CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia;
CSL Behring, Research and Development, CH-3000 Bern, Switzerland;
J Immunol. 2014 Jun 1;192(11):5031-8. doi: 10.4049/jimmunol.1301611. Epub 2014 Apr 23.
High-dose i.v. Ig (IVIG) is used to treat various autoimmune and inflammatory diseases; however, the mechanism of action remains unclear. Based on the K/BxN serum transfer arthritis model in mice, IVIG suppression of inflammation has been attributed to a mechanism involving basophils and the binding of highly sialylated IgG Fc to DC-SIGN-expressing myeloid cells. The requirement for sialylation was examined in the collagen Ab-induced arthritis (CAbIA) and K/BxN serum transfer arthritis models in mice. High-dose IVIG (1-2 g/kg body weight) suppressed inflammatory arthritis when given prophylactically. The same doses were also effective in the CAbIA model when given subsequent to disease induction. In this therapeutic CAbIA model, the anti-inflammatory effect of IVIG was dependent on IgG Fc but not F(ab')2 fragments. Removal of sialic acid residues by neuraminidase had no impact on the anti-inflammatory activity of IVIG or Fc fragments. Treatment of mice with basophil-depleting mAbs did not abrogate the suppression of either CAbIA or K/BxN arthritis by IVIG. Our data confirm the therapeutic benefit of IVIG and IgG Fc in Ab-induced arthritis but fail to support the significance of sialylation and basophil involvement in the mechanism of action of IVIG therapy.
高剂量静脉注射免疫球蛋白（IVIG）用于治疗各种自身免疫和炎症性疾病；然而，其作用机制仍不清楚。基于 K/BxN 血清转移关节炎小鼠模型，IVIG 对炎症的抑制作用归因于一种机制，涉及嗜碱性粒细胞和高度唾液酸化 IgG Fc 与表达 DC-SIGN 的髓样细胞结合。在胶原抗体诱导的关节炎（CAbIA）和 K/BxN 血清转移关节炎模型中，检查了唾液酸化的必要性。高剂量 IVIG（1-2 g/kg 体重）预防性给药时可抑制炎症性关节炎。在随后诱导疾病的 CAbIA 模型中，相同剂量也有效。在这种治疗性 CAbIA 模型中，IVIG 的抗炎作用依赖于 IgG Fc，但不依赖于 F(ab')2 片段。神经氨酸酶去除唾液酸残基对 IVIG 或 Fc 片段的抗炎活性没有影响。用嗜碱性粒细胞耗竭 mAb 处理小鼠不能消除 IVIG 对 CAbIA 或 K/BxN 关节炎的抑制作用。我们的数据证实了 IVIG 和 IgG Fc 在 Ab 诱导的关节炎中的治疗益处，但不能支持唾液酸化和嗜碱性粒细胞参与 IVIG 治疗作用机制的重要性。
