Edwards C K, Zhou T, Zhang J, Baker T J, De M, Long R E, Borcherding D R, Bowlin T L, Bluethmann H, Mountz J D
Department of Immunology, Hoechst Marion Roussel, Cincinnati, OH 45215, USA.
J Immunol. 1996 Aug 15;157(4):1758-72.
We have used fas-defective MRL-lpr/lpr mice to study the effects of the staphylococcal enterotoxin superantigens on the development of autoimmune, inflammatory joint disease in animals that are susceptible to the development of rheumatoid arthritis-like disease. We show that systematic administration by a single i.p. injection of staphylococcal enterotoxin B (SEB; 10 micrograms/mouse) caused a mild, inflammatory arthritis +30 days postchallenge in the knee joints of young (< 2-mo-old) MRL-lpr/lpr mice, but not aged-matched MRL +/+ mice. In aged (> 8-mo-old) MRL-lpr/lpr mice, but not in aged MRL +/+ mice, SEB caused a severe, inflammatory arthritis, as assessed histologically, and systemic autoimmune disease, including glomerulonephritis and autoantibody production. Furthermore, in aged MRL-lpr/lpr mice, SEB but not heat-denatured SEB caused acute weight loss and elevated levels of serum proinflammatory cytokines. Compared with highly purified peritoneal macrophages obtained from either aged MRL +/+, young MRL-lpr/lpr, or young MRL +/+, peritoneal macrophages obtained from aged MRL-lpr/lpr mice constitutively expressed 2- to 10-fold greater levels of TNF-alpha, IL-1 beta, IL-6, and IL-10, and produced elevated amounts of these cytokines when treated in vitro with SEB. SEB-challenged aged MRL-lpr/lpr mice treated with anti-TNF mAb (100 micrograms/mouse; every other day), anti-V beta 8 TCR mAb (250 micrograms/mouse; every other day), or orally with the novel TNF-alpha inhibitor MDL 201,449A (9-[(1R, 3R)-trans-cyclopentan-3-ol] adenine; 25 mg/kg/day) exhibited reduced inflammatory arthritis, autoantibody formation, and serum TNF-alpha levels, but not IL-10 levels, after +30 days of treatment. These data suggest that SEB is an extremely potent macrophage-activating factor in vitro and in vivo, enhancing several aspects of autoimmune disease in MRL-lpr/lpr mice, and that anti-TNF therapies may have potential use in inflammatory arthritis.
我们使用Fas缺陷型MRL-lpr/lpr小鼠来研究葡萄球菌肠毒素超抗原对易患类风湿关节炎样疾病的动物自身免疫性炎症性关节病发展的影响。我们发现，通过单次腹腔注射葡萄球菌肠毒素B（SEB；10微克/只小鼠）进行全身给药，在年轻（<2月龄）MRL-lpr/lpr小鼠的膝关节中，在攻击后30天引起了轻度炎症性关节炎，但在年龄匹配的MRL +/+小鼠中未出现。在老年（>8月龄）MRL-lpr/lpr小鼠中，但不在老年MRL +/+小鼠中，SEB引起了严重的炎症性关节炎，经组织学评估，以及全身性自身免疫性疾病，包括肾小球肾炎和自身抗体产生。此外，在老年MRL-lpr/lpr小鼠中，SEB而非热变性SEB导致急性体重减轻和血清促炎细胞因子水平升高。与从老年MRL +/+、年轻MRL-lpr/lpr或年轻MRL +/+获得的高度纯化的腹腔巨噬细胞相比，从老年MRL-lpr/lpr小鼠获得的腹腔巨噬细胞组成性地表达的TNF-α、IL-1β、IL-6和IL-10水平高2至10倍，并且在体外用SEB处理时产生这些细胞因子的量增加。用抗TNF单克隆抗体（100微克/只小鼠；每隔一天）、抗Vβ8 TCR单克隆抗体（250微克/只小鼠；每隔一天）或口服新型TNF-α抑制剂MDL 201,449A（9-[(1R, 3R)-反式环戊烷-3-醇]腺嘌呤；25毫克/千克/天）处理SEB攻击的老年MRL-lpr/lpr小鼠，在治疗30天后，炎症性关节炎、自身抗体形成和血清TNF-α水平降低，但IL-10水平未降低。这些数据表明，SEB在体外和体内是一种极其有效的巨噬细胞激活因子，增强了MRL-lpr/lpr小鼠自身免疫性疾病的多个方面，并且抗TNF疗法可能在炎症性关节炎中有潜在用途。
