Opdenakker Ghislain, Dillen Chris, Fiten Pierre, Martens Erik, Van Aelst Ilse, Van den Steen Philippe E, Nelissen Inge, Starckx Sofie, Descamps Francis J, Hu Jialiang, Piccard Helene, Van Damme Jo, Wormald Mark R, Rudd Pauline M, Dwek Raymond A
Rega Institute for Medical Research, Laboratory of Immunobiology, University of Leuven, Belgium.
Biochim Biophys Acta. 2006 Apr;1760(4):610-5. doi: 10.1016/j.bbagen.2005.12.014. Epub 2006 Jan 6.
The role of extracellular proteolysis in innate and adaptive immunity and the interplay between cytokines, chemokines and proteinases are gradually becoming recognized as critical factors in autoimmune processes. Many of the involved proteinases, including those of the plasminogen activator and matrix metalloproteinase cascades, and also several cytokines and chemokines, are glycoproteins. The stability, interactions with inhibitors or receptors, and activities of these molecules are fine-controlled by glycosylation. We studied gelatinase B or matrix metalloproteinase-9 (MMP-9) as a glycosylated enzyme involved in autoimmunity. In the joints of rheumatoid arthritis patients, CXC chemokines, such as interleukin-8/CXCL8, recruit and activate neutrophils to secrete prestored neutrophil collagenase/MMP-8 and gelatinase B/MMP-9. Gelatinase B potentiates interleukin-8 at least tenfold and thus enhances neutrophil and lymphocyte influxes to the joints. When cartilage collagen type II is cleaved at a unique site by one of several collagenases (MMP-1, MMP-8 or MMP-13), it becomes a substrate of gelatinase B. Human gelatinase B cleaves the resulting two large collagen fragments into at least 33 peptides of which two have been shown to be immunodominant, i.e., to elicit activation and proliferation of autoimmune T cells. One of these two remnant epitopes contains a glycan which is important for its immunoreactivity. In addition to the role of gelatinase B as a regulator in adaptive immune processes, we have also demonstrated that it destroys interferon-beta, a typical innate immunity effector molecule and therapeutic cytokine in multiple sclerosis. Furthermore, glycosylated interferon-beta, expressed in Chinese hamster ovary cells, was more resistant to this proteolysis than recombinant interferon-beta from bacteria. These data not only prove that glycosylation of proteins is mechanistically important in the pathogenesis of autoimmune diseases, but also show that targeting of glycosylated proteinases or the use of glycosylated cytokines seems also critical for the treatment of autoimmune diseases.
细胞外蛋白水解在先天性和适应性免疫中的作用以及细胞因子、趋化因子和蛋白酶之间的相互作用，正逐渐被视为自身免疫过程中的关键因素。许多参与其中的蛋白酶，包括纤溶酶原激活物和基质金属蛋白酶级联反应中的蛋白酶，以及几种细胞因子和趋化因子，都是糖蛋白。这些分子的稳定性、与抑制剂或受体的相互作用以及活性都受到糖基化的精细调控。我们研究了明胶酶B或基质金属蛋白酶-9（MMP-9），一种参与自身免疫的糖基化酶。在类风湿性关节炎患者的关节中，CXC趋化因子，如白细胞介素-8/CXCL8，招募并激活中性粒细胞，使其分泌预先储存的中性粒细胞胶原酶/MMP-8和明胶酶B/MMP-9。明胶酶B使白细胞介素-8的效力增强至少十倍，从而增加中性粒细胞和淋巴细胞向关节的流入。当II型软骨胶原在几个胶原酶（MMP-1、MMP-8或MMP-13）之一的独特位点被切割时，它就成为明胶酶B的底物。人明胶酶B将产生的两个大胶原片段切割成至少33个肽段，其中两个已被证明具有免疫显性，即能引发自身免疫性T细胞的激活和增殖。这两个残余表位之一含有一个对其免疫反应性很重要的聚糖。除了明胶酶B作为适应性免疫过程中的调节因子的作用外，我们还证明它能破坏干扰素-β，一种在多发性硬化症中典型的先天性免疫效应分子和治疗性细胞因子。此外，在中国仓鼠卵巢细胞中表达的糖基化干扰素-β比来自细菌的重组干扰素-β对这种蛋白水解更具抗性。这些数据不仅证明蛋白质糖基化在自身免疫性疾病的发病机制中具有重要的机制意义，而且还表明靶向糖基化蛋白酶或使用糖基化细胞因子似乎对自身免疫性疾病的治疗也至关重要。
