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

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.

Muscle pathology of antisynthetase syndrome according to antibody subtypes

“…ARS, antisynthetase syndrome (all subtypes); DM, dermatomyositis; IBM, inclusion body myositis; IMNM, immune-mediated necrotizing myopathy; P-MM, possible myositis mimics. pathological features among these ASS subtypes including PFN, MHC class I upregulation and prominent perifascicular MHC class II expression; only one PL-12 ASS had negative MHC class II expression [41]. In line with the pathological features, the proteomic profiling of muscle associated with these three antibodies show no significant difference [ 41].…”

High-Dimensional Cytometry Dissects Immunological Fingerprints of Idiopathic Inflammatory Myopathies

“…Two previous studies reported elevated levels of circulating Tfh cells in IIM (PM and DM patients) compared to healthy controls [ 25 , 26 ]. Further, we previously substantiated the presence of Tfh cells in ASyS muscle in comparison to non-diseased controls [ 21 ]. Promoting antigen-specific B cells [ 27 ], Tfh cells might provide a pro-stimulatory framework for B cell pathology in ASyS.…”

“…First, ASyS is characterized by antibodies against the aminoacyl-transferase RNA synthetases, commonly against Jo-1, OJ, PL-7 or PL-12. To better understand disease specific pathways of autoimmunity, we investigated ASyS pathology in a previous study [ 21 ]. Here, we identified an extra-medullary inflammatory micro-milieu maintaining activated B cells.…”

Coordinated immune dysregulation in juvenile dermatomyositis revealed by single-cell genomics

“…However, recent immunophenotyping work in a large cohort of JDM patients that found simultaneous expansion of CXCR5-central memory B cells and Th2 cells provides support for further investigation into extra-follicular B-T cell help in JDM (15). Alternatively, this skewing could represent more mature B cells homing to tissues as has been described in antisynthetase syndrome (48,49). Functional work to support or negate the extrafollicular pathway in JDM will be critical to determine if this is a targetable pathway therapeutically.…”