| Title: |
Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity |
| Authors: |
Israel, L; Wang, Y; Bulek, K; Della Mina, E; Zhang, Z; Pedergnana, V; Chrabieh, M; Lemmens, NA; Sancho-Shimizu, V; Descatoire, M; Lasseau, T; Israelsson, E; Lorenzo, L; Yun, L; Belkadi, A; Moran, A; Weisman, LE; Vandenesch, F; Batteux, F; Weller, S; Levin, M; Herberg, J; Abhyankar, A; Prando, C; Itan, Y; Van Wamel, WJB; Picard, C; Abel, L; Chaussabel, D; Li, X; Beutler, B; Arkwright, PD; Casanova, J-L; Puel, A |
| Source: |
800 ; 789 |
| Publisher Information: |
CELL PRESS |
| Publication Year: |
2017 |
| Collection: |
Imperial College London: Spiral |
| Subject Terms: |
Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Cell Biology; PYOGENIC BACTERIAL-INFECTIONS; STAPHYLOCOCCUS-AUREUS; PRIMARY IMMUNODEFICIENCIES; SIGNAL-TRANSDUCTION; CRYSTAL-STRUCTURE; MYD88 DEFICIENCY; CUTTING EDGE; TIR DOMAIN; TLR2; GENE; LTA; TIRAP; anti-LTA antibodies; incomplete clinical penetrance; lipoteichoic acid; primary immunodeficiency; staphylococcus aureus; toll-like receptors; Developmental Biology; 06 Biological Sciences; 11 Medical And Health Sciences |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
CELL; http://hdl.handle.net/10044/1/45808; https://dx.doi.org/10.1016/j.cell.2017.01.039 |
| DOI: |
10.1016/j.cell.2017.01.039 |
| Availability: |
http://hdl.handle.net/10044/1/45808; https://doi.org/10.1016/j.cell.2017.01.039 |
| Rights: |
© 2017 Elsevier Inc. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.DB06C90E |
| Database: |
BASE |