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

J Autoimmun. 2020 Jan:106:102306. doi: 10.1016/j.jaut.2019.102306. Epub 2019 Aug 2.

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.

Keywords: ANCA specificity; ANCA vasculitis; Autoreactive T cells; Epitope specificity; Immunodominant epitopes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*

Substances

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