Pathogenesis of Anti-Interferon-Gamma Autoantibodies Diseases

Background: Anticytokine autoantibody is new found mechanism to explain the previous idiopathic infectious disease in human adult. Anti-IFN- autoantibodies (autoAbs) 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 genetic deficiency of IFN- receptors. We have observed high prevalence of anti-IFN- autoAbs and identified more than 25 Taiwanese/Han patients. These data suggested anti-IFN- autoAbs are a common mechanism to explain the NTM infection in Taiwan and patient number is highly under-estimated; our observation was supported by one other studying in both Taiwan and Thailand population. 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 HLA haplotype DRB1*16:02 and DQB1*05:02 was strong associated with production of anti-IFN- autoAbs. This important finding suggested a particular mechanism of break tolerance to produce anti-IFN- autoAbs. Moreover, half of patients suffered from chronic and severe NTM infection even with available anti-mycobacterial antibiotic treatment; development of new treatment of NTM infection is urgent needed. However, the molecular mechanisms of anti-IFN- autoAbs disease, including the autoantibodies epitope, the neutralizing mechanism and possible mechanism of the generation of autoantibodies, are never been studied. Aims: We are interested in studying the molecular feature of anti-IFN- autoAbs and developing new therapeutic strategy. In this proposal, there are four main goals will be achieved: (1) characterize the epitope of anti-IFN- autoAbs and clone the autoantibodies production B cells; (2) establish a proof of principle therapeutic strategy by using modified recombinant anti-IFN- without neutralizing by autoantibodies; (3) discuss the possibility of molecule mimicry to explain mechanism of the generation of autoantibodies to IFN-; (4) establish anti-IFN- autoAbs mice model to perform in vivo studying. Expected Results and Significance: We will characterize the epitope of anti-IFN- autoantibodies; based on our preliminary data, it is highly possible that C-terminal of IFN- is the major epitope for most autoantibodies. This result can provide a molecular mechanism to explain the neutralizing effect. By identifying the epitope, we expect to product a modified IFN- to restore the IFN- signaling without autoantibodies interfere. By searching the similar sequence to epitope, we could identify possible microbial antigen as the origin of production of autoantibodies to IFN- and we will apply more molecular experiment to test this hypothesis of Molecular Mimicry. Anti-IFN- autoAbs mice model will serve as an experiment model to test our in vitro finding. Anti-IFN- autoAbs is one unique and threatening disease for our society and is most important prototype of anticytokine diseases. Our studying is very critical for better understand, treatment and prevention of anti-IFN- autoAbs diseases and related anticytokine diseases.

Project ID:PC10207-0419
External Project ID:NSC102-2320-B182-024