TP53 mutations coincide with the ectopic expression of activation-induced cytidine deaminase in the fibroblast-like synoviocytes derived from a fraction of patients with rheumatoid arthritis
TP53 mutations coincide with the ectopic expression of activation-induced cytidine deaminase in the fibroblast-like synoviocytes derived from a fraction of patients with rheumatoid arthritis
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DOI：
10.1111/j.1365-2249.2010.04163.x
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发表时间：
2010-07-01
影响因子：
4.6
通讯作者：
Ishihara, K.
中科院分区：
文献类型：
--
作者：
Igarashi, H.;Hashimoto, J.;Ishihara, K.
类风湿关节炎（RA）的主要特征是成纤维细胞样滑膜细胞（FLS）增生和关节破坏，这是由慢性自身免疫性炎症产生的炎性细胞因子引起的。RA-FLS的肿瘤样表型的细胞内在获得也可能是侵袭性增殖和侵袭的原因，这得到以下事实的支持：在某些情况下，RA-FLS具有肿瘤抑制基因TP 53的突变。然而，RA-FLS中TP 53突变的潜在分子机制尚未阐明。最近有报道称，炎症组织中的非淋巴细胞异位表达激活诱导的胞苷脱氨酶（AID）基因，该基因不仅在生发中心B淋巴细胞的免疫球蛋白（IG）基因可变区，而且在TP 53的编码区诱导体细胞超突变。实时聚合酶链反应（PCR）分析显示，我们建立的RA-FLS系中有一半以上（9个中的5个）的AID表达显著增加。肿瘤坏死因子（TNF）-α，甚至生理浓度的β-雌二醇不能诱导骨关节炎-FLS中的AID转录，增强了RA-FLS中的AID转录。此外，艾滋病阳性RA-FLS呈现出更高频率的TP 53体细胞突变。细胞学和免疫组织化学分析清楚地表明，在RA滑膜的FLS的AID异位表达。这些数据强烈地表明RA的一个新的后果; AID在RA-FLS中的异位表达导致TP 53的体细胞突变和功能障碍，导致RA-FLS获得肿瘤样性质。
P>Main features of rheumatoid arthritis (RA), hyperplasia of fibroblast-like synoviocytes (FLS) and joint destruction are caused by inflammatory cytokines produced in chronic autoimmune inflammation. Cell-intrinsic acquisition of tumour-like phenotypes of RA-FLS could also be responsible for the aggressive proliferation and invasion, which are supported by the fact that in some cases RA-FLS has mutations of a tumour suppressor gene TP53. However, the underlying molecular mechanism for TP53 mutations in RA-FLS has not yet been clarified. Recently it has been reported that the non-lymphoid cells in the inflammatory tissues express ectopically the activation-induced cytidine deaminase (AID) gene that induces somatic hypermutations, not only at the immunoglobulin (Ig) gene variable regions in germinal centre B lymphocytes but also at coding regions in TP53. Real-time polymerase chain reaction (PCR) analyses revealed more than half (five of nine) of the RA-FLS lines we established showed the markedly increased expression of AID. AID transcription in RA-FLS was augmented by tumour necrosis factor (TNF)-alpha and even by physiological concentration of beta-oestradiol that could not induce AID transcription in osteoarthritis-FLS. Furthermore, AID-positive RA-FLS presented a higher frequency of somatic mutations in TP53. Cytological and immunohistochemical analyses demonstrated clearly the ectopic expression of AID in the FLS at the RA synovium. These data suggested strongly a novel consequence of RA; the ectopic expression of AID in RA-FLS causes the somatic mutations and dysfunction of TP53, leading to acquisition of tumour-like properties by RA-FLS.