Pathogenesis of inflammatory arthropathy developed in HTLV-I transgenic mice

我们最近报道了一种类似类风湿性关节炎的炎性关节病，在携带人类t细胞白血病病毒1型（HTLV-1）基因组env-pX区域的转基因小鼠中发病率很高（Iwakura et al., Science, 1991）。病理与类风湿关节炎非常相似，滑膜细胞过度生长，炎症细胞浸润，骨和软骨糜烂，以及肠膜形成(Rheum。Arth. 36,1612,1993)，而且，免疫球蛋白的络合型碳水化合物链中有很大一部分缺乏末端半乳糖残基（BBRC,192,1004,1993）。为了阐明这种疾病的发病机制，我们发现在转基因关节中，炎症因子的基因包括il -1 α、il -1 β、IL-2、IL-6、tnf - α和ifn - γ以及MHC基因被激活（提交）。有趣的是，这些小鼠产生了抗IgG、II型胶原蛋白（IIC）和热休克蛋白（HSPs）的抗体，并伴有IgG高γ球蛋白血症。因此，htlv - 1可以引起自身免疫。由于关节炎的发展在很大程度上受小鼠遗传背景的影响，因此认为自身免疫参与了其发病机制。这些观察结果表明，这些小鼠不仅有助于分析类风湿关节炎的致病性，而且有助于研究自身免疫的致病性和细胞因子在其发展中的作用。我们现在正在使用这种转基因小鼠系统详细研究逆转录病毒与宿主的相互作用。

We have recently reported on an inflammatory arthropathy resembling rheumatoid arthritis that develops in high incidence among transgenic mice that carry the env-pX region of the human T-cell leukemia virus type-1 (HTLV-1) genome (Iwakura et al., Science, 1991). The pathology was very similar to that of rheumatoid arthritis with synovial cell overgrowth, inflammatory cell infiltration, bone and cartilage erosion, and pannus formation (Rheum. Arth. 36,1612,1993), and moreover, a large proportion of the complex-type carbohydrate chains of the immunoglobulins lacked the terminal galactose residue (BBRC,192,1004,1993). In an effort to elucidate the pathogenesis of this disease, we found that genes for inflammatory cytokines including IL-1alpha, IL-1beta, IL-2, IL-6, TNF-alpha, and IFN-gamma as well as MHC genes were activated in the transgenic joints (submitted). Interestingly, these mice produced antibodies against IgG,type II collagen (IIC), and heat shock proteins (HSPs) accompanied by IgG hypergammaglobulinemia. Thus, it was shown that HTLV-I can cause autoimmunity. Since development of arthritis was greatly affected by the genetic background of the mice, involvement of autoimmunity in the pathogenesis was suggested. These observations show that these mice are useful not only to analyze pathogenicity of rheumatoid arthritis but also to study pathogenicity of autoimmunity and roles of cytokines in its development. We are now studying retrovirus-host interactions in details using this transgenic mouse system.