PMID- 27525523
OWN - NLM
STAT- MEDLINE
DCOM- 20170810
LR  - 20231213
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Linking)
VI  - 22
IP  - 9
DP  - 2016 Sep
TI  - Identification of a major epitope by anti-interferon-gamma autoantibodies in patients 
      with mycobacterial disease.
PG  - 994-1001
LID - 10.1038/nm.4158 [doi]
AB  - The binding of autoantibodies (autoAbs) to interferon (IFN)-gamma 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-gamma 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-gamma receptor (IFN-gammaR) activation to impair 
      IFN-gamma-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-gamma. We generated an 
      epitope-erased variant of IFN-gamma (EE-IFN-gamma), in which the major neutralizing 
      epitope region was altered. The binding affinity of anti-IFN-gamma autoAbs for 
      EE-IFN-gamma was reduced by about 40%, as compared to that for IFN-gamma1-131. Moreover, 
      EE-IFN-gamma activated the IFN-gammaR downstream signaling pathway ex vivo, 
      irrespectively of anti-IFN-gamma autoAbs. In conclusion, we identified a common, 
      crucial B cell epitope that bound to anti-IFN-gamma autoAbs in patients, and we 
      propose a molecular-mimicry model for autoAb development. In addition, treatment 
      with EE-IFN-gamma might be worth investigating in patients producing anti-IFN-gamma 
      autoAbs.
FAU - Lin, Chia-Hao
AU  - Lin CH
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
AD  - Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, 
      Taiwan.
FAU - Chi, Chih-Yu
AU  - Chi CY
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
AD  - Division of Infectious Diseases, Department of Internal Medicine, China Medical 
      University Hospital, Taichung, Taiwan.
AD  - School of Medicine, College of Medicine, China Medical University, Taichung, 
      Taiwan.
FAU - Shih, Han-Po
AU  - Shih HP
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
FAU - Ding, Jing-Ya
AU  - Ding JY
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
FAU - Lo, Chia-Chi
AU  - Lo CC
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
FAU - Wang, Shang-Yu
AU  - Wang SY
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
AD  - Division of Trauma and Emergency Surgery, Department of General Surgery, Chang 
      Gung Memorial Hospital, Taoyuan, Taiwan.
FAU - Kuo, Chen-Yen
AU  - Kuo CY
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
AD  - Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial 
      Hospital, Taoyuan, Taiwan.
FAU - Yeh, Chun-Fu
AU  - Yeh CF
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
AD  - Division of Infectious Diseases, Department of Internal Medicine, Chang Gung 
      Memorial Hospital, Taoyuan, Taiwan.
AD  - Chang Gung University College of Medicine, Taoyuan, Taiwan.
FAU - Tu, Kun-Hua
AU  - Tu KH
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
AD  - Chang Gung University College of Medicine, Taoyuan, Taiwan.
AD  - Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, 
      Taipei, Taiwan.
FAU - Liu, Shou-Hsuan
AU  - Liu SH
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
AD  - Chang Gung University College of Medicine, Taoyuan, Taiwan.
AD  - Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, 
      Taipei, Taiwan.
FAU - Chen, Hung-Kai
AU  - Chen HK
AD  - Laboratory of Translational Medicine, Development Center for Biotechnology, New 
      Taipei City, Taiwan.
FAU - Ho, Chen-Hsuan
AU  - Ho CH
AD  - Laboratory of Translational Medicine, Development Center for Biotechnology, New 
      Taipei City, Taiwan.
FAU - Ho, Mao-Wang
AU  - Ho MW
AD  - Division of Infectious Diseases, Department of Internal Medicine, China Medical 
      University Hospital, Taichung, Taiwan.
FAU - Lee, Chen-Hsiang
AU  - Lee CH
AD  - Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang 
      Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 
      Taiwan.
FAU - Lai, Hsin-Chin
AU  - Lai HC
AD  - Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, 
      Taiwan.
AD  - Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung 
      University, Taoyuan, Taiwan.
FAU - Ku, Cheng-Lung
AU  - Ku CL
AD  - Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of 
      Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
AD  - Division of Infectious Diseases, Department of Internal Medicine, Chang Gung 
      Memorial Hospital, Taoyuan, Taiwan.
AD  - Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung 
      University, Taoyuan, Taiwan.
AD  - Graduate Institute of Clinical Medical Science, China Medical University, 
      Taichung, Taiwan.
LA  - eng
PT  - Journal Article
DEP - 20160815
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Autoantibodies)
RN  - 0 (Autoantigens)
RN  - 0 (Epitopes)
RN  - 0 (Epitopes, B-Lymphocyte)
RN  - 0 (Fungal Proteins)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Interleukin-12 Subunit p40)
RN  - 0 (Receptors, Interferon)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
CIN - Nat Med. 2016 Sep 7;22(9):973-5. PMID: 27603131
MH  - Animals
MH  - Antibodies, Neutralizing/*immunology
MH  - Aspergillus
MH  - Autoantibodies/*immunology
MH  - Autoantigens/immunology
MH  - Case-Control Studies
MH  - Cross Reactions
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Epitope Mapping
MH  - Epitopes/*immunology
MH  - Epitopes, B-Lymphocyte
MH  - Fungal Proteins/immunology
MH  - HLA-DR Antigens/immunology
MH  - Haplotypes
MH  - Histocompatibility Antigens Class II/genetics
MH  - Humans
MH  - Immunization
MH  - Immunoblotting
MH  - Interferon-gamma/*immunology
MH  - Interleukin-12 Subunit p40/immunology
MH  - Mycobacterium Infections
MH  - Rats
MH  - Receptors, Interferon/immunology
MH  - Interferon gamma Receptor
EDAT- 2016/08/16 06:00
MHDA- 2017/08/11 06:00
CRDT- 2016/08/16 06:00
PHST- 2016/03/22 00:00 [received]
PHST- 2016/07/01 00:00 [accepted]
PHST- 2016/08/16 06:00 [entrez]
PHST- 2016/08/16 06:00 [pubmed]
PHST- 2017/08/11 06:00 [medline]
AID - nm.4158 [pii]
AID - 10.1038/nm.4158 [doi]
PST - ppublish
SO  - Nat Med. 2016 Sep;22(9):994-1001. doi: 10.1038/nm.4158. Epub 2016 Aug 15.