학술논문
Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response
Document Type
Article
Author
Shih, Han-Po; Ding, Jing-Ya; Sotolongo Bellón, Junel; Lo, Yu-Fang; Chung, Pei-Han; Ting, He-Ting; Peng, Jhan-Jie; Wu, Tsai-Yi; Lin, Chia-Hao; Lo, Chia-Chi; Lin, You-Ning; Yeh, Chun-Fu; Chen, Jiun-Bo; Wu, Ting-Shu; Liu, Yuag-Meng; Kuo, Chen-Yen; Wang, Shang-Yu; Tu, Kun-Hua; Ng, Chau Yee; Lei, Wei-Te; Tsai, Yu-Huan; Chen, Jou-Han; Chuang, Ya-Ting; Huang, Jing-Yi; Rey, Félix A.; Chen, Hung-Kai; Chang, Tse-Wen; Piehler, Jacob; Chi, Chih-Yu; Ku, Cheng-Lung
Source
The Journal of Experimental Medicine; September 2022, Vol. 219 Issue: 9 pe20212126-e20212126, 1p
Subject
Language
ISSN
00221007; 15409538
Abstract
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.