Molecular Mechanism of Anti-Interferon-Gamma Autoantibodies Disease in Patients with Nontuberculous Mycobacterial Infection

Molecular Mechanism of Anti-Interferon-gamma Autoantibodies Disease in Patients with Nontuberculous Mycobacterial Infection. Background: Anticytokine autoantibody is new found mechanism to explain the previous idiopathic infectious disease in human adult. Currently a “mimicry molecule” hypothesis has been proposed to explain the break tolerance in human antoimmune diseases. In this theory, the immune tolerance might be broken by microorganisms due to the similarity between microbial peptides and self-antigens. Recently, anti-interferon-gamma (IFN-γ) autoantibodies have been demonstrated in adult patients with severe nontuberculous mycobacteria (NTM) infection, and the phenotype presented in these adult patients is very similar to that observed in those children with inborn genetic deficiency of IFN-γ receptor 1 and receptor 2. There are 21 adult patients with anti- IFN-γ autoantibodies found world-wide; however, the molecular mechanism in the generation of autoantibodies to IFN-γ is largely unknown. The majority of patients with anti-IFN-γ autoantibodies are Asia descent and this observation strongly suggests that there is a gene-based association, such as a certain HLA allele. We have found 13 Taiwanese/Han patients with anti-IFN-γ autoantibodies, and our patients present very unique manifestations: severe NTM and salmonella infections, normal immunological profile and absence of clinical signs or laboratory evidences of autoimmune diseases. Nevertheless, we had found a common HLA haplotype HLA-DR in 9 of 10 patients analyzed with a significant P value ＜10-7. Our data suggest that patients with anti-IFN-γ autonatibodies have a strong genetic factor and might have a general and common etiology to develop this unique infectious disease. Various HLA haplotypes and infectious diseases have been linked to numerous autoimmune diseases in human. Aims: We are interested in studying the molecular basis of development of anti-IFN-γ autoantibodies among patients with severe NTM infections and keen to develop a novel therapeutic strategy based on the molecular mechanisms of these autoantibodies. In our project, there are two main goals will be clarified: (1) if the development of anti-IFN-γ autoantibody is induced by “mimicry molecule” mechanism (2) to establish a proof of principle alternative therapeutic strategy to anti-IFN-γ autoantibodies and other anticytokine autoantibodies diseases. Experiment Desgin: We are planning to (1) determinate the epitope of anti-IFN-γ autoantibodies (2) identify the potential mimicry antigen from microbes. (3) design a therapeutic mutant IFN-γ for treating these patients. By EB virus-immortalized method, we are also planning to establish the anti-IFN-γ autoantibody producing B-cell lines from patients to get high purity anti-IFN-γ autoantibodies as a critical material in for these purposes. Expected Results: We expect that the anti-IFN-γ autoantibodies will recognize a specific region in this cytokine and we will identify the origin mimicry molecule from pathogen, these data will be a solid evidence to explain the association between HLAs and infectious diseases. Exposure to certain specific microorganisms might help to explain the role of environmental factor and the high prevalence rate of anti-IFN-γ autoantibodies in Taiwanese with this particular disease. Finally, we are planning to establish a proof of principle model to treat the anticytokine autoantibodies-related diseases.

Project ID:PC10007-1138
External Project ID:NSC100-2314-B182-050