Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions
Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions
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DOI：
10.1172/jci6886
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发表时间：
1999-12-01
影响因子：
15.9
通讯作者：
Arnold, B
中科院分区：
文献类型：
--
作者：
Dubois, B;Masure, S;Arnold, B
基质金属蛋白酶(MMPs)及其抑制物(TIMPs)的调控表达在多种生理过程中发挥作用。为了确定这些因子在体内的不平衡表达如何促进或影响病理过程，我们通过用反义定向的新霉素抗性基因取代催化和锌结合区域来敲除小鼠明胶酶B基因。成年明胶酶B缺陷小鼠和野生型对照小鼠可诱发出神经系统疾病、血脑屏障通透性和中枢神经系统组织病理学评分相似的实验性自身免疫性脑脊髓炎(EAE)。然而，尽管患病对照组动物表现出坏死性尾部病变和骨关节组织的增生，但成年明胶酶B缺陷小鼠对这种尾部病理具有抵抗力。4周龄以下的明胶酶B缺陷小鼠与年龄匹配的对照组相比，对EAE的易感性显著降低，即使随着年龄的增长，它们仍然对尾部病变具有抵抗力。这些数据表明，明胶酶B的表达在免疫系统的发育中发挥了作用，在个体发育中，缺乏这种基质金属蛋白酶会改变发生自身免疫的倾向。
Regulated expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) plays a role in various physiological processes. To determine in vivo how unbalanced expression of these factors can promote or affect the course of pathologies, we knocked out the mouse gelatinase B gene by replacing the catalytic and zinc-binding domains with an antisense-oriented neomycin resistance gene. Adult gelatinase B-deficient mice and wild-type controls could be induced to develop experimental autoimmune encephalomyelitis (EAE) with similar scores for neurologic disease, blood-brain barrier permeability, and central nervous system histopathology. However, whereas diseased control animals showed necrotizing tail lesions with hyperplasia of osteocartilaginous tissue, adult gelatinase B-deficient mice were resistant to this tail pathology. Gelatinase B-deficient mice younger than 4 weeks of age were significantly less susceptible to the development of EAE than were age matched controls and, even as they aged, they remained resistant to tail lesions. These data illustrate that gelatinase B expression plays a role in the development of the immune system and that, in ontogenesis, the propensity to develop autoimmunity is altered by the absence of this MMP.