Identification of a receptor required for the anti-inflammatory activity of IVIG
Identification of a receptor required for the anti-inflammatory activity of IVIG
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DOI：
10.1073/pnas.0810163105
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发表时间：
2008-12-16
影响因子：
11.1
通讯作者：
Ravetch, Jeffrey V.
中科院分区：
文献类型：
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作者：
Anthony, Robert M.;Wermeling, Fredrik;Ravetch, Jeffrey V.
静脉注射 Ig (IVIG) 的抗炎活性源自一小部分汇集的 IgG 分子，这些分子的 Fc 连接聚糖上含有末端 α2,6-唾液酸键。这些抗炎特性可以通过适当唾液酸化的 IgG Fc 片段的完全重组制剂来重现。我们现在证明，这些唾液酸化的 Fc 需要脾边缘区巨噬细胞上表达的特定 C 型凝集素 SIGN-R1（特定的 ICAM-3 抓取非整合素相关 1）。脾切除术、脾边缘区 SIGN-R1(+) 细胞丢失、SIGN-R1 碳水化合物识别域 (CRD) 的阻断或 SIGN-R1 基因缺失会消除 IVIG 或唾液酸化 Fc 片段的抗炎活性。尽管 SIGN-R1 之前并未被证明可以与唾液酸化聚糖结合，但我们证明，与类似的唾液酸化双触角糖蛋白相比，它优先与 2,6-唾液酸化 Fc 结合，因此表明特异性结合位点是由 IgG Fc 的唾液酸化产生的。 SIGN-R1 的人类直系同源物 DC-SIGN 显示出与 SIGN-R1 相似的结合特异性，但其细胞分布不同，这可能解释了在 IVIG 保护中观察到的一些物种差异。因此，这些研究鉴定了唾液酸化 Fc 特异性的抗体受体，并提出了 IVIG 触发抑制炎症的初始步骤。
The anti-inflammatory activity of intravenous Ig (IVIG) results from a minor population of the pooled IgG molecules that contains terminal alpha 2,6-sialic acid linkages on their Fc-linked glycans. These anti-inflammatory properties can be recapitulated with a fully recombinant preparation of appropriately sialylated IgG Fc fragments. We now demonstrate that these sialylated Fcs require a specific C-type lectin, SIGN-R1, (specific ICAM-3 grabbing non-integrin-related 1) expressed on macrophages in the splenic marginal zone. Splenectomy, loss of SIGN-R1(+) cells in the splenic marginal zone, blockade of the carbohydrate recognition domain (CRD) of SIGN-R1, or genetic deletion of SIGN-R1 abrogated the anti-inflammatory activity of IVIG or sialylated Fc fragments. Although SIGN-R1 has not previously been shown to bind to sialylated glycans, we demonstrate that it preferentially binds to 2,6-sialylated Fc compared with similarly sialylated, biantennary glycoproteins, thus suggesting that a specific binding site is created by the sialylation of IgG Fc. A human orthologue of SIGN-R1, DC-SIGN, displays a similar binding specificity to SIGN-R1 but differs in its cellular distribution, potentially accounting for some of the species differences observed in IVIG protection. These studies thus identify an antibody receptor specific for sialylated Fc, and present the initial step that is triggered by IVIG to suppress inflammation.