抗丙型干擾素自體抗體與人類白血球抗原在成人瀰漫性非結核分枝桿菌感染

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Title:	抗丙型干擾素自體抗體與人類白血球抗原在成人瀰漫性非結核分枝桿菌感染 Anti-Interferon-Gamma Autoantibodies and Human Leukocyte Antigens in Adult Patients with Disseminated Non-Tuberculous Mycobacterial Infections
Authors:	齊治宇;Chih-Yu Chi
Contributors:	臨床醫學研究所博士班
Keywords:	抗丙型干擾素自體抗體;非結核分枝桿菌;瀰漫性;人類白血球抗原;anti-interferon gamma autoantibody;non-tuberculous mycobacterium;dissemination;human leukocyte anigens
Date:	2013-12-03
Issue Date:	2014-10-02 09:45:40 (UTC+8)
Publisher:	中國醫藥大學
Abstract:	背景：分枝桿菌可引發形形色色的感染症並且危害人體健康，其中又以肺結核菌所造成的疾病最引人矚目。相對於肺結核菌而言，非結核分枝桿菌通常被認為是環境中的菌種，並且在一般的觀念中也認為這類分枝桿菌較不具有臨床的致病性。然而，隨著醫療技術的進展與免疫受損宿主的增加，非結核分枝桿菌所造成的疾病已漸漸地被醫學界所正視。非結核分枝桿菌所引發的感染通常只侷限在身體的某個部位，只有在少數情況下會造成全身性的散布，也就是所謂的瀰漫性感染。就成人而言，罹患瀰漫性非結核分枝桿菌感染的病患多是肇因於免疫功能缺損。近幾年中，科學家們陸續地發現到抗丙型干擾素自體抗體可能在瀰漫性非結核分枝桿菌感染的過程中扮演了舉足輕重的角色。然而，在詳細檢視這些已發表的文章後，我們不難發現到有相當比例的患者有著自體免疫疾病的問題。除此之外，這些罹病的患者大多屬於亞洲人種。這個現象似乎暗示著某個或者是某些共同的基因存在於這群病患身上。針對過去作者已發表的結果，本研究的主要目的是要釐清以下兩項議題。第一、抗丙型干擾素自體抗體在健康成人感染瀰漫性非結核分枝桿菌的角色。第二、是否有特定的共同基因存在。方法：研究對象主要是針對大於18歲、先前健康但其後感染瀰漫性非結核分枝桿菌的成人。臨床檢體依照現有的標準流程處理。病人及對照組的全血或是週邊血液單核細胞分別在特定的狀況下接受卡介苗疫苗株或是細胞激素的刺激。所產生的細胞激素以酵素免疫分析法測定。聚合酵素鏈鎖反應被用來分析病患身上所具有的人類白血球抗原。統計方法則是採用美國疾病管制及預防中心所提供的統計軟體。結果：我們一共找到19位病患，其中2位患者因提早死亡並未納入本研究計畫中。在納入的17位病患中，9位為男性患者，平均年齡為60歲。淋巴腫(尤其是頸部)是最常見的臨床症候(15/17)，骨髓炎緊接其後。除了分枝桿菌感染之外，35% 與71% 的病患也分別受到沙門氏桿菌與帶狀皰疹的感染。這些病患的血液中都存在著具有生物活性且高親合性的抗丙型干擾素自體抗體(IgG)。兩個特定的對偶基因[DRB116:02 DQB105:02 (odds ratios 8.68, 95% CI: 3.47–21.90, P=1.1×10-6 與7.16, 95% CI: 3.02–17.05, P=1×10-7)] 可以在82 % 的病患身上偵測到。結論：在本研究中我們證實了下列幾件事。第一、對於先前健康但之後發生瀰漫性非結核分枝桿菌感染的成人而言，抗丙型干擾素自體抗體扮演了重要的致病角色。第二、這些自體抗體的存在與特定對偶基因之間有著高度的關聯性。第三、丙型干擾素似乎在控制潛伏性帶狀皰疹病毒的感染上有著一定的角色地位。 Background: Mycobacterial infections, especially those caused by Mycobacterium tuberculosis (TB), make a significant mortality and morbidity in humans. On the other hand, nontuberculous mycobacteria (NTM) are usually regarded as environmental organisms and to be less virulent to humankind. These microorganisms (NTM), however, are increasingly recognized as a human pathogen recently. Infection caused by NTM is usually localized, but rarely disseminated. Adult patients with disseminated nontuberculous mycobacterial (dNTM) infections usually have severe immune system defects, such as malignancy, chronic steroid use, organ transplantation and human immunodeficiency virus infection. Recently, several reports have shown that anti-interferon-γ (IFN-γ) autoantibodies may play an important role in the pathogenicity of dNTM infections. Among those reported cases with anti-IFN-γ autoantibodies, a considerable proportion of them show either clinical or laboratory evidence of autoimmune disease. One other interesting finding in these patients was that the majority of them are of Asian descent, which may suggest the involvement of a common genetic factor. The aims of this study are to clarify the role of anti-IFN-γ autoantibodies in previously healthy individuals with dNTM infections and try to find out the possible genetic factor involved. Methods: Adult patients (age more than 18 years, without co-morbidities) suffered from dNTM infections were enrolled into the current study. Clinical specimens were collected, processed and subsequently incubated in the Mycobacteria Growth Indicator Tube System. Blood samples from patients and donors were also collected and peripheral blood mononuclear cells (PBMC) were obtained by Ficoll-Paque density-gradient centrifugation. Serum cytokines were measured with an enzyme-linked immunoassay using specified human cytokine kits. Mouse anti-human Immunoglobulin G (IgG) was used for autoantibody identification. Human leukocyte antigen (HLA) polymorphisms of target genes were determined using a sequence-based typing (SBT) method. The odds ratio (OR), 95% confidence interval (CI) and 2-tailed P values were obtained using StatCalc (EpiInfo Version 6.0; Centers for Disease Control and Prevention). Results: Nineteen formerly healthy adults who later developed dNTM infections were identified, 2 of whom died before further investigation was possible; therefore, 17 patients were included in the present study. Nine patients (53%) were male and the average age was 60 years. Lymphadenopathy (15/17), particularly of the cervical nodes, was the most common clinical presentation, followed by osteomyelitis (12/17). In addition to dNTM infection, 35% and 71% of our patients also suffered from salmonellosis and herpes zoster, respectively; both types of infections have rarely been reported in previous dNTM infection cases. This observation suggests that IFN-?? may be crucial in controlling salmonella infection and reactivating latent varicella-zoster virus (VZV) infection in humans. High-titer anti-IFN-γ autoantibodies capable of inhibiting interleukin-12 (IL-12) production in vitro were found in the plasma of all of these patients and these autoantibodies belonged to the class of IgG. Two HLA alleles, DRB116:02 DQB105:02 (odds ratios 8.68, 95% CI: 3.47–21.90, P=1.1×10-6, Pc=3.08×10-5 and 7.16, 95% CI: 3.02–17.05, P=1×10-7, Pc=1.4×10-6, respectively), were found in 82 % (14/17) of those patients. Conclusions: Our data suggest that anti-IFN-γ autoantibodies may play a critical role in the pathogenesis of dNTM infections and reactivation of latent varicella-zoster virus infection and are associated with HLA-DRB116:02 and DQB105:02.
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