Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
Nature. 2011 Jun 19;475(7354):110-3. doi: 10.1038/nature10134.
High-dose intravenous immunoglobulin is a widely used therapeutic preparation of highly purified immunoglobulin G (IgG) antibodies. It is administered at high doses (1-2 grams per kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical settings. This anti-inflammatory activity of intravenous immunoglobulin is triggered by a minor population of IgG crystallizable fragments (Fcs), with glycans terminating in α2,6 sialic acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN; also known as CD209). Here, to characterize this response in detail, we generated humanized DC-SIGN mice (hDC-SIGN), and demonstrate that the anti-inflammatory activity of intravenous immunoglobulin can be recapitulated by the transfer of bone-marrow-derived sFc-treated hDC-SIGN(+) macrophages or dendritic cells into naive recipients. Furthermore, sFc administration results in the production of IL-33, which, in turn, induces expansion of IL-4-producing basophils that promote increased expression of the inhibitory Fc receptor FcγRIIB on effector macrophages. Systemic administration of the T(H)2 cytokines IL-33 or IL-4 upregulates FcγRIIB on macrophages, and suppresses serum-induced arthritis. Consistent with these results, transfer of IL-33-treated basophils suppressed induced arthritic inflammation. This novel DC-SIGN-T(H)2 pathway initiated by an endogenous ligand, sFc, provides an intrinsic mechanism for maintaining immune homeostasis that could be manipulated to provide therapeutic benefit in autoimmune diseases.
高剂量静脉注射免疫球蛋白是一种广泛应用的高度纯化免疫球蛋白 G（IgG）抗体治疗制剂。它以高剂量（每公斤 1-2 克）给药，用于抑制多种临床情况下自身抗体触发的炎症。静脉注射免疫球蛋白的这种抗炎活性是由 IgG 可结晶片段（Fc）的一小部分触发的，其糖基末端为α2,6 唾液酸（sFc），靶向表达凝集素树突状细胞特异性 ICAM-3 抓取非整联蛋白（DC-SIGN；也称为 CD209）的髓样调节细胞。在这里，为了详细描述这种反应，我们生成了人源化 DC-SIGN 小鼠（hDC-SIGN），并证明静脉注射免疫球蛋白的抗炎活性可以通过骨髓来源的 sFc 处理的 hDC-SIGN(+)巨噬细胞或树突状细胞转移到幼稚受体中得到重现。此外，sFc 给药导致白细胞介素 33（IL-33）的产生，反过来又诱导产生白细胞介素 4 的嗜碱性粒细胞的扩增，从而促进效应巨噬细胞上抑制性 Fc 受体 FcγRIIB 的表达增加。T(H)2 细胞因子 IL-33 或 IL-4 的全身给药上调巨噬细胞上的 FcγRIIB，并抑制血清诱导的关节炎。与这些结果一致，IL-33 处理的嗜碱性粒细胞的转移抑制了诱导的关节炎炎症。这种由内源性配体 sFc 引发的新型 DC-SIGN-T(H)2 途径为维持免疫内稳态提供了内在机制，可通过该机制在自身免疫性疾病中提供治疗益处。
