Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response

Han-Po Shih, Jing Ya Ding, Junel Sotolongo Bellón, Yu Fang Lo, Pei Han Chung, He Ting Ting, Jhan Jie Peng, Tsai Yi Wu, Chia Hao Lin, Chia Chi Lo, You Ning Lin, Chun Fu Yeh, Jiun Bo Chen, Ting Shu Wu, Yuag Meng Liu, Chen Yen Kuo, Shang Yu Wang, Kun Hua Tu, Chau Yee Ng, Wei Te LeiYu-Huan Tsai, Jou Han Chen, Ya Ting Chuang, Jing Yi Huang, Félix A. Rey, Hung Kai Chen, Tse Wen Chang, Jacob Piehler, Chih Yu Chi*, Cheng Lung Ku*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

6 Scopus citations


Anti-interferon (IFN)–γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ–reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD < 10−9 M) binding to IFN-γ, but only eight neutralized IFN-γ–STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I–III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1–IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody–IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ–responsive cells.

Original languageEnglish
Article numbere20212126
JournalJournal of Experimental Medicine
Issue number9
StatePublished - 2022

Bibliographical note

Publisher Copyright:
© 2022 Shih et al. Tpublication date (see.


Dive into the research topics of 'Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response'. Together they form a unique fingerprint.

Cite this