The role of collagen antibodies in mediating arthritis

This review examines evidence that rheumatoid arthritis (RA) depends on autoimmunity to articular collagen, and mechanisms whereby autoantibodies to type II collagen contribute to disease development. Three major autoantigenic reactants have been identified in RA; the corresponding autoantibodies are rheumatoid factor (RF), antibodies to citrullinated peptide antigens (ACPA), citrullinated peptides (anti-CCP), and anti-type II collagen (anti-CII). Both RF and ACPA are well-validated and predictive markers of severe erosive RA, but cannot be linked to pathogenesis. By contrast, in various animal species immunized with CII there occurs an erosive inflammatory arthritis resembling that seen in human RA, together with antibodies to CII with an epitope specificity similar to that in RA. We discuss the well-known role of immune complexes in the induction of inflammation within the joint, and present recent data showing, additionally, that antibodies to CII cause direct damage to cartilage in vitro. The close resemblances between human RA and collagen-induced arthritis in animals suggest that autoimmunity, and particularly autoantibodies to CII, are important for both the initiation and perpetuation of RA in a dual manner: as contributors to the inflammation associated with immune complex deposition, and as agents with direct degradative effects on cartilage integrity and its repair.     

Gender differences and protective effects of testosterone in collagen induced arthritis in rats

To understand the gender differences noticed in autoimmune disorders, particularly rheumatoid arthritis, we used a rat model of collagen induced arthritis (CIA). This study was carried out in two parts. In the first study, severity of inflammation was compared between male and female rats with respect to radiology, histology, activities of lysosomal enzymes, lipid peroxidation, immune response to type II collagen and the level of prostaglandin, a major inflammatory mediator. Since female rats developed severe inflammation, this study was extended to confirm if testosterone at physiological concentration had protective effect against CIA. Hence, studies were carried out on the effect of testosterone application on castrated arthritic rats. Female arthritic rats were also treated with testosterone to find out the effectiveness of the androgen in the presence of female hormones. Results of this study conclusively showed that testosterone possessed significant anti-inflammatory effects at physiological concentration and exerted its action in a gender nonspecific manner.     

口服Ⅱ型胶原蛋白诱导佐剂性关节炎大鼠免疫耐受的研究

目的：对口服可溶性Ⅱ型胶原蛋白（typeⅡcollagen，CⅡ）诱导佐剂性关节炎（adju-vantarthritis，AA）大鼠免疫耐受的治疗作用及其机制进行研究，并与雷公藤多甙的疗效进行比较。方法：建立大鼠AA模型，观察其口服CⅡ雷公藤多甙后关节肿胀度及病理学变化；检测相关的免疫学指标，包括迟发型超敏反应、循环免疫复合物、血清中抗CⅡ抗体的抗结核杆菌抗体水平。结果：①口服CⅡ能缓解AA大鼠的四肢关节症状和全身症状，减轻关节腔内滑膜增生及炎细胞浸润，效果较雷公藤多甙显著。②口服CⅡ使AA大鼠迟发型超敏反应减弱，循环免疫复合物及血清中抗CⅡ抗体水平降低。结论：口服CⅡ对AA大鼠有明显的近期治疗效果，其作用机制可能与抑制Th1细胞介导的细胞免疫，增强Th2细胞介导的体液免疫有关。     

cDNA微阵列对不同时期胶原诱导性关节炎大鼠PBMC基因表达谱的初步研究

目的 研究胶原诱导性关节炎（collagen induced arthritis，CIA）大鼠不同时期外周血单个核细胞（peripheral blood mononuclear cells，PBMC）基因表达谱，寻找与疾病炎症相关的特异表达基因，初步探讨类风湿关节炎（rheumatoid arthritis，RA）的发病机制。方法 以含有96个基因的功能基因组芯片研究CIA大鼠发病早期、高峰期和后期及正常大鼠的PBMC基因表达谱。结果 cDNA微阵列检测结果显示，CIA早期差异表达基因（〉2或〈0．5）有19个，高峰期25个，后期17个以及三个时期持续表达的上调基因有10个。差异表达基因主要涉及白细胞介素及其受体、趋化因子及其受体、转化生长因子配体及受体等。结论 CIA不同时期基因的差异表达可能与RA病情的持续进展有关，为进一步探讨细胞因子在RA的作用提供理论依据。     

周期联合甲氨蝶呤和环磷酰胺对大鼠胶原诱导性关节炎滑膜细胞周期蛋白D1表达的研究

目的 通过研究大鼠胶原诱导件关节炎(CIA)滑膜组织细胞周期蛋白D1(cyclin D1)的表达以及甲氨蝶呤(MTX)和环磷酰胺(CTX)对其的影响,从周期调控的角度探讨两者联合治疗类风湿关节炎(RA)可能的协同效应机制.方法 建立Ⅱ型胶原诱导的雌性Wistar大鼠CIA模型,随机分为正常对照组、CIA模型对照组、小剂量MTX治疗组(每周0.9 mg/kg)、大剂量MTX治疗组(每周2.7mg/kg)、小剂量CTX间歇治疗组(每3周24 mg/kg)、联合治疗组(MTX每周0.9 mg/kg+CTX每3周24mg/kg).治疗24周后全部动物处死取材,再经同定、脱钙、包埋,原位杂交法检测滑膜细胞周期蛋白cyclin D1 mRNA.结果 CIA模型组大鼠关节滑膜组织的cvclin D1 mRNA的阳性染色强度明显高于正常对照组(P＜0.05),各治疗组滑膜cvclin D1 mRNA下调,联合治疗组cyclin D1 mRNA表达最低,各组间平均灰度值差异有统计学意义(P＜0.05).MTX与CTX存在药物交互作用(P＜0.05),联合治疗组优于单用药治疗组.结论 提示MTX和CTX联合治疗为协同效应,可能的重要机制是使滑膜cyclin D1 mRNA下调,从而抑制了滑膜细胞异常增殖.