PMID- 31383567
OWN - NLM
STAT- MEDLINE
DCOM- 20210608
LR  - 20240403
IS  - 1095-9157 (Electronic)
IS  - 0896-8411 (Print)
IS  - 0896-8411 (Linking)
VI  - 106
DP  - 2020 Jan
TI  - Restricted myeloperoxidase epitopes drive the adaptive immune response in 
      MPO-ANCA vasculitis.
PG  - 102306
LID - S0896-8411(19)30408-1 [pii]
LID - 10.1016/j.jaut.2019.102306 [doi]
AB  - BACKGROUND: Treatment of autoimmune diseases has relied on broad 
      immunosuppression. Knowledge of specific interactions between human leukocyte 
      antigen (HLA), the autoantigen, and effector immune cells, provides the 
      foundation for antigen-specific therapies. These studies investigated the role of 
      HLA, specific myeloperoxidase (MPO) epitopes, CD4(+) T cells, and ANCA 
      specificity in shaping the immune response in patients with anti-neutrophil 
      cytoplasmic autoantibody (ANCA) vasculitis. METHODS: HLA sequence-based typing 
      identified enriched alleles in our patient population (HLA-DPB1*04:01 and 
      HLA-DRB4*01:01), while in silico and in vitro binding studies confirmed binding 
      between HLA and specific MPO epitopes. Class II tetramers with MPO peptides were 
      utilized to detect autoreactive CD4(+) T cells. TCR sequencing was performed to 
      determine the clonality of T cell populations. Longitudinal peptide ELISAs 
      assessed the temporal nature of anti-MPO(447-461) antibodies. Solvent 
      accessibility combined with chemical modification determined the buried regions 
      of MPO. RESULTS: We identified a restricted region of MPO that was recognized by 
      both CD4(+) T cells and ANCA. The autoreactive T cell population contained 
      CD4(+)CD25(intermediate)CD45RO+ memory T cells and secreted IL-17A. T cell 
      receptor (TCR) sequencing demonstrated that autoreactive CD4(+) T cells had 
      significantly less TCR diversity when compared to naive and memory T cells, 
      indicating clonal expansion. The anti-MPO(447-461) autoantibody response was 
      detectable at onset of disease in some patients and correlated with disease 
      activity in others. This region of MPO that is targeted by both T cells and 
      antibodies is not accessible to solvent or chemical modification, indicating 
      these epitopes are buried. CONCLUSIONS: These observations reveal interactions 
      between restricted MPO epitopes and the adaptive immune system within ANCA 
      vasculitis that may inform new antigen-specific therapies in autoimmune disease 
      while providing insight into immunopathogenesis.
CI  - Copyright (c) 2019 Elsevier Ltd. All rights reserved.
FAU - Free, Meghan E
AU  - Free ME
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA. Electronic address: meghan_free@med.unc.edu.
FAU - Stember, Katherine G
AU  - Stember KG
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA; UNC Department of Pathology and Laboratory Medicine, CB 
      #7525, Brinkhous-Bullitt Building, Chapel Hill, NC, 27599, USA.
FAU - Hess, Jacob J
AU  - Hess JJ
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA.
FAU - McInnis, Elizabeth A
AU  - McInnis EA
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA.
FAU - Lardinois, Olivier
AU  - Lardinois O
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA.
FAU - Hogan, Susan L
AU  - Hogan SL
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA.
FAU - Hu, Yichun
AU  - Hu Y
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA.
FAU - Mendoza, Carmen
AU  - Mendoza C
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA.
FAU - Le, Andrew K
AU  - Le AK
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA.
FAU - Guseman, Alex J
AU  - Guseman AJ
AD  - UNC Department of Chemistry, CB #3290, Chapel Hill, NC, 27599, USA.
FAU - Pilkinton, Mark A
AU  - Pilkinton MA
AD  - Vanderbilt Center for Translational Immunology and Infectious Diseases, A2200 
      MCN, 1161 21st Avenue South, Nashville, TN, 37232, USA.
FAU - Bortone, Dante S
AU  - Bortone DS
AD  - UNC Lineberger Comprehensive Cancer Center, CB #7295, Chapel Hill, NC, 27599, 
      USA.
FAU - Cowens, Kristen
AU  - Cowens K
AD  - UNC Lineberger Comprehensive Cancer Center, CB #7295, Chapel Hill, NC, 27599, 
      USA.
