Newkirk M M, Novick J, Stevenson M M, Fournier M J, Apostolakos P
Department of Medicine, McGill University, Montreal General Hospital Research Institute, Quebec, Canada.
Clin Exp Immunol. 1996 Nov;106(2):259-64. doi: 10.1046/j.1365-2249.1996.d01-847.x.
In order to understand better the origins of the elevated levels of the glycoform of IgG that lacks galactose on both arms of the oligosaccharide chain (G0%) located in the Fc, which occurs in man and mouse with age, and in particular in autoimmune disease, we investigated the clearance of two glycosylated forms of IgG2a and IgG1 in normal (BALB/c) and autoimmune-prone (MRL/1pr, MRL/+, and non-obese diabetic (NOD)) mice. To investigate the possibility of different rates of catabolism, enzymatically generated glycoforms of monomeric IgG1 and IgG2a (fully glycosylated or G0%), were iodinated and injected into the tail vein of the mice. We found that the G0% IgG2a remained in circulation significantly longer than the fully glycosylated variants, in all of the mouse strains tested. In contrast, the two forms of IgG1 had similar kinetics in all the autoimmune-prone mice, whereas in BALB/c, there was a longer half-life (t1/2) for G0% IgG1. These data suggest that there may be differences in the ability of the IgG glycoforms to bind to the Fc gamma receptors, in particular Fc gamma RI. The clearance rates were found to vary among the strains studied, with MRL/1pr having the fastest catabolic rates for all glycoforms and IgG subclasses tested. This appeared to be due to the presence of circulating IgG and IgM rheumatoid factors (RF). There were significantly increased frequencies and titres for both IgM and IgG RF in MRL/1pr mice compared with the other strains. In contrast, interferon-gamma, known to induce the Fc gamma RI, was found to be similar in the sera, in all of the strains of mice examined. These results suggest that RF probably play an important biological function in the MRL/1pr mice and aid in the clearance of circulating IgG. Our study shows that the state of glycosylation of IgG affects the t1/2 in vivo, and that by removing the terminal sugars (sialic acid and galactose), the antibody (IgG2a) will remain in circulation significantly longer. These observations may thus provide a partial explanation for the increase in relative percentage of this glycoform that occurs with age.
为了更好地理解位于Fc段、寡糖链双臂均缺乏半乳糖的IgG糖型（G0%）水平升高的起源，这种情况在人和小鼠中会随着年龄增长出现，尤其在自身免疫性疾病中出现，我们研究了正常（BALB/c）和易患自身免疫性疾病（MRL/1pr、MRL/+和非肥胖糖尿病（NOD））小鼠体内两种糖基化形式的IgG2a和IgG1的清除情况。为了研究不同分解代谢速率的可能性，将酶促产生的单体IgG1和IgG2a糖型（完全糖基化或G0%）进行碘化并注入小鼠尾静脉。我们发现，在所有测试的小鼠品系中，G0% IgG2a在循环中的存留时间明显长于完全糖基化变体。相比之下，两种形式的IgG1在所有易患自身免疫性疾病的小鼠中具有相似的动力学，而在BALB/c小鼠中，G0% IgG1的半衰期（t1/2）更长。这些数据表明，IgG糖型与Fcγ受体，特别是FcγRI结合的能力可能存在差异。研究发现清除率在不同品系间有所不同，MRL/1pr对所有测试的糖型和IgG亚类的分解代谢速率最快。这似乎是由于循环中的IgG和IgM类风湿因子（RF）的存在。与其他品系相比，MRL/1pr小鼠中IgM和IgG RF的频率和滴度均显著增加。相比之下，已知可诱导FcγRI的干扰素-γ在所有检测的小鼠品系血清中相似。这些结果表明，RF可能在MRL/1pr小鼠中发挥重要的生物学功能，并有助于清除循环中的IgG。我们的研究表明，IgG的糖基化状态会影响体内的t1/2，并且通过去除末端糖（唾液酸和半乳糖），抗体（IgG2a）在循环中的存留时间会明显延长。因此，这些观察结果可能为这种糖型的相对百分比随年龄增长而增加提供部分解释。
