Vermeire K, Heremans H, Vandeputte M, Huang S, Billiau A, Matthys P
Laboratory of Immunobiology, Rega Institute, University of Leuven, Belgium.
J Immunol. 1997 Jun 1;158(11):5507-13.
Collagen-induced arthritis (CIA) is a model for rheumatoid arthritis. Here, we describe experiments showing that IFN-gamma receptor knockout (IFN-gammaR alpha KO) mice of the DBA/1 strain develop CIA more readily than their wild-type counterparts. Symptoms of disease started 10 days earlier and the cumulative incidence of arthritis was significantly higher in the mutant mice than in wild-type mice. Similarly, accelerated onset of the disease was also found in wild-type DBA/1 mice treated with neutralizing mAbs against IFN-gamma. Histologic examination of the joints revealed a massive infiltration of the synovium with mononuclear cells and neutrophils, hyperplasia, and severe pannus formation in IFN-gammaR alpha KO mice when such inflammatory lesions were not yet detectable in wild-type mice. Serum levels of anti-collagen type II Abs, including total IgG and IgM, as well as IgG1, IgG2a, and IgG2b isotypes were found to be lower in the mutant mice. IL-2 and IL-4 remained undetectable in sera of both groups of mice, but did appear in the circulation after anti-CD3 Ab challenge. Significantly higher IL-2 and lower IL-4 serum levels were found in anti-CD3-challenged IFN-gammaR alpha KO mice than in wild-type counterparts, both at an early and at a later stage of the disease. These observations indicate that endogenous IFN-gamma counteracts development of collagen-induced arthritis and suggest that IFN-gamma does so by up-regulating IL-4 production and/or down-regulating IL-2 production. The data are in line with the concept of a pathogenic role of Th1-type cellular immunity in CIA in spite of a decreased Ab response to collagen type II.
胶原诱导性关节炎（CIA）是类风湿性关节炎的一种模型。在此，我们描述了一些实验，这些实验表明DBA/1品系的干扰素-γ受体敲除（IFN-γRα KO）小鼠比其野生型同窝小鼠更容易患上CIA。疾病症状提前10天出现，突变小鼠中关节炎的累积发病率显著高于野生型小鼠。同样，在用抗干扰素-γ的中和单克隆抗体处理的野生型DBA/1小鼠中也发现了疾病的加速发作。关节的组织学检查显示，当野生型小鼠中尚未检测到此类炎症病变时，IFN-γRα KO小鼠的滑膜出现大量单核细胞和中性粒细胞浸润、增生以及严重的血管翳形成。发现突变小鼠中抗II型胶原抗体的血清水平，包括总IgG和IgM以及IgG1、IgG2a和IgG2b亚型均较低。两组小鼠血清中均未检测到IL-2和IL-4，但在抗CD3抗体激发后出现在循环中。在疾病的早期和晚期，抗CD3激发的IFN-γRα KO小鼠血清中IL-2水平显著高于野生型同窝小鼠，而IL-4水平则较低。这些观察结果表明内源性干扰素-γ可对抗胶原诱导性关节炎的发展，并提示干扰素-γ是通过上调IL-4产生和/或下调IL-2产生来实现的。尽管对II型胶原的抗体反应有所降低，但这些数据与Th1型细胞免疫在CIA中的致病作用概念相符。
