Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)—variant surface antigens that are expressed on infected erythrocytes¹—bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies^2,3. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to β2 microglobulin and RIFINs through their apical domains^4,5. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable–constant (VH–CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN–LILRB1 D3 interaction that is similar to that of RIFIN–LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH–CH1 elbow without affecting VH–VL or CH1–CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH–CH1 elbow.

一些恶性疟原虫重复散布的多肽家族 (RIFIN)（在受感染的红细胞上表达的变体表面抗原¹）与抑制性受体 LAIR1 结合，将编码 LAIR1 的 DNA 插入免疫球蛋白基因中会产生 RIFIN 特异性抗体^2,3。在这里，我们通过寻找包含 LILRB1 的抗体来解决这一发现的一般相关性，LILRB1 是另一种通过其顶端结构域与 β2 微球蛋白和 RIFIN 结合的抑制性受体^4,5。通过对来自马里的一群捐献者的血浆进行筛查，我们确定了具有含有 LILRB1 抗体的个体。从三个供体分离的 B 细胞克隆显示，在编码非顶端 LILRB1 胞外结构域 3 和 4 (D3D4) 或在可变-恒定 (VH-CH1) 弯头中单独编码 D3 的开关区域中存在大量 DNA 插入。通过质谱和结合测定，我们鉴定了一大组与 LILRB1 D3 结合的 RIFIN。RIFIN 与 LILRB1 D3D4 或含有 D3D4 的抗体 Fab 复合物的晶体和冷冻电子显微镜结构揭示了 RIFIN-LILRB1 D3 相互作用的模式，与 RIFIN-LAIR1 相似。Fab 显示出非常规的三角形结构，其中插入的 LILRB1 结构域打开了 VH-CH1 肘部，而不影响 VH-VL 或 CH1-CL 配对。总的来说，这些发现表明 RIFIN 通过 D3 与 LILRB1 结合，并通过一个自然选择的例子说明了通过将受体结构域插入 VH-CH1 肘部来创建新型抗体的一般原理。