Descamps Francis J, Van den Steen Philippe E, Nelissen Inge, Van Damme Jo, Opdenakker Ghislain
Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Adv Exp Med Biol. 2003;535:69-77. doi: 10.1007/978-1-4615-0065-0_5.
Autoimmune diseases are characterized by inflammation and by the development and maintenance of antibodies and T lymphocytes against "self" antigens. Although the etiology of these diseases is unknown, they have a number of cellular and molecular mechanisms in common. Pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), are upregulated and activate the inflammatory process. Chemokines recruit and activate leukocytes to release proteases, including matrix metalloproteinases (MMPs). These proteases degrade proteins into remnant fragments, which often constitute immunodominant epitopes. Either by direct loading into major histocompatibility complex (MHC) molecules or after classical antigen uptake, processing and MHC presentation, these remnant epitopes are presented to autoreactive T lymphocytes. Also, posttranslationally modified remnant peptides may stimulate B cells to produce autoantibodies. This forms the basis of the "Remnant Epitopes Generate Autoimmunity" (REGA) model. We have documented evidences for this model in multiple sclerosis (MS), rheumatoid arthritis (RA) and diabetes, which are summarized here. Furthermore, three topics will be addressed to illustrate the importance of glycobiology in the pathogenesis of autoimmune diseases. In MS, gelatinase B or MMP-9 is a pathogenic glycoprotein of which the sugars contribute to its interactions with the tissue inhibitor of metalloproteinases-1 (TIMP-1) and thus assist in the determination of the enzyme activity. In RA, gelatinase B cleaves denatured type II collagen into remnant epitopes, some of which constitute immunodominant glycopeptides. This implies that immunodominant epitope scanning experiments should preferably be done with natural posttranslationally modified glycopeptides, rather than with unmodified (synthetic) peptides. Sugars can also be used as molecular probes to induce autoimmune diseases. One of the best examples is the induction of acute pancreatitis, insulitis and diabetes by streptozotocin. In addition, gelatinase B is upregulated in pancreatitis and cleaves insulin. The most efficient cleavage by gelatinase B leads to a major insulin remnant epitope.
自身免疫性疾病的特征是炎症以及针对“自身”抗原的抗体和T淋巴细胞的产生与维持。尽管这些疾病的病因尚不清楚，但它们有许多共同的细胞和分子机制。促炎细胞因子，如白细胞介素-1（IL-1）和肿瘤坏死因子（TNF），上调并激活炎症过程。趋化因子募集并激活白细胞以释放蛋白酶，包括基质金属蛋白酶（MMPs）。这些蛋白酶将蛋白质降解为残余片段，这些片段通常构成免疫显性表位。这些残余表位通过直接加载到主要组织相容性复合体（MHC）分子中，或在经典抗原摄取、加工和MHC呈递后，呈递给自身反应性T淋巴细胞。此外，翻译后修饰的残余肽可能刺激B细胞产生自身抗体。这构成了“残余表位引发自身免疫”（REGA）模型的基础。我们已在多发性硬化症（MS）、类风湿性关节炎（RA）和糖尿病中记录了该模型的证据，在此进行总结。此外，将讨论三个主题以说明糖生物学在自身免疫性疾病发病机制中的重要性。在MS中，明胶酶B或MMP-9是一种致病糖蛋白，其糖基有助于其与金属蛋白酶组织抑制剂-1（TIMP-1）相互作用，从而有助于确定酶活性。在RA中，明胶酶B将变性的II型胶原切割成残余表位，其中一些构成免疫显性糖肽。这意味着免疫显性表位扫描实验最好使用天然翻译后修饰的糖肽，而不是未修饰的（合成）肽。糖也可用作诱导自身免疫性疾病的分子探针。最好的例子之一是链脲佐菌素诱导急性胰腺炎、胰岛炎和糖尿病。此外，明胶酶B在胰腺炎中上调并切割胰岛素。明胶酶B最有效的切割产生一个主要的胰岛素残余表位。
