口腔鏈球菌所引起的感染性心內膜炎中嗜中性白血球胞外網狀結構的形成及其在自體抗體生成所扮演的角色

Abstract

外來病原菌感染在自體免疫疾病的發生扮演的重要的角色，如：風濕熱(rheumatic fever)或Guillaine-Barre’ syndrome。感染性心內膜炎(Infective endocarditis, IE) 是一種高死亡率，及高復發率的感染症，主要由葡萄球菌及口腔鏈球菌，如：轉糖鏈球菌(Streptococcus mutans)所引起。感染性心內膜炎患者常伴隨不正常的免疫學表現 ，如腎絲球腎炎、Osler nodes及Roth spots。由臨床的統計發現口鏈球菌引起之擴散性全身性感染的患者(包含感染性心內膜炎患者)，體內可偵測到多種自體抗體的生成。近年來在全身性紅斑性狼瘡(Systemic lupus erythematosus, SLE)的研究指出，嗜中性白血球釋放的嗜中性白血球胞外網結構(neutrophil extracellular traps, NETs)可做為一種自體抗原刺激自體抗體的產生。實驗室先前的研究發現，NETs會存在於感染性心內膜炎大鼠瓣膜的贅疣中。故本篇研究便是要去探討NETs在口鏈球菌引起之擴散性全身性感染(包含感染性心內膜炎)的患者的自體抗體生成中所所扮演的角色。研究結果發現，在擴散性全身性感染(包含感染性心內膜炎)的患者可偵測到抗NET s抗體的生成；並且也在轉糖鏈球菌感染造成之菌血症及感染性心內膜炎大鼠體內偵測到抗雙股去氧核醣核酸抗體及抗牛心脂抗體生成。免疫螢光染色的結果顯示，擴散性全身性感染(包含感染性心內膜炎)的患者而非菌血症大鼠的血清可以和人類NETs反應。另一方面，利用特定抗血清去除大鼠的嗜中性白血球發現，感染性心內膜炎大鼠的贅疣上NETs的形成有減少的現象；在菌血症大鼠也發現，體內抗體生成的情形也有降低的情形。本篇的研究結果顯示，在口腔鏈球菌感染之全身性擴散性感染的病人中，NETs在自體抗體產生扮演了重要的角色；而菌血症的大鼠中，轉糖鏈球菌的感染可以引起自體抗體的生成。

Infections play important roles in triggering autoimmune diseases, as found in rheumatic fever or Guillaine-Barre’ syndrome. Infective endocarditis (IE), with highly mortality and recurrent rates, is caused primarily by staphylococci and oral streptococci (including Streptococcus mutans). IE is frequently accompanied with immunopathological manifestations such as glomerulonephritis, Osler nodes, or Roth spots. Our previous study found that autoantibody production could be detected in patients with disseminated systemic infections caused by oral streptococci, including IE. Neutrophil extracellular traps (NETs) could act as autoantigens to induce autoantibody production in Systemic lupus erythematosus (SLE). We have also identified in the rat endocarditis model the existence of NETs in vegetations. The specific aim of this study is to investigate if NETs are involved in autoantibody production disseminated systemic infections and IE. The production of anti-NETs -dsDNA or -cadiolipin antibodies could be detectable in patients with disseminated systemic infections and also in the experimental rat models of bacteremia or IE. The serum from the patient, but not from the infected rats, could react with human NETs, suggesting the specificity of the anti-NETs antibody. By using specific anti-PMN antibody to deplete the neutrophils, the NETs formation was reduced in the rat IE experimental model and the autoantibody production was also reduced in the rats with bacteremia. Taken together, these data suggest NETs played important role in autoantibody production in patients with disseminated systemic infections, and the autoantibodies production was induced in rat with S. mutans infection.