title: Identification of a major epitope by anti-interferon-γ autoantibodies in patients with mycobacterial disease.
abstract: The binding of autoantibodies (autoAbs) to interferon (IFN)-γ in people with mycobacterial diseases has become an emerging medical concern. Many patients display specific human leukocyte antigen (HLA) class II haplotypes, which suggests that a common T cell-dependent and B cell-dependent mechanism might underlie the production of specific anti-IFN-γ autoAbs. We show here that these autoAbs target a major epitope (amino acids 121-131, designated position (P)121-131) in a region crucial for IFN-γ receptor (IFN-γR) activation to impair IFN-γ-mediated activities. The amino acid sequence of this epitope is highly homologous to a stretch in the Noc2 protein of Aspergillus spp., which was cross-reactive with autoAbs from patients. Rats immunized with Aspergillus Noc2 developed antibodies that reacted with human IFN-γ. We generated an epitope-erased variant of IFN-γ (EE-IFN-γ), in which the major neutralizing epitope region was altered. The binding affinity of anti-IFN-γ autoAbs for EE-IFN-γ was reduced by about 40%, as compared to that for IFN-γ1-131. Moreover, EE-IFN-γ activated the IFN-γR downstream signaling pathway ex vivo, irrespectively of anti-IFN-γ autoAbs. In conclusion, we identified a common, crucial B cell epitope that bound to anti-IFN-γ autoAbs in patients, and we propose a molecular-mimicry model for autoAb development. In addition, treatment with EE-IFN-γ might be worth investigating in patients producing anti-IFN-γ autoAbs.
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chia-Hao
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|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.
authors.forename: Chih-Yu
authors.initials: CY
authors.lastname: Chi
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Han-Po
authors.initials: HP
authors.lastname: Shih
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Ding
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lo
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Division of Trauma and Emergency Surgery, Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Shang-Yu
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chen-Yen
authors.initials: CY
authors.lastname: Kuo
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Yeh
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, 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, Taipei, Taiwan.
authors.forename: Kun-Hua
authors.initials: KH
authors.lastname: Tu
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, 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, Taipei, Taiwan.
authors.forename: Shou-Hsuan
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Laboratory of Translational Medicine, Development Center for Biotechnology, New Taipei City, Taiwan.
authors.forename: Hung-Kai
authors.initials: HK
authors.lastname: Chen
authors.affiliation: Laboratory of Translational Medicine, Development Center for Biotechnology, New Taipei City, Taiwan.
authors.forename: Chen-Hsuan
authors.initials: CH
authors.lastname: Ho
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Mao-Wang
authors.initials: MW
authors.lastname: Ho
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chen-Hsiang
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.|Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsin-Chin
authors.initials: HC
authors.lastname: Lai
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Ku
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001230:Aspergillus; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D016022:Case-Control Studies; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D018985:Epitopes, B-Lymphocyte; D005656:Fungal Proteins / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007114:Immunization; D015151:Immunoblotting; D007371:Interferon-gamma / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000276:immunology; D009164:Mycobacterium Infections; D051381:Rats; D017471:Receptors, Interferon / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D018985:Epitopes, B-Lymphocyte; D005656:Fungal Proteins; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D053762:Interleukin-12 Subunit p40; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor