IgG Subclass Determines Suppression Versus Enhancement of Humoral Alloimmunity to Kell RBC Antigens in Mice
IgG Subclass Determines Suppression Versus Enhancement of Humoral Alloimmunity to Kell RBC Antigens in Mice
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DOI：
10.3389/fimmu.2020.01516
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发表时间：
2020-07-16
影响因子：
7.3
通讯作者：
Zimring, James C.
中科院分区：
文献类型：
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作者：
Shinde, Paurvi;Howie, Heather L.;Zimring, James C.
长期以来人们已经认识到，免疫球蛋白不仅是体液免疫的效应终点，而且在调节抗体应答本身中具有复杂的作用。供体来源的抗RhD IgG已被用作免疫预防剂以防止母体对RhD的同种免疫超过50年。尽管抗RhD抗体能显著降低胎儿和新生儿溶血性疾病的发生率（对于RhD同种异体抗原），但抗RhD抗体在某些情况下也会失败，甚至在某些情况下会矛盾地增强免疫应答。产生单克隆抗RhD的尝试在很大程度上失败了，一些单克隆抑制小于供体来源的抗RhD，而其他单克隆增强免疫力。这些困难可能导致，部分原因是抗RhD的机制仍不清楚。然而，存在大量证据拒绝简单清除RhD + RBC或掩蔽抗原的常见解释。供体来源的抗RhD是4种不同IgG亚型的混合物。据我们所知，尚未对不同IgG亚型在免疫调节中发挥的作用进行分析;并且，仅IgG 1和IgG 3作为单克隆抗体进行了检测。多次尝试在小鼠中引发对人RhD表位的同种免疫应答都失败了。为了规避这一限制，我们利用一个易于处理的动物模型的红细胞同种异体免疫，使用人类凯尔糖蛋白作为抗原，以测试IgG亚型对免疫调节的红细胞同种异体抗原的抗体的影响。我们报告说，抗红细胞IgG的能力，以提高，抑制（在IgM反应的水平），或没有效果是在这个模型系统中的IgG亚类的功能。
It has long been appreciated that immunoglobulins are not just the effector endpoint of humoral immunity, but rather have a complex role in regulating antibody responses themselves. Donor derived anti-RhD IgG has been used for over 50 years as an immunoprophylactic to prevent maternal alloimmunization to RhD. Although anti-RhD has dramatically decreased rates of hemolytic disease of the fetus and newborn (for the RhD alloantigen), anti-RhD also fails in some cases, and can even paradoxically enhance immune responses in some circumstances. Attempts to generate a monoclonal anti-RhD have largely failed, with some monoclonals suppressing less than donor derived anti-RhD and others enhancing immunity. These difficulties likely result, in part, because the mechanism of anti-RhD remains unclear. However, substantial evidence exists to reject the common explanations of simple clearance of RhD + RBCs or masking of antigen. Donor derived anti-RhD is a mixture of 4 different IgG subtypes. To the best of our knowledge an analysis of the role different IgG subtypes play in immunoregulation has not been carried out; and, only IgG1 and IgG3 have been tested as monoclonals. Multiple attempts to elicit alloimmune responses to human RhD epitopes in mice have failed. To circumvent this limitation, we utilize a tractable animal model of RBC alloimmunization using the human Kell glycoprotein as an antigen to test the effect of IgG subtype on immunoregulation by antibodies to RBC alloantigens. We report that the ability of an anti-RBC IgG to enhance, suppress (at the level of IgM responses), or have no effect is a function of the IgG subclass in this model system.