University Institute of Immunology, Bern, Switzerland CSL Behring AG, Bern, Switzerland.
Allergy. 2011 Aug;66(8):1030-7. doi: 10.1111/j.1398-9995.2011.02579.x. Epub 2011 Mar 9.
Intravenous immunoglobulin (IVIG) preparations are increasingly used for the treatment of autoimmune and chronic inflammatory diseases. Naturally occurring autoantibodies against Siglec-9 and Fas are thought to contribute to the anti-inflammatory effects of IVIG via cell death regulation of leukocytes and tissue cells. Dimeric IVIG fractions are suspected to contain idiotypic (Id)-anti-idiotypic complexes of antibodies, which might also include anti-Siglec-9 and anti-Fas autoantibodies.
Dimeric IVIG fractions were separated from monomeric IVIG by size-exclusion chromatography and remonomerized by low pH treatment. Binding studies of total, monomeric, and dimeric IVIG were performed using surface plasmon resonance and flow cytometry on primary human neutrophils.
Anti-Siglec-9 and anti-Fas autoantibodies were contained in both monomeric and dimeric IVIG fractions, but anti-Siglec-9 antibodies were highly enriched in dimeric IVIG. The propensity to engage in dimer formation was paratope dependent. IVIG binding to Siglec-9 was specific and sialylation independent. Interestingly, we detected anti-idiotypic antibodies (anti-Ids) against anti-Siglec-9 autoantibodies in dimeric, but not in monomeric fractions of IVIG.
Our study supports the concept that idiotype-anti-idiotype (Id-anti-Id) interactions contribute to the dimer formation in IVIG preparations. To our knowledge, this is the first description of Id-anti-Id dimers of death receptor-specific antibodies in IVIG. Such Id-anti-Id interactions might determine the activity of immunomodulatory antibodies present both in IVIG and the patient.
静脉注射免疫球蛋白（IVIG）制剂越来越多地用于治疗自身免疫和慢性炎症性疾病。天然存在的针对 Siglec-9 和 Fas 的自身抗体被认为通过白细胞和组织细胞的细胞死亡调节来发挥 IVIG 的抗炎作用。二聚体 IVIG 部分被怀疑含有抗体的独特型（Id）-抗独特型复合物，其中可能还包括抗 Siglec-9 和抗 Fas 自身抗体。
通过尺寸排阻色谱法将二聚体 IVIG 部分从单体 IVIG 中分离出来，并通过低 pH 处理使其重新单体化。使用表面等离子体共振和流式细胞术在原代人中性粒细胞上进行总、单体和二聚体 IVIG 的结合研究。
抗 Siglec-9 和抗 Fas 自身抗体存在于单体和二聚体 IVIG 部分中，但抗 Siglec-9 抗体在二聚体 IVIG 中高度富集。与二聚体形成的倾向依赖于变构位。IVIG 与 Siglec-9 的结合是特异性的，与唾液酸化无关。有趣的是，我们在二聚体 IVIG 中而不是单体 IVIG 部分中检测到针对抗 Siglec-9 自身抗体的抗独特型抗体（抗 Id）。
我们的研究支持这样一种概念，即独特型-抗独特型（Id-anti-Id）相互作用有助于 IVIG 制剂中二聚体的形成。据我们所知，这是首次描述 IVIG 中死亡受体特异性抗体的 Id-anti-Id 二聚体。这种 Id-anti-Id 相互作用可能决定了存在于 IVIG 和患者中的免疫调节抗体的活性。
