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

Journal of Autoimmunity
Meghan E FreeRonald J Falk

Abstract

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. 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. 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 ...Continue Reading

Citations

Aug 29, 2020·Nature Reviews. Disease Primers·A Richard KitchingRenate Kain
May 7, 2020·Frontiers in Immunology·Lani ShochetA Richard Kitching
Apr 30, 2021·Journal of Translational Autoimmunity·Daisuke TsukuiHajime Kono
May 4, 2021·The Journal of Clinical Investigation·Karolin WieberMichael Hertl
Jul 3, 2021·International Journal of Molecular Sciences·Antje MüllerPeter Lamprecht
Aug 17, 2021·Frontiers in Immunology·Dragana Odobasic, Stephen R Holdsworth

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