Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis
Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis
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DOI：
10.1172/jci57522
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
van de Beek, Diederik
中科院分区：
文献类型：
--
作者：
Woehrl, Bianca;Brouwer, Matthijs C.;van de Beek, Diederik
肺炎球菌脑膜炎是细菌性脑膜炎最常见和最严重的形式。死亡率很高，大约一半的幸存者会出现长期后遗症。疾病转归与蛛网膜下腔促炎症反应的严重程度有关。补体系统介导关键的炎症过程，在动物研究中被认为是肺炎球菌脑膜炎疾病严重程度的调节因子。此外，编码补体途径蛋白的基因中的SNPs与肺炎球菌感染的易感性有关，尽管尚未建立与疾病严重程度或预后的关联。在这里，我们在细菌性脑膜炎患者中进行了一项强有力的前瞻性全国遗传关联研究，发现常见的非同义补体成分5(C5)SNP(Rs17611)与不良疾病结局相关。细菌性脑膜炎患者脑脊液中C5片段水平与预后不良的多项临床指标相关。与这些人类数据一致的是，与WT小鼠相比，患有肺炎球菌脑膜炎的C5a受体缺陷小鼠的脑脊液白细胞计数较低，脑损伤也较少。用C5特异性单抗辅助治疗可防止所有肺炎球菌脑膜炎小鼠死亡。因此，我们的结果表明，C5特异性单抗可能是一种有前途的肺炎球菌脑膜炎的抗炎辅助治疗方法。
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5 a receptor-deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis.