Pathogenic autoantibodies to IFN-gamma act through the impedance of receptor assembly and Fc-mediated response
Autor(en): | Shih, Han-Po Ding, Jing-Ya Bellon, Junel Sotolongo 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, Felix A. Chen, Hung-Kai Chang, Tse-Wen Piehler, Jacob Chi, Chih-Yu Ku, Cheng-Lung |
Stichwörter: | ADULT-ONSET IMMUNODEFICIENCY; CLINICAL-FEATURES; DIMERIZATION; EXPRESSION; IMMUNITY; Immunology; INBORN-ERRORS; INTERFERON-GAMMA; Medicine, Research & Experimental; MYCOBACTERIAL INFECTION; NEUTRALIZING ANTIBODIES; Research & Experimental Medicine; SUSCEPTIBILITY | Erscheinungsdatum: | 2022 | Herausgeber: | ROCKEFELLER UNIV PRESS | Journal: | JOURNAL OF EXPERIMENTAL MEDICINE | Volumen: | 219 | Ausgabe: | 9 | Zusammenfassung: | Anti-interferon (IFN)-y autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-y function, but their effects on IFN-y signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-gamma-reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (K-D < 10(-9) M) binding to IFN-y, but only eight neutralized IFN-gamma-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-gamma. We found that site I mAb neutralized IFN-gamma by blocking its binding to IFN-gamma R1. Site II and III mAbs bound the receptor-bound IFN-gamma on the cell surface, abolishing IFN-gamma R1-1FN-gamma R2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody-IFN-gamma complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-gamma signaling and by eliminating IFN-gamma-responsive cells. |
ISSN: | 0022-1007 | DOI: | 10.1084/jem.20212126 |
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geprüft am 16.05.2024