High pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia
High pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia
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DOI：
10.1084/jem.190.11.1689
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发表时间：
1999-12-06
影响因子：
15.3
通讯作者：
Izui, S
中科院分区：
文献类型：
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作者：
Fossati-Jimack, L;Reininger, L;Izui, S
为了评估低亲和力抗红细胞 (RBC) 自身抗体在诱导贫血中的效力，我们生成了 4C8 IgM 抗小鼠 RBC 自身抗体的免疫球蛋白 (Ig)G2a 类别转换变体，并将其致病潜力与其 IgM 同种型和高亲和力 34-3C IgG2a 自身抗体的致病潜力进行了比较。 4C8 IgG2a 变体的红细胞结合活性几乎检测不到，比具有高结合亲合力的 IgM 同种型和 34-3C IgG2a 单克隆抗体 (mAb) 的红细胞结合活性至少低 1,000 倍。 4C8 mAb 的这种低亲和力特征与注射 4C8 IgG2a 的小鼠循环血液中未检测到调理红细胞一致。然而，4C8 IgG2a 变体具有高致病性，与其 IgM 同种型和 34-3C IgG2a mAb 一样有效，因为它能够与参与红细胞吞噬作用的 Fc 受体相互作用。此外，我们的结果表明，低亲和力ISM同种型的五聚体形式通过促进红细胞的结合和凝集，对其致病活性至关重要。低亲和力自身抗体如果与适当的重链效应子功能相结合，其致病力非常高，这凸显了 Ig 重链恒定区在自身免疫性溶血性贫血中的关键作用，而自身抗原结合亲和力的作用相对较小。
To assess the potency of low-affinity anti-red blood cell (RBC) autoantibodies in the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch variant of a 4C8 IgM anti-mouse RBC autoantibody, and compared its pathogenic potential with that of its IgM isotype and a high-affinity 34-3C IgG2a autoantibody. The RBC-binding activity of the 4C8 IgG2a variant was barely detectable, at least 1,000 times lower than that of its IgM isotype, having a high-binding avidity, and that of the 34-3C IgG2a monoclonal antibody (mAb). This low-affinity feature of the 4C8 mAb was consistent with the lack of detection of opsonized RBCs in the circulating blood from the 4C8 IgG2a-injected mice. However, the 4C8 IgG2a variant was highly pathogenic, as potent as its IgM isotype and the 34-3C IgG2a mAb, due to its capacity to interact with Fc receptors involved in erythrophagocytosis. In addition, our results indicated that the pentameric form of the low-affinity ISM isotype, by promoting the binding and agglutination of RBCs, is critical for its pathogenic activity. Demonstration of the remarkably high pathogenic potency of low-affinity autoantibodies, if combined with appropriate heavy chain effector functions, highlights the critical role of the Ig heavy chain constant regions, but the relatively minor role of autoantigen-binding affinities, in autoimmune hemolytic anemia.