Morphologic and Molecular Patterns of Polymyositis With Mitochondrial Pathology and Inclusion Body Myositis

Felix Kleefeld; Akinori Uruha; Anne Schänzer; Anna Nishimura; Andreas Roos; Udo Schneider; Hans H Goebel; Markus Schuelke; Katrin Hahn; Corinna Preusse; Werner Stenzel

doi:10.1212/WNL.0000000000201103

Morphologic and Molecular Patterns of Polymyositis With Mitochondrial Pathology and Inclusion Body Myositis

Neurology. 2022 Nov 15;99(20):e2212-e2222. doi: 10.1212/WNL.0000000000201103. Epub 2022 Oct 4.

Authors

Affiliations

¹ From the Department of Neurology (F.K., W.S., K.H.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Department of Neurology (A.U.), Tokyo Metropolitan Neurological Hospital, Japan; Institute of Neuropathology (A.S., A.N.), Justus Liebig University, Giessen, Germany; Pediatric Neurology (A.R.), University Children's Hospital, University of Duisburg-Essen, Faculty of Medicine, Germany, and Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, Germany; Departments of Rheumatology (U.S.) and Neuropathology (H.H.G.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Department of Neuropathology (H.H.G.), University Medical Center, Mainz, Germany and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Department of Neuropediatrics (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Cand Department of Neurology with Institute for Translational Neurology (C.P.), University Hospital Münster, Münster, Germany and Department of Neuropathology (C.P., W.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.
² From the Department of Neurology (F.K., W.S., K.H.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Department of Neurology (A.U.), Tokyo Metropolitan Neurological Hospital, Japan; Institute of Neuropathology (A.S., A.N.), Justus Liebig University, Giessen, Germany; Pediatric Neurology (A.R.), University Children's Hospital, University of Duisburg-Essen, Faculty of Medicine, Germany, and Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, Germany; Departments of Rheumatology (U.S.) and Neuropathology (H.H.G.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Department of Neuropathology (H.H.G.), University Medical Center, Mainz, Germany and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Department of Neuropediatrics (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Cand Department of Neurology with Institute for Translational Neurology (C.P.), University Hospital Münster, Münster, Germany and Department of Neuropathology (C.P., W.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany. werner.stenzel@charite.de.

PMID: 36195449
DOI: 10.1212/WNL.0000000000201103

Abstract

Background and objective: To characterize morphological and molecular underpinnings of polymyositis with mitochondrial pathology (PM-Mito) in comparison with sporadic inclusion body myositis (IBM) and to define common and distinct pathophysiologic features with a focus on interferon (IFN)-associated inflammation and T-cell response.

Methods: In this cross-sectional study, skeletal muscle biopsy samples and clinical and laboratory data from patients with PM-Mito and IBM were analyzed at Charité university hospital in Berlin, Germany. All available PM-Mito biopsy samples, an equal number of randomly selected IBM biopsy samples, and randomly selected nondiseased controls (NDCs) were included in the study. Biopsy samples were studied by histopathology, immunohistochemistry, and quantitative PCR (qPCR) and compared with biopsies derived from NDCs. Primary outcomes included cell counts for immunohistochemistry and gene expression (fold-change values compared with those in NDCs) for qPCR.

Results: Twenty-five skeletal muscle biopsy samples of patients with PM-Mito and IBM were included in the study and compared with 5 biopsy samples from NDCs. PM-Mito and IBM qualitatively harbored a strikingly similar molecular signature and shared important histopathologic features. Expression of IFN-induced guanylate-binding protein (GBP)6 and T-cell function-related KLRG1 distinguished IBM from PM-Mito biopsies with IBM patients showing significantly higher expression of GBP6 and KLRG1. Cryptic exon expression was detected in both patient groups with IBM patients showing higher expression levels. Skeletal muscle biopsies from IBM patients showed significantly more GBP6⁺ cells and KLRG1⁺ lymphocytes in comparison with biopsies from patients with PM-Mito. CD45⁺, CD68⁺, CD57⁺, PD1⁺, and CD8⁺ cytotoxic T cells were also significantly more abundant in patients with IBM. Clinically, patients with PM-Mito presented with a spectrum of muscle-related symptoms including myalgia, proximal paraparesis, proximal tetraparesis, and incomplete IBM-like patterns. Thirteen of 14 (93%) patients with PM-Mito for whom clinical follow-up was available later developed clinically defined IBM. Notably, 2 follow-up biopsies obtained 5 and 7 years after the first ones were available in this cohort, both showing histopathologic progress to net IBM including GBP6 and KLRG1 upregulation.

Discussion: Our combined data suggest that specific IFN-mediated inflammation plays a key role in both IBM and PM-Mito. GBP6 was identified as a new molecule of type II IFN-induced inflammation distinguishing IBM from PM-Mito. Skeletal muscles from both groups harbor dysfunctional T cells of similar type, albeit in different quantity. T-cell senescence exemplified by KLRG1 positivity does not play a significant role in PM-Mito. Based on these findings, we propose to include PM-Mito in the spectrum of IBM (IBM-spectrum disease [IBM-SD]) as a possible early form of this disease. The establishment of IBM-SD as a larger entity could potentially have a significant effect on the design of trials and therapeutic interventions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biopsy
Cross-Sectional Studies
Humans
Inflammation / pathology
Muscle, Skeletal / pathology
Myositis* / pathology
Myositis, Inclusion Body* / pathology
Polymyositis*