Aberrant MHC class II expression in mouse joints leads to arthritis with extraarticular manifestations similar to rheumatoid arthritis
Aberrant MHC class II expression in mouse joints leads to arthritis with extraarticular manifestations similar to rheumatoid arthritis
复制标题
DOI：
10.1073/pnas.0606450103
复制
发表时间：
2006-09-26
影响因子：
11.1
通讯作者：
Peterlin, B. Matija
中科院分区：
文献类型：
--
作者：
Kanazawa, Satoshi;Ota, Shusuke;Peterlin, B. Matija
类风湿性关节炎（RA）的遗传易感性与某些MHC II类分子有关。为了阐明这些决定因素在RA中的作用，我们制造了D1CC转基因小鼠，该小鼠通过MHC II类途径表达参与抗原加工和递呈的基因。II类反激活子由大鼠胶原II型启动子和增强子转录而来，指导这些基因的表达。在具有H-2(q) （DBA/1）基因背景的D1CC小鼠中，佐剂中少量的牛II型胶原可诱导类似IRA的炎症性关节炎。重要的是，这些刺激对DBA/1小鼠没有影响。89%的D1CC小鼠患上了慢性疾病，关节肿胀、发红和发热，这与滑膜增生、滑膜形成和单核浸润有关。类似类风湿结节的肉芽肿病变和间质性肺炎也被观察到。与RA患者一样，在炎症期检测到抗环瓜氨酸肽抗体。最后，D1CC小鼠的关节表现为关节旁脱矿，严重的关节间隙狭窄和糜蚀，导致强直，但没有骨赘的出现。因此，关节中MIHC II类的异常表达促进了严重糜烂性炎性多关节炎的发展，这与RA非常相似。
Genetic susceptibility to rheumatoid arthritis (RA) is associated with certain MHC class II molecules. To clarify the role of these determinants in RA, we generated the D1CC transgenic mouse that expressed genes involved in antigen processing and presentation by the MHC class II pathway in joints. The class II transactivator, which was transcribed from the rat collagen type II promoter and enhancer, directed the expression of these genes. In D1CC mice congenic for the H-2(q) (DBA/1) background, small amounts of bovine collagen type II in adjuvant induced reproducibly an inflammatory arthritis resembling IRA. Importantly, these stimuli had no effect in DBA/1 mice. Eighty-nine percent of D1CC mice developed chronic disease with joint swelling, redness, and heat in association with synovial proliferation as well as pannus formation and mononuclear infiltration of synovial membranes. Granulomatous lesions resembling rheumatoid nodules and interstitial pneumonitis also were observed. As in patients with RA, anticyclic citrullinated peptide antibodies were detected during the inflammatory stage. Finally, joints in D1CC mice displayed juxtaarticular demineralization, severe joint space narrowing, and erosions, which led to ankylosis, but without the appearance of osteophytes. Thus, aberrant expression of MIHC class II in joints facilitates the development of severe erosive inflammatory polyarthritis, which is very similar to RA.