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

Autor:	Shih HP; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan., Ding JY; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan., Sotolongo Bellón J; Division of Biophysics, Department of Biology, University of Osnabruck, Osnabruck, Germany., Lo YF; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan., Chung PH; Elixiron Immunotherapeutics, Taipei, Taiwan., Ting HT; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan., Peng JJ; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan., Wu TY; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan., Lin CH; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan., Lo CC; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan., Lin YN; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan., Yeh CF; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.; Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan., Chen JB; Genomics Research Center, Academia Sinica, Taipei, Taiwan., Wu TS; Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan.; Chang Gung University College of Medicine, Taoyuan, Taiwan., Liu YM; Division of Infectious Diseases, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan., Kuo CY; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.; Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan., Wang SY; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.; Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan., Tu KH; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.; Chang Gung University College of Medicine, Taoyuan, Taiwan.; Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan., Ng CY; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.; Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Taiwan., Lei WT; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.; Department of Pediatrics, Hsinchu MacKay Memorial Hospital, Hsinchu, Taiwan., Tsai YH; Laboratory of Host-Microbe Interactions and Cell Dynamics, Institute of Microbiology and Immunology, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan., Chen JH; Genomics Research Center, Academia Sinica, Taipei, Taiwan., Chuang YT; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan., Huang JY; Elixiron Immunotherapeutics, Taipei, Taiwan., Rey FA; Structural Virology Unit, Department of Virology, Institut Pasteur, Paris, France., Chen HK; Elixiron Immunotherapeutics, Taipei, Taiwan., Chang TW; Genomics Research Center, Academia Sinica, Taipei, Taiwan., Piehler J; Division of Biophysics, Department of Biology, University of Osnabruck, Osnabruck, Germany., Chi CY; Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.; School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan., Ku CL; Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.; Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.; Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2022 Sep 05; Vol. 219 (9). Date of Electronic Publication: 2022 Jul 14.
DOI:	10.1084/jem.20212126
Abstrakt:	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.)
Databáze:	MEDLINE
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