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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. © 2022 Shih et al.

Citation

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 Lei, Yu-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. Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response. The Journal of experimental medicine. 2022 Sep 05;219(9)

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PMID: 35833912

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