PD1 pathway in immune-mediated myopathies
Pathogenesis of dysfunctional T cells revisited
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Abstract
Objective To investigate the relevance of dysfunctional T cells in immune-mediated myopathies. We analyzed T-cell exhaustion and senescence, in the context of programmed cell death protein 1 (PD1)-related immunity in skeletal muscle biopsies from patients with immune-mediated necrotizing myopathy (IMNM), sporadic inclusion body myositis (sIBM), and myositis induced by immune checkpoint inhibitors (irMyositis).
Methods Skeletal muscle biopsies from 12 patients with IMNM, 7 patients with sIBM, and 8 patients with irMyositis were analyzed by immunostaining and immunofluorescence as well as by quantitative PCR. Eight biopsies from nondisease participants served as controls.
Results CD3+CD8+ T cells in biopsies from IMNM, sIBM, and irMyositis were largely PD1-positive, while CD68+ macrophages were sparsely positive to the ligand of programmed cell death protein 1 (PD-L1). The sarcolemma of myofibers was PD-L2+ and was colocalized with major histocompatibility complex (MHC) class I. CD68+ macrophages were colocalized with PD-L2. Senescent T cells were strongly enriched in skeletal muscle of sIBM, revealing a distinct immunologic signature. Biopsies from patients with irMyositis showed mild signs of senescence and exhaustion.
Conclusion Persistent exposure to antigens in IMNMs and sIBM may lead to T-cell exhaustion, a process controlled by the PD1 receptor and its cognate ligands PD-L1/PD-L2. To our knowledge, these data are the first evidence of presence of dysfunctional T cells and relevance of the PD1 pathway in IMNM, sIBM, and irMyositis. These findings may guide the way to a novel understanding of the immune pathogenesis of immune-mediated myopathies.
Glossary
- CTL=
- cytotoxic T cell;
- HMGCR=
- 3-hydroxy-3-methylglutaryl-coenzyme A reductase;
- ICI=
- immune checkpoint inhibitors;
- IMNM=
- immune mediated necrotizing myopathy;
- IFNγ=
- gamma interferon;
- irMyositis=
- myositis induced by immune checkpoint inhibitors;
- MHC=
- major histocompatibility complex;
- mRNA=
- messanger ribonuclein acid;
- MSA=
- myositis-specific antibody;
- PD1=
- programmed cell death protein 1;
- PD-L1/2=
- ligand of programmed cell death protein 1/2;
- qPCR=
- quantitative PCR;
- sIBM=
- sporadic Inclusion body myositis;
- SRP=
- signal recognition particle
Footnotes
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NN.
The Article Processing Charge was funded by the authors.
- Received September 7, 2018.
- Accepted in final form January 23, 2019.
- Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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