti-LTA antibodies
KW - incomplete clinical penetrance
KW - lipoteichoic acid
KW - primary immunodeficiency
KW - staphylococcus aureus
KW - toll-like receptors
UR - http://www.scopus.com/inward/record.url?scp=85014006510&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014006510&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2017.01.039
DO - 10.1016/j.cell.2017.01.039
M3 - Article
C2 - 28235196
AN - SCOPUS:85014006510
VL - 168
SP - 789-800.e10
JO - Cell
JF - Cell
SN - 0092-8674
IS - 5
ER -