Normandie Univ, UNIROUEN, IRIB, Inserm, U1234, Departement of Immunology, Rouen University Hospital, Rouen, France.
Department of Internal Medicine and Clinical Immunology, Sorbonne Université, UPMC, Inserm, U974, Center of Research in Myology, Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Paris, France.
Ann Rheum Dis. 2019 Jan;78(1):131-139. doi: 10.1136/annrheumdis-2018-213518. Epub 2018 Oct 11.
In autoimmunity, autoantibodies (aAb) may be simple biomarkers of disease or true pathogenic effectors. A form of idiopathic inflammatory myopathy associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) aAb has been individualised and is referred to as immune-mediated necrotising myopathy (IMNM). The level of aAb correlates with IMNM activity and disease may respond to immunosuppression, suggesting that they are pathogenic. We aimed to evaluate the pathogenicity of IgG from patients with anti-SRP or anti-HMGCR aAb by developing the first mouse model of IMNM.
IgG from patients suffering from anti-SRP or anti-HMGCR associated IMNM were passively transferred to wild-type, Rag2 or complement C3 mice. Muscle deficiency was evaluated by muscle strength on electrostimulation and grip test. Histological analyses were performed after haematoxylin/eosin staining or by immunofluorescence or immunohistochemistry analysis. Antibody levels were quantified by addressable laser bead assay (ALBIA).
Passive transfer of IgG from patients suffering from IMNM to C57BL/6 or Rag2 mice provoked muscle deficiency. Pathogenicity of aAb was reduced in C3 mice while increased by supplementation with human complement. Breakage of tolerance by active immunisation with SRP or HMGCR provoked disease.
This study demonstrates that patient-derived anti-SRP and anti-HMGCR IgG are pathogenic towards muscle through a complement-mediated mechanism, definitively establishing the autoimmune character of IMNM. These data support the use of plasma exchanges and argue for evaluating complement-targeting therapies in IMNM.
在自身免疫中，自身抗体（aAb）可能是疾病的简单生物标志物，也可能是真正的致病性效应物。一种与抗信号识别颗粒（SRP）或抗 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGCR）aAb 相关的特发性炎症性肌病已被个体化，并被称为免疫介导的坏死性肌病（IMNM）。aAb 水平与 IMNM 活性相关，疾病可能对免疫抑制有反应，这表明它们具有致病性。我们旨在通过开发首个 IMNM 小鼠模型来评估抗 SRP 或抗 HMGCR aAb 患者 IgG 的致病性。
将患有抗 SRP 或抗 HMGCR 相关 IMNM 的患者的 IgG 被动转移到野生型、Rag2 或补体 C3 小鼠中。通过电刺激和握力测试评估肌肉无力。通过苏木精/伊红染色或免疫荧光或免疫组织化学分析进行组织学分析。通过可寻址激光珠测定法（ALBIA）定量抗体水平。
将 IMNM 患者的 IgG 被动转移到 C57BL/6 或 Rag2 小鼠中会引起肌肉无力。在 C3 小鼠中，aAb 的致病性降低，而通过补充人补体则增加。用 SRP 或 HMGCR 主动免疫打破耐受会引发疾病。
本研究表明，源自患者的抗 SRP 和抗 HMGCR IgG 通过补体介导的机制对肌肉具有致病性，明确确立了 IMNM 的自身免疫性质。这些数据支持使用血浆置换，并为评估 IMNM 中的补体靶向治疗提供了依据。
