Rifai A, Fadden K, Morrison S L, Chintalacharuvu K R
Department of Pathology, Rhode Island Hospital, Brown University, Providence, Rhode Island 02903, USA.
J Exp Med. 2000 Jun 19;191(12):2171-82. doi: 10.1084/jem.191.12.2171.
Human immunoglobulin (Ig)A exists in blood as two isotypes, IgA1 and IgA2, with IgA2 present as three allotypes: IgA2m(1), IgA2m(2), and IgA2m(n). We now demonstrate that recombinant, chimeric IgA1 and IgA2 differ in their pharmacokinetic properties. The major pathway for the clearance of all IgA2 allotypes is the liver. Liver-mediated uptake is through the asialoglycoprotein receptor (ASGR), since clearance can be blocked by injection of excess galactose-Ficoll ligand and suppressed in ASGR-deficient mice. In contrast, only a small percentage of IgA1 is cleared through this pathway. The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1. IgA1 and IgA2 that are not rapidly eliminated by the ASGR are both removed through an undefined ASGR-independent pathway with half-lives of 14 and 10 h, respectively. The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2. In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.
人免疫球蛋白（Ig）A在血液中以两种同种型存在，即IgA1和IgA2，其中IgA2又有三种同种异型：IgA2m(1)、IgA2m(2)和IgA2m(n)。我们现在证明，重组嵌合IgA1和IgA2的药代动力学特性有所不同。所有IgA2同种异型清除的主要途径是肝脏。肝脏介导的摄取是通过去唾液酸糖蛋白受体（ASGR）进行的，因为注射过量的半乳糖-菲可配体可阻断清除，且在ASGR缺陷小鼠中清除会受到抑制。相比之下，只有一小部分IgA1通过该途径清除。缺乏铰链区及其相关O-连接碳水化合物的IgA1的清除速度比野生型IgA1更快。未被ASGR快速清除的IgA1和IgA2均通过一条未明确的不依赖ASGR的途径被清除，其半衰期分别为14小时和10小时。IgA2而非IgA1通过肝脏的快速清除可能部分解释了为什么IgA1的血清水平高于IgA2。此外，ASGR功能障碍或影响该受体识别的N-连接糖基化改变（而非O-聚糖改变）可能是肝病和IgA肾病中血清IgA升高的原因。
