Stadlmann Johannes, Weber Alfred, Pabst Martin, Anderle Heinz, Kunert Renate, Ehrlich Hartmut J, Peter Schwarz Hans, Altmann Friedrich
Department of Chemistry, University of Natural Resources and Applied Life Sciences (BOKU), Vienna, Austria.
Proteomics. 2009 Sep;9(17):4143-53. doi: 10.1002/pmic.200800931.
Polyspecific human IgG preparations are indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. In addition, intraveneous IgG (IVIG) is used to treat patients with autoimmune and systemic inflammatory diseases. Lectin chromatography on Sambucus nigra agglutinin stood at the cradle of the hypothesis that the anti-inflammatory properties depend on sialylation of the N-glycans in the Fc region of IgG. A detailed analysis of fractions obtained by lectin chromatography revealed that binding of IVIG is essentially mediated by Fab glycosylation. Moreover, experiments with a monoclonal antibody from a human cell line and IVIG Fc fragments indicated that at least two sialic acids in the Fc region of an antibody are required for lectin binding. Such glycoforms contain either two monosialylated glycans or a disialylated glycan and constitute 1% or less of the total human IgG. Arguably this small proportion holds the entire anti-inflammatory potency. A new mass spectrometric quantification method of IgG subclass ratio revealed that the IVIG Fc preparation essentially consists of IgG1. This observation may be relevant when studying the effect of human Fc in murine models of inflammation because mouse IgG subclasses differ substantially in their interaction with receptors.
多特异性人免疫球蛋白制剂适用于治疗与体液免疫缺陷相关的原发性免疫缺陷疾病。此外，静脉注射免疫球蛋白（IVIG）用于治疗自身免疫性疾病和全身性炎症疾病患者。基于黑接骨木凝集素的凝集素色谱法催生了这样一种假说，即抗炎特性取决于免疫球蛋白Fc区域中N-聚糖的唾液酸化。对通过凝集素色谱法获得的组分进行的详细分析表明，IVIG的结合主要由Fab糖基化介导。此外，对来自人细胞系的单克隆抗体和IVIG Fc片段进行的实验表明，抗体Fc区域中至少需要两个唾液酸才能与凝集素结合。此类糖型包含两个单唾液酸化聚糖或一个双唾液酸化聚糖，占总人免疫球蛋白的比例不超过1%。可以说，这一小部分承载了全部的抗炎效力。一种新的免疫球蛋白亚类比例质谱定量方法显示，IVIG Fc制剂主要由IgG1组成。在研究人Fc在小鼠炎症模型中的作用时，这一观察结果可能具有相关性，因为小鼠免疫球蛋白亚类在与受体的相互作用方面存在很大差异。
