In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy
In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy
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DOI：
10.1136/annrheumdis-2018-213518
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发表时间：
2019-01-01
影响因子：
27.4
通讯作者：
Boyer, Olivier
中科院分区：
文献类型：
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作者：
Bergua, Cecile;Chiavelli, Helene;Boyer, Olivier
目的在自身免疫中，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效应因子。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，被称为免疫介导性坏死性肌病(IMNM)。AAB水平与IMNM活性相关，疾病可能对免疫抑制有反应，提示它们是致病的。目的通过建立抗SRP或抗HMGCR AAB的IMNM小鼠模型，评价抗SRP或抗HMGCR AAB患者的免疫球蛋白在体内的致病性。方法将抗SRP或抗HMGCR相关的IMNM患者的免疫球蛋白被动转移到野生型、Rag2(-/-)或补体C3(-/-)小鼠体内。通过电刺激肌力和握力试验评价肌力。苏木精/伊红染色或免疫荧光或免疫组织化学分析后进行组织学分析。结果被动地将免疫球蛋白从IMNM患者转移到C57BL/6或Rag2(-/-)小鼠可引起肌肉功能缺失。AAB对C3(-/-)小鼠的致病性降低，而补充人补体则增强。结论本研究证实患者来源的抗SRP+和抗HMGCR(+)免疫球蛋白通过补体介导的机制在体内对肌肉产生致病作用，明确了IMNM的自身免疫特性。这些数据支持血浆交换的使用，并支持在IMNM中评估补体靶向治疗。
Objectives 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 in vivo by developing the first mouse model of IMNM.Methods I gG 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).Results 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.Conclusion This study demonstrates that patient-derived anti-SRP+ and anti-HMGCR(+) IgG are pathogenic towards muscle in vivo 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.