Identification of a major epitope by anti-interferon-γ autoantibodies in patients with mycobacterial disease

Lin, C. C.; Chi, Chih-Yu; Shih, Han-Po; Ding, Jing-Ya; Lo, Chia-Chi; Wang, Shang‐Yu; Kuo, Chen-Yen; Yeh, Chun‐Fu; Tu, Kun-Hua; Liu, Shou-Hsuan; Chen, Hung-Kai; Ho, C.L.; Ho, Mao‐Wang; Lee, Chen‐Hsiang; Lai, Hsin-Chin; Ku, Cheng‐Lung

doi:10.1038/nm.4158

Cited by 78 publications

(106 citation statements)

References 46 publications

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“…Our previous study showed that NK cells can directly kill M. tuberculosis and M. kansasii by releasing the cytolytic proteins perforin and granulysin (36). We also reported that anti-IFN-g autoantibodies associated with specific MHC haplotypes play a crucial role in patients with mycobacterial infection (37). In the current study, we characterized the role of NK cells and IFN-g during early stages of M. kansasii infection in the lungs.…”

mentioning

confidence: 74%

NK Cell–Derived IFN-γ Protects against Nontuberculous Mycobacterial Lung Infection

Lai

Chang

Lin

et al. 2018

The Journal of Immunology

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In developed countries, pulmonary nontuberculous mycobacteria (NTM) infections are more prevalent than infections. Given the differences in the pathogenesis of NTM and infections, separate studies are needed to investigate the pathological effects of NTM pathogens. Our previous study showed that anti-IFN-γ autoantibodies are detected in NTM-infected patients. However, the role of NK cells and especially NK cell-derived IFN-γ in this context has not been studied in detail. In the current study, we show that NK1.1 cell depletion increases bacterial load and mortality in a mouse model of pulmonary NTM infection. NK1.1 cell depletion exacerbates NTM-induced pathogenesis by reducing macrophage phagocytosis, dendritic cell development, cytokine production, and lung granuloma formation. Similar pathological phenomena are observed in IFN-γ-deficient (IFN-γ) mice following NTM infection, and adoptive transfer of wild-type NK cells into IFN-γ mice considerably reduces NTM pathogenesis. Injection of rIFN-γ also prevents NTM-induced pathogenesis in IFN-γ mice. We observed that NK cells represent the main producers of IFN-γ in the lungs and production starts as soon as 1 d postinfection. Accordingly, injection of rIFN-γ into IFN-γ mice 1 d (but not 2 wk) postinfection significantly improves immunity against NTM infection. NK cells also stimulate mycobacterial killing and IL-12 production by macrophages. Our results therefore indicate that IFN-γ production by NK cells plays an important role in activating and enhancing innate and adaptive immune responses at early stages of pulmonary NTM infection.

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confidence: 74%

NK Cell–Derived IFN-γ Protects against Nontuberculous Mycobacterial Lung Infection

Lai

Chang

Lin

et al. 2018

The Journal of Immunology

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“…This epitope displays a high degree of sequence homology to the Aspergillus Noc2 protein. It was postulated that in the warm and humid environment of Southeast Asia where exposure to Aspergillus species is common in everyday life, some individuals might develop anti-IFN-γ autoantibodies due to molecular mimicry (198). The co-evolution of anti-IFN-γ autoantibody production as the susceptibility trait amongst Southeast Asians, and the high prevalence of T. marneffei , NTM, and mellioidosis in this region is a unique combination not observed in the rest of the world, and it is so interesting that exposure to a common environmental fungal agent could indirectly induce susceptibility to other pathogens.…”

Section: Protective Immunity Against Endemic Mycoses Conferred By Cytmentioning

confidence: 99%

Cellular and Molecular Defects Underlying Invasive Fungal Infections—Revelations from Endemic Mycoses

Lee

Lau

2017

Front. Immunol.

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The global burden of fungal diseases has been increasing, as a result of the expanding number of susceptible individuals including people living with human immunodeficiency virus (HIV), hematopoietic stem cell or organ transplant recipients, patients with malignancies or immunological conditions receiving immunosuppressive treatment, premature neonates, and the elderly. Opportunistic fungal pathogens such as Aspergillus, Candida, Cryptococcus, Rhizopus, and Pneumocystis jiroveci are distributed worldwide and constitute the majority of invasive fungal infections (IFIs). Dimorphic fungi such as Histoplasma capsulatum, Coccidioides spp., Paracoccidioides spp., Blastomyces dermatiditis, Sporothrix schenckii, Talaromyces (Penicillium) marneffei, and Emmonsia spp. are geographically restricted to their respective habitats and cause endemic mycoses. Disseminated histoplasmosis, coccidioidomycosis, and T. marneffei infection are recognized as acquired immunodeficiency syndrome (AIDS)-defining conditions, while the rest also cause high rate of morbidities and mortalities in patients with HIV infection and other immunocompromised conditions. In the past decade, a growing number of monogenic immunodeficiency disorders causing increased susceptibility to fungal infections have been discovered. In particular, defects of the IL-12/IFN-γ pathway and T-helper 17-mediated response are associated with increased susceptibility to endemic mycoses. In this review, we put together the various forms of endemic mycoses on the map and take a journey around the world to examine how cellular and molecular defects of the immune system predispose to invasive endemic fungal infections, including primary immunodeficiencies, individuals with autoantibodies against interferon-γ, and those receiving biologic response modifiers. Though rare, these conditions provide importance insights to host defense mechanisms against endemic fungi, which can only be appreciated in unique climatic and geographical regions.

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“…Other fungi such as Blastomyces dermatitidis and some Aspergillus spp. have developed mechanisms to mimic mammalian regulatory molecules and suppress host immunity 129,130 . The skin and the mucosal surfaces of animals and humans are rich on nutrients and provide temperate environment for commensal fungal symbionts to thrive.…”

Section: Introductionmentioning

confidence: 99%

Fungal dysbiosis: immunity and interactions at mucosal barriers

2017

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Fungi and mammals share a co-evolutionary history and are involved in a complex web of interactions. Studies focused on commensal bacteria suggest that pathologic changes in the microbiota, historically termed as ‘dysbiosis’, are at the root of many inflammatory diseases of non-infectious origin. Yet, the importance of dysbiosis in the fungal community— the mycobiota — was only recently acknowledged to have a pathological role as novel findings suggest that mycobiota disruption can have detrimental effects on host immunity. Fungal dysbiosis and homeostasis are dynamic processes that are probably more common than actual fungal infections, and therefore constantly shape the immune response. In this Review, we summarize specific patterns associated with fungal dysbiosis, and discuss how mucosal immunity has evolved to distinguish fungal infection from dysbiosis and how it responds to these different conditions. We propose that gut microbiota dysbiosis is a collective feature of complex interactions between prokaryotic and eukaryotic microbial communities that can affect immunity and influence health and disease.

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Identification of a major epitope by anti-interferon-γ autoantibodies in patients with mycobacterial disease

Cited by 78 publications

References 46 publications

NK Cell–Derived IFN-γ Protects against Nontuberculous Mycobacterial Lung Infection

NK Cell–Derived IFN-γ Protects against Nontuberculous Mycobacterial Lung Infection

Cellular and Molecular Defects Underlying Invasive Fungal Infections—Revelations from Endemic Mycoses

Fungal dysbiosis: immunity and interactions at mucosal barriers

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