Israel Laura, Wang Ying, Bulek Katarzyna, Della Mina Erika, Zhang Zhao, Pedergnana Vincent, Chrabieh Maya, Lemmens Nicole A, Sancho-Shimizu Vanessa, Descatoire Marc, Lasseau Théo, Israelsson Elisabeth, Lorenzo Lazaro, Yun Ling, Belkadi Aziz, Moran Andrew, Weisman Leonard E, Vandenesch François, Batteux Frederic, Weller Sandra, Levin Michael, Herberg Jethro, Abhyankar Avinash, Prando Carolina, Itan Yuval, van Wamel Willem J B, Picard Capucine, Abel Laurent, Chaussabel Damien, Li Xiaoxia, Beutler Bruce, Arkwright Peter D, Casanova Jean-Laurent, Puel Anne
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA.
Cell. 2017 Feb 23;168(5):789-800.e10. doi: 10.1016/j.cell.2017.01.039.
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.
单基因疾病不完全外显的分子基础尚不清楚。我们在此描述了8名患有常染色体隐性TIRAP缺陷的相关个体。先证者在儿童期发生了危及生命的葡萄球菌疾病，但其他7名纯合子未出现。所有TIRAP缺陷个体的成纤维细胞和白细胞对所有Toll样受体1/2（TLR1/2）、TLR2/6和TLR4激动剂的反应均受损。然而，仅在索引病例个体（唯一缺乏LTA特异性抗体（Abs）的家庭成员）中，全血对TLR2/6激动剂葡萄球菌脂磷壁酸（LTA）的反应被消除。抗LTA单克隆抗体（mAb）可使患者的这种缺陷反应得到逆转，但不能使白细胞介素-1受体相关激酶4（IRAK-4）缺陷个体的反应得到逆转。抗LTA mAb还挽救了缺乏TIRAP但不缺乏TLR2或MyD88的小鼠的巨噬细胞反应。因此，获得性抗LTA Abs可挽救遗传性TIRAP缺陷个体对葡萄球菌LTA的TLR2依赖性免疫，这解释了不完全外显的原因。TIRAP和抗LTA Ab联合缺陷是该患者葡萄球菌疾病的基础。
