摘要:感染是調控自體免疫疾病發展的重要環境因子,例如 rheumatic feve 或Guillaine-Barre´ syndrome 的致病被認為與細菌感染有關。感染性心內膜炎(Infectiveendocarditis)是一種主要由口腔鏈球菌(如 S. mutans, S. sanguinis, S. mitis/oralis)或葡萄球菌(如 S. aureus or S. epidermidis)在心臟上所引起的一種具有高致死率及再復發率的感染性疾病,並常伴隨著如 glomerulonephritis, Osler nodes, Roth spots 等免疫病理病徵的發生。我們初步的結果發現到在感染性心內膜炎及其他的全身性細菌感染的病患中,可偵測到大幅自體抗體的增加,包含抗雙股去氧核醣核酸(dsDNA)、抗磷脂質(phospholipids)及抗嗜中性白血球胞外網狀結構(neutrophil extracellular traps, NETs)等的自體免疫抗體;而在本次計畫中我們提出兩種可能的分子機制,第一是由細菌感染所引起的抗嗜中性白血球胞外網狀結構,可能作為自體免疫抗原,在感染性心內膜炎及其他的全身性細菌感染中會刺激自體免疫抗體的產生;第二是自體免疫疾的病人體內的抗磷脂質自體免疫抗體可能造成非細菌引起的血栓心內膜炎(nonbacterial thrombotic endocarditis, NBTE)的產生,可讓細菌附著進一步造成感染性心內膜炎;因此,為了研究在全身性細菌感染所造成的疾病,包含感染性心內膜炎中,自體免疫抗體產生的分子機制,我們提出的目標及實驗設計為:1. 在活體中研究嗜中性白血球胞外網狀結構在全身性細菌感染疾病引發自體免疫抗體產生所扮演的角色。2. 探討針對嗜中性白血球胞外網狀結構產生自體免疫抗體的分子機制。3. 建立抗磷脂質症候群的小鼠模型,並研究自體免疫抗體在感染性心內膜炎的致病機轉中所扮演的角色。在本計畫中,我們將探討在感染性心內膜炎中及其他全身性細菌感染疾病自體免疫抗體產生的分子機制,其在研究感染性疾病領域中是個全新的研究方向;此外,我們將與台大醫院感染科的專家們進行感染性心內膜炎中及其他全身性細菌感染疾病臨床檢體的收集,並分析這些病人的臨床特徵;我們可預期,由本計畫所得到的結果將在感染性疾病,包含感染性心內炎的免疫致病機轉提供重要的資訊。
Abstract: Infections are major players in the environmental factors which modulate thedevelopment of autoimmune diseases, as found in rheumatic fever or Guillaine-Barre´syndrome that is associated with bacterial infections. Infective endocarditis (IE) is aninfectious disease, with high mortality and recurrent rates, caused primarily by commensaloral Streptococci (S. mutans, S. sanguinis, S. mitis/oralis), or Staphylococci (S. aureus or S.epidermidis) on the heart valves. IE is also accompanied with immunopathologicalmanifestations such as glomerulonephritis, Osler nodes, Roth spots, etc. Our preliminaryresults showed that in patients with commensal oral Streptococci induced IE or disseminatedsystemic infections, a marked increase in auto-antibody production against dsDNA,phospholipid and neutrophil extracellular traps (NETs) was found. Two hypothetic molecularmechanisms have been proposed in this proposal. The first is the NETs production induced bybacterial infection could serve as autoantigen to induce autoantibody production indisseminated systemic infections, including IE. The second is the presence of antiphospholipidautoantibodies may predispose nonbacterial thrombotic endocarditis (NBTE) formation,which could serve as colonization site for bacteria to cause IE. Therefore, in order toinvestigate the molecular mechanism of autoantibody production in disseminated systemicinfection, including IE, the specific aims and the experimental designs will be:1. Investigation of the roles of NETs in the induction of autoantibody production indisseminated systemic infection in vivo2. Elucidation of the underlying molecular mechanism of the production of autoantibodiesagainst NETs3. Establishment of the mouse model with antiphospholipid syndrome (APS) to investigatethe roles of autoantibodies in the pathogenesis of IEIn this proposal, we will elucidate the molecular mechanism of autoantibody productionin IE and in other disseminated systemic infections cause by oral streptococci, which is anovel insight in the study of the infectious disease. Furthermore, we will cooperate with thespecialists in the department of infectious disease in National Taiwan University Hospital(NTUH) to collect the clinical samples form patients with IE and other disseminated systemicinfections, and analyze the clinical characteristics of these patients. Results obtained from thisproposal will offer significant information for the immuno-pathogenesis of infectious disease,including IE.