The protection receptor for IgG catabolism is the beta(2)-microglobulin-containing neonatal intestinal transport receptor
The protection receptor for IgG catabolism is the beta(2)-microglobulin-containing neonatal intestinal transport receptor
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DOI：
10.1073/pnas.93.11.5512
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发表时间：
1996-05-28
影响因子：
11.1
通讯作者：
Anderson, CL
中科院分区：
文献类型：
--
作者：
Junghans, RP;Anderson, CL
30多年前，布兰贝尔发表了以他名字命名的假说[布兰贝尔，F. W. R.，亨明斯，W. A. 和莫里斯，I. G.（1964年）《自然》（伦敦）203卷，1352 - 1355页]，该假说一直是关于IgG分解代谢思考的基石。为了解释IgG相对于其他血浆蛋白的较长生存期以及其在高浓度IgG时分解代谢分数增加的模式，布兰贝尔假定存在特异性IgG“保护受体”（FcRp），它会在胞饮泡中结合IgG并将其转运重新导向循环；当FcRp饱和时，多余的未结合IgG就会进入无限制的溶酶体分解代谢。布兰贝尔随后假定了新生儿肠道转运受体（FcRn），并表明其具有类似的可饱和特性。FcRn最近已被克隆，但FcRp尚未被确定。利用一种破坏FcRn和肠道IgG转运的基因敲除技术，我们表明这种损伤也破坏了IgG保护受体，支持了这两种受体是同一物质的观点。突变型小鼠的IgG分解代谢比野生型小鼠快10倍，IgG水平相应较低，而两组之间的IgA相同，这表明了对IgG系统的特异性影响。还表明突变型小鼠中FcRp的破坏消除了随着IgG浓度升高IgG生存期缩短的经典模式。最后，在正常小鼠中对单体抗原 - 抗体复合物的研究显示出差异分解代谢，即抗原在内体中解离并进入溶酶体，而相关抗体则返回循环；在突变型小鼠中，差异分解代谢丧失，整个复合物以与白蛋白相同的加速速率被清除，这表明FcRp在差异分解代谢机制中起核心作用。因此，在新生儿中短暂介导FcRn功能的同一受体蛋白在整个生命过程中被证明其功能上主要以FcRp的形式表达，解决了长期以来关于IgG保护受体身份的谜团。这一结果还确定了再循环表面受体类别中一个重要的新成员，并使得能够设计蛋白质适应性改造以利用这一机制来提高其他治疗性蛋白质在体内的生存期。
More than 30 years ago, Brambell published the hypothesis bearing his name [Brambell, F. W. R., Hemmings, W. A. & Morris, I. G. (1964) Nature (London) 203, 1352-1355] that remains as the cornerstone for thinking on IgG catabolism. To explain the long survival of IgG relative to other plasma proteins and its pattern of increased fractional catabolism with high concentrations of IgG, Brambell postulated specific IgG ''protection receptors'' (FcRp) that would bind IgG in pinocytic vacuoles and redirect its transport to the circulation; when the FcRp was saturated, the excess unbound IgG then would pass to unrestricted lysosomal catabolism. Brambell subsequently postulated the neonatal gut transport receptor (FcRn) and showed its similar saturable character. FcRn was recently cloned but FcRp has not been identified. Using a genetic knockout that disrupts the FcRn and intestinal IgG transport, we show that this lesion also disrupts the IgG protection receptor, supporting the identity of these two receptors. IgG catabolism was 10-fold faster and IgG levels were correspondingly lower in mutant than in wild-type mice, whereas IgA was the same between groups, demonstrating the specific effects on the IgG system. Disruption of the FcRp in the mutant mice was also shown to abrogate the classical pattern of decreased IgG survival with higher IgG concentration. Finally, studies in normal mice with monomeric antigen-antibody complexes showed differential catabolism in which antigen dissociates in the endosome and passes to the lysosome, whereas the associated antibody is returned to circulation; in mutant mice, differential catabolism was lost and the whole complex cleared at the same accelerated rate as albumin, showing the central role of the FcRp to the differential catabolism mechanism. Thus, the same receptor protein that mediates the function of the FcRn transiently in the neonate is shown to have its functionally dominant expression as the FcRp throughout life, resolving a longstanding mystery of the identity of the receptor for the protection of IgG. This result also identifies an important new member of the class of recycling surface receptors and enables the design of protein adaptations to exploit this mechanism to improve survivals of other therapeutic proteins in vivo.