Restricted myeloperoxidase epitopes drive the adaptive immune response in MPO-ANCA vasculitis.

Abstract

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-MPO447-461 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+CD25intermediateCD45RO+ 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 naïve and memory T cells, indicating clonal expansion. The anti-MPO447-461 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.

• Authors: Meghan E Free, Katherine G Stember, Jacob J Hess, Elizabeth A McInnis, Olivier Lardinois, Susan L Hogan, Yichun Hu, Carmen Mendoza, Andrew K Le, Alex J Guseman, Mark A Pilkinton, Dante S Bortone, Kristen Cowens, John Sidney, Edita Karosiene, Bjoern Peters, Eddie James, William W Kwok, Benjamin G Vincent, Simon A Mallal, J Charles Jennette, Dominic J Ciavatta, Ronald J Falk
• Journal: Journal of autoimmunity (J Autoimmun) Vol. 106 Pg. 102306 (01 2020) ISSN: 1095-9157 [Electronic] England
• PMID: 31383567 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Antineutrophil Cytoplasmic
• Autoantibodies
• Autoantigens
• Epitopes
• Receptors, Antigen, T-Cell
• Peroxidase

Topics

• Adaptive Immunity (immunology)
• Amino Acid Sequence
• Animals
• Antibodies, Antineutrophil Cytoplasmic (immunology)
• Autoantibodies (immunology)
• Autoantigens (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Cells, Cultured
• Epitopes (immunology)
• Humans
• Leukocytes, Mononuclear (immunology)
• Longitudinal Studies
• Mice
• Peroxidase (immunology)
• Receptors, Antigen, T-Cell (immunology)
• Vasculitis (immunology)