Tanaka M, Ozaki S, Osakada F, Mori K, Okubo M, Nakao K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
Int Immunol. 1998 Sep;10(9):1305-14. doi: 10.1093/intimm/10.9.1305.
In an attempt to identify autoantigens of synovium in rheumatoid arthritis (RA), we constructed lambda phage expression cDNA libraries from synovium and screened them by IgG purified from synovial fluids, both of which were derived from RA patients. As a result of this unique combination of the libraries and probes, we cloned follistatin-related protein (FRP) as a novel autoantigen in systemic rheumatic diseases. FRP is a secreted protein containing a similar amino acid sequence to follistatin, an inhibitor of activin. FRP was first cloned as a transforming growth factor-beta1-inducible protein (called TSC-36) from a mouse osteoblastic cell line and was suggested to have some roles in the negative regulation of cellular growth. Immunoblotting analyses detected synovial fluid and serum anti-FRP antibodies of IgG class more frequently in RA than any other systemic rheumatic diseases and controls. Synovial fluid anti-FRP antibodies appeared in 44% of RA (n = 18) and none of osteoarthritis (OA) (n = 15) patients. Serum antibodies were detected in 30% of RA (n = 67), 17% of systemic sclerosis (n = 18), 10% of systemic lupus erythematosus (n = 51) and Sjögren's syndrome (n = 10), and none of polymyositis/dermatomyositis (n = 13) patients and healthy subjects (n = 30). These antibodies recognized an EC domain, an extracellular Ca2+ binding module. In anti-FRP antibody-positive RA patients, serum C-reactive protein level and erythrocyte sedimentation rate were more elevated than negative patients (P < 0.05 and P < 0.01, respectively). FRP gene expression was higher in RA than OA synovium (P < 0.05). However, there was no difference between these groups in the amount of synovial FRP, suggesting its elevated turnover in RA. As follistatin inhibits activin, FRP might inhibit some growth factor-like molecule. Detection of anti-FRP antibodies, possibly having disease-promoting effects as the blocking antibodies, could be one of the markers for clinical evaluation of systemic rheumatic diseases.
为了鉴定类风湿关节炎（RA）中滑膜的自身抗原，我们从滑膜构建了λ噬菌体表达cDNA文库，并用从滑液中纯化的IgG对其进行筛选，文库和滑液均来自RA患者。由于文库和探针的这种独特组合，我们克隆了卵泡抑素相关蛋白（FRP），它是一种系统性风湿性疾病中的新型自身抗原。FRP是一种分泌蛋白，其氨基酸序列与激活素的抑制剂卵泡抑素相似。FRP最初是从小鼠成骨细胞系中作为转化生长因子-β1诱导蛋白（称为TSC-36）克隆出来的，并被认为在细胞生长的负调控中发挥一定作用。免疫印迹分析检测到，与其他任何系统性风湿性疾病及对照相比，RA患者滑液和血清中IgG类抗FRP抗体更为常见。44%的RA患者（n = 18）出现滑液抗FRP抗体，而骨关节炎（OA）患者（n = 15）均未出现。30%的RA患者（n = 67）、17%的系统性硬化症患者（n = 18）、10%的系统性红斑狼疮患者（n = 51）和干燥综合征患者（n = 10）检测到血清抗体，而多发性肌炎/皮肌炎患者（n = 13）和健康受试者（n = 30）均未检测到。这些抗体识别一个EC结构域，即一个细胞外Ca2+结合模块。在抗FRP抗体阳性的RA患者中，血清C反应蛋白水平和红细胞沉降率比阴性患者更高（分别为P < 0.05和P < 0.01）。RA滑膜中FRP基因表达高于OA滑膜（P < 0.05）。然而，这些组之间滑膜FRP的量没有差异，表明其在RA中的周转率升高。由于卵泡抑素抑制激活素，FRP可能抑制某些生长因子样分子。检测可能作为封闭抗体具有促病作用的抗FRP抗体，可能是系统性风湿性疾病临床评估的标志物之一。
