Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis
Creators: name: Preuße, Corinna
name: Paesler, Barbara
name: Nelke, Christopher
name: Cengiz, Derya
name: Müntefering, Thomas
name: Roos, Andreas
name: Amelin, Damien
name: Allenbach, Yves
name: Uruha, Akinori
name: Dittmayer, Carsten
name: Hentschel, Andreas
name: Pawlitzki, Marc
name: Hoffmann, Sarah
name: Timm, Sara
name: Louis, Sarah Leonard
name: Dengler, Nora F.
name: Wiendl, Heinz
name: Lünemann, Jan D.
name: Sickmann, Albert
name: Hervier, Baptiste
name: Meuth, Sven G.
name: Schneider, Udo
name: Schänzer, Anne
name: Krause, Sabine
name: Tomaras, Stylianos
name: Feist, Eugen
name: Hasseli, Rebecca
name: Goebel, Hans-Hilmar
name: Gallay, Laure
name: Streichenberger, Nathalie
name: Benveniste, Olivier
name: Stenzel, Werner
name: Ruck, Tobias
Publisher: name: Charité - Universitätsmedizin Berlin
Year: 2022
Subjects: subject: Anti-synthetase syndrome
subject: PL-7
subject: PL-12
subject: Jo-1
subject: Plasma cells
subject: Pathophysiology
subject: 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

description: Anti-synthetase syndrome (ASyS)-associated myositis is a major subgroup of the idiopathic inflammatory myopathies (IIM) and is characterized by disease chronicity with musculoskeletal, dermatological and pulmonary manifestations. One of eight autoantibodies against the aminoacyl-transferase RNA synthetases (ARS) is detectable in the serum of affected patients. However, disease-specific therapeutic approaches have not yet been established. To obtain a deeper understanding of the underlying pathogenesis and to identify putative therapeutic targets, we comparatively investigated the most common forms of ASyS associated with anti-PL-7, anti-PL-12 and anti-Jo-1. Our cohort consisted of 80 ASyS patients as well as healthy controls (n = 40), diseased controls (n = 40) and non-diseased controls (n = 20). We detected a reduced extent of necrosis and regeneration in muscle biopsies from PL-12(+) patients compared to Jo-1(+) patients, while PL-7(+) patients had higher capillary dropout in biopsies of skeletal muscle. Aside from these subtle alterations, no significant differences between ASyS subgroups were observed. Interestingly, a tissue-specific subpopulation of CD138(+) plasma cells and CXCL12(+)/CXCL13(+)CD20(+) B cells common to ASyS myositis were identified. These cells were localized in the endomysium associated with alkaline phosphatase(+) activated mesenchymal fibroblasts and CD68(+)MHC-II(+)CD169(+) macrophages. An MHC-I+ and MHC-II+ MxA negative type II interferon-driven milieu of myofiber activation, topographically restricted to the perifascicular area and the adjacent perimysium, as well as perimysial clusters of T follicular helper cells defined an extra-medullary immunological niche for plasma cells and activated B cells. Consistent with this, proteomic analyses of muscle tissues from ASyS patients demonstrated alterations in antigen processing and presentation. In-depth immunological analyses of peripheral blood supported a B-cell/plasma-cell-driven pathology with a shift towards immature B cells, an increase of B-cell-related cytokines and chemokines, and activation of the complement system. We hypothesize that a B-cell-driven pathology with the presence and persistence of a specific subtype of plasma cells in the skeletal muscle is crucially involved in the self-perpetuating chronicity of ASyS myositis. This work provides the conceptual framework for the application of plasma-cell-targeting therapies in ASyS myositis.