Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis.
Corinna PreußeBarbara PaeslerChristopher NelkeDerya CengizThomas MünteferingAndreas RoosDamien AmelinYves AllenbachAkinori UruhaCarsten DittmayerAndreas HentschelMarc PawlitzkiSarah HoffmannSara TimmSarah Leonard LouisNora F DenglerHeinz WiendlJan D LünemannAlbert SickmannBaptiste HervierSven G MeuthUdo SchneiderAnne SchänzerSabine KrauseStylianos TomarasEugen FeistRebecca HasseliHans-Hilmar GoebelLaure GallayNathalie StreichenbergerOlivier BenvenisteWerner StenzelTobias RuckPublished in: Acta neuropathologica (2022)
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.
Keyphrases
- skeletal muscle
- end stage renal disease
- newly diagnosed
- induced apoptosis
- ejection fraction
- chronic kidney disease
- type diabetes
- cell cycle arrest
- stem cells
- prognostic factors
- patient reported outcomes
- gene expression
- rheumatoid arthritis
- cell death
- insulin resistance
- mesenchymal stem cells
- cell proliferation
- drug delivery
- high resolution
- endoplasmic reticulum stress
- single molecule
- optical coherence tomography
- systemic sclerosis
- pulmonary hypertension
- pi k akt
- study protocol
- extracellular matrix