Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis

Preuße, Corinna; Paesler, Barbara; Nelke, Christopher; Cengiz, Derya; Müntefering, Thomas; Roos, Andreas; Amelin, Damien; Allenbach, Yves; Uruha, Akinori; Dittmayer, Carsten; Hentschel, Andreas; Pawlitzki, Marc; Hoffmann, Sarah; Timm, Sara; Louis, Sarah Leonard; Dengler, Nora F.; Wiendl, Heinz; Lunemann, Jan D.; Sickmann, Albert; Hervier, Baptiste; Meuth, Sven G.; Schneider, Udo; Schänzer, Anne; Krause, Sabine; Tomaras, Stylianos; Feist, Eugen; Hasseli, Rebecca; Goebel, Hans-Hilmar; Gallay, Laure; Streichenberger, Nathalie; Benveniste, Olivier; Stenzel, Werner und Ruck, Tobias (2022): Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis. In: Acta Neuropathologica, Bd. 144, Nr. 2: S. 353-372

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0001-6322
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 417011907
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 418901501