PT  - JOURNAL ARTICLE
AU  - Samuel Knauss
AU  - Corinna Preusse
AU  - Yves Allenbach
AU  - Sarah Leonard-Louis
AU  - Mehdi Touat
AU  - Norina Fischer
AU  - Helena Radbruch
AU  - Ronja Mothes
AU  - Vitali Matyash
AU  - Wolfgang Böhmerle
AU  - Matthias Endres
AU  - Hans-Hilmar Goebel
AU  - Olivier Benveniste
AU  - Werner Stenzel
TI  - PD1 pathway in immune-mediated myopathies
AID  - 10.1212/NXI.0000000000000558
DP  - 2019 May 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e558
VI  - 6
IP  - 3
4099  - http://nn.neurology.org/content/6/3/e558.short
4100  - http://nn.neurology.org/content/6/3/e558.full
SO  - Neurol Neuroimmunol Neuroinflamm2019 May 01; 6
AB  - 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.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