Journal article

Publication year: 2022

Pages: 353-372

Journal: Acta Neuropathologica

Volume number: 144

Issue number: 2

ISSN: 0001-6322

eISSN: 1432-0533

Open access status: Hybrid

DOI Link: https://doi.org/10.1007/s00401-022-02438-z

Publisher: Springer

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.

Harvard Citation style: Preusse, C., Paesler, B., Nelke, C., Cengiz, D., Muentefering, T., Roos, A., et al. (2022) Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis, Acta Neuropathologica, 144(2), pp. 353-372. https://doi.org/10.1007/s00401-022-02438-z

APA Citation style: Preusse, C., Paesler, B., Nelke, C., Cengiz, D., Muentefering, T., Roos, A., Amelin, D., Allenbach, Y., Uruha, A., Dittmayer, C., Hentschel, A., Pawlitzki, M., Hoffmann, S., Timm, S., Louis, S., Dengler, N., Wiendl, H., Lunemann, J., Sickmann, A., ...Ruck, T. (2022). Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis. Acta Neuropathologica. 144(2), 353-372. https://doi.org/10.1007/s00401-022-02438-z