FAU - Sidney, John
AU  - Sidney J
AD  - La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, 
      92037, USA.
FAU - Karosiene, Edita
AU  - Karosiene E
AD  - La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, 
      92037, USA.
FAU - Peters, Bjoern
AU  - Peters B
AD  - La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, 
      92037, USA.
FAU - James, Eddie
AU  - James E
AD  - Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA, 98101, USA.
FAU - Kwok, William W
AU  - Kwok WW
AD  - Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA, 98101, USA.
FAU - Vincent, Benjamin G
AU  - Vincent BG
AD  - UNC Lineberger Comprehensive Cancer Center, CB #7295, Chapel Hill, NC, 27599, 
      USA; UNC Division of Hematology/Oncology, Department of Medicine, Physician's 
      Office Building, 3rd Floor, 170 Manning Drive, CB #7305, Chapel Hill, NC, 27599, 
      USA; UNC Curriculum in Bioinformatics and Computational Biology, CB #7264, Chapel 
      Hill, NC, 27599, USA.
FAU - Mallal, Simon A
AU  - Mallal SA
AD  - Vanderbilt Center for Translational Immunology and Infectious Diseases, A2200 
      MCN, 1161 21st Avenue South, Nashville, TN, 37232, USA.
FAU - Jennette, J Charles
AU  - Jennette JC
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA; UNC Department of Pathology and Laboratory Medicine, CB 
      #7525, Brinkhous-Bullitt Building, Chapel Hill, NC, 27599, USA.
FAU - Ciavatta, Dominic J
AU  - Ciavatta DJ
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA; UNC Department of Genetics and Molecular Biology, Coker 
      Hall, 120 South Road, CB #3280, Chapel Hill, NC, 27599, USA.
FAU - Falk, Ronald J
AU  - Falk RJ
AD  - UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel 
      Hill, NC, 27599, USA; UNC Department of Pathology and Laboratory Medicine, CB 
      #7525, Brinkhous-Bullitt Building, Chapel Hill, NC, 27599, USA.
LA  - eng
GR  - T32 DK007750/DK/NIDDK NIH HHS/United States
GR  - P01 DK058335/DK/NIDDK NIH HHS/United States
GR  - TL1 TR001110/TR/NCATS NIH HHS/United States
GR  - R01 DK125350/DK/NIDDK NIH HHS/United States
GR  - P30 CA016086/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190802
PL  - England
TA  - J Autoimmun
JT  - Journal of autoimmunity
JID - 8812164
RN  - 0 (Antibodies, Antineutrophil Cytoplasmic)
RN  - 0 (Autoantibodies)
RN  - 0 (Autoantigens)
RN  - 0 (Epitopes)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - EC 1.11.1.7 (Peroxidase)
SB  - IM
MH  - Adaptive Immunity/*immunology
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antibodies, Antineutrophil Cytoplasmic/*immunology
MH  - Autoantibodies/immunology
MH  - Autoantigens/immunology
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - Cells, Cultured
MH  - Epitopes/*immunology
MH  - Humans
MH  - Leukocytes, Mononuclear/immunology
MH  - Longitudinal Studies
MH  - Mice
MH  - Peroxidase/*immunology
MH  - Receptors, Antigen, T-Cell/immunology
MH  - Vasculitis/*immunology
PMC - PMC6930338
MID - NIHMS1536492
OTO - NOTNLM
OT  - ANCA specificity
OT  - ANCA vasculitis
OT  - Autoreactive T cells
OT  - Epitope specificity
OT  - Immunodominant epitopes
COIS- The authors have declared that no conflict of interest exists.
EDAT- 2019/08/07 06:00
MHDA- 2021/06/09 06:00
PMCR- 2021/01/01
CRDT- 2019/08/07 06:00
PHST- 2019/06/28 00:00 [received]
PHST- 2019/07/16 00:00 [revised]
PHST- 2019/07/17 00:00 [accepted]
PHST- 2019/08/07 06:00 [pubmed]
PHST- 2021/06/09 06:00 [medline]
PHST- 2019/08/07 06:00 [entrez]
PHST- 2021/01/01 00:00 [pmc-release]
AID - S0896-8411(19)30408-1 [pii]
AID - 10.1016/j.jaut.2019.102306 [doi]
PST - ppublish
SO  - J Autoimmun. 2020 Jan;106:102306. doi: 10.1016/j.jaut.2019.102306. Epub 2019 Aug 
      2.