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

• DOI: 10.1084/jem.20212126
• Publication Date: 2022-07-14T13:43:48Z
• Authors: Han-Po Shih; Jing-Ya Ding; Junel Sotolongo B...; 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
• Keywords: STAT1

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