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
N1 - Funding Information:
We thank the patient and her family for participating in the study and all the members of both branches of the laboratory for discussions. We thank J. Bustamante and S.Y. Zhang for providing the plasma samples and S. Fahy, J. Flatot, M. Courat, L. Amar, and Y. Nemiroskaya for their assistance. We also thank R. Desvaux and N. Goudin for their help at the imaging platform. We thank Biosynexus for providing us with pagibaximab (anti-LTA Ab). The Laboratory of Human Genetics of Infectious Diseases is supported by INSERM, Paris Descartes University, the Imagine Institute, ANR-10-LABX-62-IBEID, ANR-2012-BSV3-0003-02, ANR-10-IAHU-01, the St. Giles Foundation, the National Center for Research Resources, the National Center for Advancing Sciences (NCATS) grant number 8UL1TR000043 from the NIH, and The Rockefeller University. This work was partly supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115523, COMBACTE, from the European Union's FP7/2007-2013 and EFPIA. L.I. was supported by Fondation pour la Recherche M?dicale. C. Prando was supported by the Thrasher Research Fund, and Y.I. was supported by the AXA Research Fund.
Publisher Copyright:
© 2017 Elsevier Inc.
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
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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 -