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.

抗合成酶综合征 (ASyS) 相关性肌炎是特发性炎症性肌病 (IIM) 的一个主要亚组，其特征是具有肌肉骨骼、皮肤病和肺部表现的慢性疾病。在受影响患者的血清中可检测到八种针对氨酰基转移酶 RNA 合成酶 (ARS) 的自身抗体中的一种。然而，尚未建立针对特定疾病的治疗方法。

为了更深入地了解潜在的发病机制并确定推定的治疗靶点，我们比较研究了与抗 PL-7、抗 PL-12 和抗 Jo-1 相关的最常见 ASyS 形式。我们的队列包括 80 名 ASyS 患者以及健康对照（n  = 40）、患病对照（n  = 40）和非患病对照（n  = 20）。与 Jo-1 ^{+患者相比，我们检测到 PL-12 +}患者肌肉活检的坏死和再生程度有所降低，而 PL-7 ⁺患者在骨骼肌活检中毛细血管脱落率较高。除了这些细微的变化外，未观察到 ASyS 亚组之间的显着差异。有趣的是，鉴定了 ASyS 肌炎常见的CD138 ⁺浆细胞和 CXCL12 ⁺ /CXCL13 ⁺ CD20 ^{+ B 细胞的组织特异性亚群。}这些细胞定位于与碱性磷酸酶⁺活化的间充质成纤维细胞和 CD68 ⁺ MHC-II ⁺ CD169 ⁺巨噬细胞相关的肌内膜。MHC-I ⁺和 MHC-II ⁺MxA 负 II 型干扰素驱动的肌纤维激活环境，在地形上局限于束周区域和邻近的肌束膜，以及 T 滤泡辅助细胞的肌束膜簇，为浆细胞和活化的 B 细胞定义了髓外免疫生态位。与此一致，来自 ASyS 患者的肌肉组织的蛋白质组学分析表明抗原加工和呈递发生了变化。外周血的深入免疫学分析支持 B 细胞/浆细胞驱动的病理学，包括向未成熟 B 细胞的转变、B 细胞相关细胞因子和趋化因子的增加以及补体系统的激活。我们假设 B 细胞驱动的病理学与骨骼肌中浆细胞特定亚型的存在和持续存在至关重要地参与了 ASyS 肌炎的自我延续慢性化。这项工作为浆细胞靶向疗法在 ASyS 肌炎中的应用提供了概念框架。