Anti-Interferon-Gamma Autoantibodies and Human Leukocyte Antigens in Adult Patients with Disseminated Non-Tuberculous Mycobacterial Infections

• Main Authors: Chih-Yu Chi, 齊治宇
• Other Authors: 李繼源
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/67921786617816480661

博士 === 中國醫藥大學 === 臨床醫學研究所博士班 === 102 === 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, DRB1*16:02 DQB1*05:02 (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-DRB1*16:02 and DQB1*05:02.