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

Nature Medicine volume 22, pages 994–1001 (2016)Cite this article

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Abstract

The binding of autoantibodies (autoAbs) to interferon (IFN)-γ in people with mycobacterial diseases has become an emerging medical concern. Many patients display specific human leukocyte antigen (HLA) class II haplotypes, which suggests that a common T cell–dependent and B cell–dependent mechanism might underlie the production of specific anti-IFN-γ autoAbs. We show here that these autoAbs target a major epitope (amino acids 121–131, designated position (P)121–131) in a region crucial for IFN-γ receptor (IFN-γR) activation to impair IFN-γ-mediated activities. The amino acid sequence of this epitope is highly homologous to a stretch in the Noc2 protein of Aspergillus spp., which was cross-reactive with autoAbs from patients. Rats immunized with Aspergillus Noc2 developed antibodies that reacted with human IFN-γ. We generated an epitope-erased variant of IFN-γ (EE-IFN-γ), in which the major neutralizing epitope region was altered. The binding affinity of anti-IFN-γ autoAbs for EE-IFN-γ was reduced by about 40%, as compared to that for IFN-γ1–131. Moreover, EE-IFN-γ activated the IFN-γR downstream signaling pathway ex vivo, irrespectively of anti-IFN-γ autoAbs. In conclusion, we identified a common, crucial B cell epitope that bound to anti-IFN-γ autoAbs in patients, and we propose a molecular-mimicry model for autoAb development. In addition, treatment with EE-IFN-γ might be worth investigating in patients producing anti-IFN-γ autoAbs.

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Figure 1: AutoAbs against IFN-γ recognize the C-terminal region of IFN-γ.
Figure 2: Multiple amino acid sequence alignment for IFN-γ from different species and EE-IFN-γ.
Figure 3: Anti-IFN-γ autoAbs against epitope P121–131 neutralize IFN-γ signaling.
Figure 4: Molecular mimicry.
Figure 5: Restoration of IFN-γ by EE-IFN-γ ex vivo.

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Acknowledgements

We thank all the clinicians and patients who participated in this study. This work was supported by the Taiwan National Health Research Institutes grant NHRI-EX100-10028SC (C.-L.K.), Taiwan Ministry of Science and Technology grant 100-2314-B-182-050 (C.-L.K.), 102-2320-B-182-024 (C.-L.K.) and 103-2320-B-182-012 (C.-L.K.), and Chang Gung Memorial Hospital grant CMRPD1F0201 (C.-L.K.), CORPD1F0041 (C.-L.K.) and BMRPB98 (C.-L.K.).

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Authors and Affiliations

  1. Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan

    Chia-Hao Lin, Chih-Yu Chi, Han-Po Shih, Jing-Ya Ding, Chia-Chi Lo, Shang-Yu Wang, Chen-Yen Kuo, Chun-Fu Yeh, Kun-Hua Tu, Shou-Hsuan Liu & Cheng-Lung Ku

  2. Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan

    Chia-Hao Lin & Hsin-Chin Lai

  3. Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

    Chih-Yu Chi & Mao-Wang Ho

  4. School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan

    Chih-Yu Chi

  5. Division of Trauma and Emergency Surgery, Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Shang-Yu Wang

  6. Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Chen-Yen Kuo

  7. Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Chun-Fu Yeh & Cheng-Lung Ku

  8. Chang Gung University College of Medicine, Taoyuan, Taiwan

    Chun-Fu Yeh, Kun-Hua Tu & Shou-Hsuan Liu

  9. Department of Nephrology, Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan

    Kun-Hua Tu & Shou-Hsuan Liu

  10. Laboratory of Translational Medicine, Development Center for Biotechnology, New Taipei City, Taiwan

    Hung-Kai Chen & Chen-Hsuan Ho

  11. Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Chen-Hsiang Lee

  12. Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan

    Hsin-Chin Lai & Cheng-Lung Ku

  13. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

    Cheng-Lung Ku

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Contributions

C.-H. Lin and C.-L.K. designed the study and analyzed the data, and wrote the manuscript; C.-H. Lin., C.-Y.C., H.-P.S., J.-Y.D. and C.-C.L. performed the research and analyzed the data; C.-F.Y., M.-W.H. and C.-H. Lee referred the patients and designed the study; S.-Y.W., C.-Y.K., K.-H.T., S.-H.L., H.-K.C., C.-H.H. and H.-C.L. analyzed the data; H.-K.C. and C.-H.H. wrote and edited the manuscript.

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Correspondence to Cheng-Lung Ku.

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Competing interests

A patent application concerning EE-IFN-γ has been submitted by C.-H. Lin, C.-Y.C., J.-Y.D., H.-P.S. and C.-L.K. on the basis of these results.

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Lin, CH., Chi, CY., Shih, HP. et al. Identification of a major epitope by anti-interferon-γ autoantibodies in patients with mycobacterial disease. Nat Med 22, 994–1001 (2016). https://doi.org/10.1038/nm.4158

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