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