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