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

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, Hung Kai Chen, Chen Hsuan Ho, Mao Wang Ho, Chen Hsiang Lee, Hsin Chin Lai, Cheng Lung Ku*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

80 Scopus citations

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.

Original languageEnglish
Pages (from-to)994-1001
Number of pages8
JournalNature Medicine
Volume22
Issue number9
DOIs
StatePublished - 01 09 2016

Bibliographical note

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© 2016 Nature America, Inc. All rights reserved.

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