Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Department of Pediatric Hematology-Oncology, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands;
Blood. 2015 Mar 12;125(11):1793-802. doi: 10.1182/blood-2014-05-579110. Epub 2014 Dec 29.
Immune-mediated platelet destruction is most frequently caused by allo- or autoantibodies via Fcγ receptor-dependent phagocytosis. Disease severity can be predicted neither by antibody isotype nor by titer, indicating that other factors play a role. Here we show that the acute phase protein C-reactive protein (CRP), a ligand for Fc receptors on phagocytes, enhances antibody-mediated platelet destruction by human phagocytes in vitro and in vivo in mice. Without antiplatelet antibodies, CRP was found to be inert toward platelets, but it bound to phosphorylcholine exposed after oxidation triggered by antiplatelet antibodies, thereby enhancing platelet phagocytosis. CRP levels were significantly elevated in patients with allo- and autoantibody-mediated thrombocytopenias compared with healthy controls. Within a week, intravenous immunoglobulin treatment in children with newly diagnosed immune thrombocytopenia led to significant decrease of CRP levels, increased platelet numbers, and clinically decreased bleeding severity. Furthermore, the higher the level of CRP at diagnosis, the longer it took before stable platelet counts were reached. These data suggest that CRP amplifies antibody-mediated platelet destruction and may in part explain the aggravation of thrombocytopenia on infections. Hence, targeting CRP could offer new therapeutic opportunities for these patients.
免疫介导的血小板破坏最常由通过 Fcγ 受体依赖性吞噬作用的同种异体或自身抗体引起。疾病的严重程度既不能由抗体同种型也不能由滴度来预测，这表明其他因素起作用。在这里，我们表明，急性反应蛋白 C 反应蛋白（CRP），吞噬细胞上 Fc 受体的配体，增强了人类吞噬细胞在体外和体内在小鼠中抗体介导的血小板破坏。在没有抗血小板抗体的情况下，CRP 对血小板没有活性，但它与抗血小板抗体触发的氧化后暴露的磷酸胆碱结合，从而增强血小板吞噬作用。与健康对照组相比，同种异体和自身抗体介导的血小板减少症患者的 CRP 水平显着升高。在儿童新诊断的免疫性血小板减少症中，静脉内免疫球蛋白治疗在一周内导致 CRP 水平显著降低，血小板数量增加，临床出血严重程度降低。此外，在诊断时 CRP 水平越高，达到稳定血小板计数所需的时间就越长。这些数据表明 CRP 放大了抗体介导的血小板破坏，并且可能部分解释了感染时血小板减少症的加重。因此，针对 CRP 可能为这些患者提供新的治疗机会。
