MICL controls inflammation in rheumatoid arthritis.
MICL controls inflammation in rheumatoid arthritis.
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DOI：
10.1136/annrheumdis-2014-206644
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发表时间：
2016-07
影响因子：
27.4
通讯作者：
Brown GD
中科院分区：
文献类型：
--
作者：
Redelinghuys P;Whitehead L;Augello A;Drummond RA;Levesque JM;Vautier S;Reid DM;Kerscher B;Taylor JA;Nigrovic PA;Wright J;Murray GI;Willment JA;Hocking LJ;Fernandes MJ;De Bari C;Mcinnes IB;Brown GD
髓系抑制性c型凝集素样受体（MICL, Clec12A）是一种主要由髓系细胞表达的c型凝集素受体（CLR）。先前的研究表明MICL参与控制炎症。利用Clec12A - / -小鼠确定该CLR在炎症病理中的作用。Clec12A - / -小鼠是商业化产生的，主要使用胶原抗体诱导的关节炎（CAIA）模型进行表征。通过临床评分、组织学、流式细胞术、辐照骨髓嵌合体的产生、阻断抗体的使用和体内成像来表征疾病的机制和进展。通过免疫组织化学和单核苷酸多态性分析确定类风湿关节炎（RA）患者MICL的特征。采用酶联免疫吸附法和点印迹法检测患者血清中抗micl抗体。micl缺陷动物没有出现泛免疫功能障碍，但在CAIA期间表现出明显加剧的炎症，这是由于骨髓细胞的不适当激活。MICL的多态性与RA患者的疾病无关，但该CLR是一部分RA患者自身抗体的靶点。在野生型小鼠中，这些抗体重现了Clec12A−/−表型。MICL在关节炎期间的炎症调节中起着重要作用，并且在RA患者的一个亚群中是一种自身抗原。这些数据提示了一种全新的RA发病机制，即骨髓细胞激活的阈值可以通过结合细胞膜表达抑制受体的自身抗体来调节。
Myeloid inhibitory C-type lectin-like receptor (MICL, Clec12A) is a C-type lectin receptor (CLR) expressed predominantly by myeloid cells. Previous studies have suggested that MICL is involved in controlling inflammation. To determine the role of this CLR in inflammatory pathology using Clec12A−/− mice. Clec12A−/− mice were generated commercially and primarily characterised using the collagen antibody-induced arthritis (CAIA) model. Mechanisms and progress of disease were characterised by clinical scoring, histology, flow cytometry, irradiation bone-marrow chimera generation, administration of blocking antibodies and in vivo imaging. Characterisation of MICL in patients with rheumatoid arthritis (RA) was determined by immunohistochemistry and single nucleotide polymorphism analysis. Anti-MICL antibodies were detected in patient serum by ELISA and dot-blot analysis. MICL-deficient animals did not present with pan-immune dysfunction, but exhibited markedly exacerbated inflammation during CAIA, owing to the inappropriate activation of myeloid cells. Polymorphisms of MICL were not associated with disease in patients with RA, but this CLR was the target of autoantibodies in a subset of patients with RA. In wild-type mice the administration of such antibodies recapitulated the Clec12A−/− phenotype. MICL plays an essential role in regulating inflammation during arthritis and is an autoantigen in a subset of patients with RA. These data suggest an entirely new mechanism underlying RA pathogenesis, whereby the threshold of myeloid cell activation can be modulated by autoantibodies that bind to cell membrane-expressed inhibitory receptors.