RT Journal Article
SR Electronic
T1 PD1 pathway in immune-mediated myopathies
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e558
DO 10.1212/NXI.0000000000000558
VO 6
IS 3
A1 Samuel Knauss
A1 Corinna Preusse
A1 Yves Allenbach
A1 Sarah Leonard-Louis
A1 Mehdi Touat
A1 Norina Fischer
A1 Helena Radbruch
A1 Ronja Mothes
A1 Vitali Matyash
A1 Wolfgang Böhmerle
A1 Matthias Endres
A1 Hans-Hilmar Goebel
A1 Olivier Benveniste
A1 Werner Stenzel
YR 2019
UL http://nn.neurology.org/content/6/3/e558.abstract
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