Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences.
Acta Naturae. 2009 Jul;1(2):66-72.
Non-enzymatic protein glycation is a source of metabolic stress that contributes to cytotoxicity and tissue damage. Hyperglycemia has been linked to elevation of advanced glycation endproducts, which mediate much of the vascular pathology leading to diabetic complications. Enhanced glycation of immunoglobulins and their accelerated vascular clearance is proposed as a natural mechanism to intercept alternative advanced glycation endproducts, thereby mitigating microvascular disease. We reported that antibodies against the glycoprotein KLH have elevated reactivity for glycopeptides from diabetic serum. These reactions are mediated by covalent binding between antibody light chains and carbonyl groups of glycated peptides. Diabetic animals that were immunized to induce reactive antibodies had attenuated diabetic nephropathy, which correlated with reduced levels of circulating and kidney-bound glycation products. Molecular analysis of antibody glycation revealed the preferential modification of light chains bearing germline-encoded lambda V regions. We previously noted that antibody fragments carrying V regions in the germline configuration are selected from a human Fv library by covalent binding to a reactive organophosphorus ester. These Fv fragments were specifically modified at light chain V region residues, which map to the combining site at the interface between light and heavy chains. These findings suggest that covalent binding is an innate property of antibodies, which may be encoded in the genome for specific physiological purposes. This hypothesis is discussed in context with current knowledge of the natural antibodies that recognize altered self molecules and the catalytic autoantibodies found in autoimmune disease.
非酶蛋白糖基化是代谢应激的一个来源，导致细胞毒性和组织损伤。高血糖与晚期糖基化终产物的升高有关，晚期糖基化终产物介导了导致糖尿病并发症的大部分血管病变。免疫球蛋白的糖化增强及其在血管中的加速清除被认为是一种天然机制，可以拦截替代的晚期糖基化终产物，从而减轻微血管疾病。我们报道称，针对糖蛋白 KLH 的抗体对来自糖尿病患者血清的糖肽具有更高的反应性。这些反应是由抗体轻链与糖化肽的羰基之间的共价键介导的。接受免疫以诱导反应性抗体的糖尿病动物的糖尿病肾病减轻，这与循环和肾脏结合的糖化产物水平降低相关。抗体糖基化的分子分析揭示了优先修饰带有胚系编码 lambda V 区的轻链。我们之前注意到，通过与反应性有机磷酯共价结合从人 Fv 文库中选择携带胚系构型 V 区的抗体片段。这些 Fv 片段在轻链 V 区残基处特异性修饰，这些残基映射到轻链和重链之间界面处的结合位点。这些发现表明，共价键合是抗体的一种固有特性，可能在基因组中为特定的生理目的而编码。这一假说在讨论当前关于识别自身改变分子的天然抗体和自身免疫性疾病中发现的催化性自身抗体的知识时进行了讨论。
