Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark.
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12485-90. doi: 10.1073/pnas.1103708108. Epub 2011 Jul 11.
Plasmodium falciparum malaria is a major cause of mortality and severe morbidity. Its virulence is related to the parasite's ability to evade host immunity through clonal antigenic variation and tissue-specific adhesion of infected erythrocytes (IEs). The P. falciparum erythrocyte membrane protein 1 (PfEMP1) family is central to both. Here, we present evidence of a P. falciparum evasion mechanism not previously documented: the masking of PfEMP1-specific IgG epitopes by nonspecific IgM. Nonspecific IgM binding to erythrocytes infected by parasites expressing the PfEMP1 protein VAR2CSA (involved in placental malaria pathogenesis and protective immunity) blocked subsequent specific binding of human monoclonal IgG to the Duffy binding-like (DBL) domains DBL3X and DBL5ε of this PfEMP1 variant. Strikingly, a VAR2CSA-specific monoclonal antibody that binds outside these domains and can inhibit IE adhesion to the specific VAR2CSA receptor chondroitin sulfate A was unaffected. Nonspecific IgM binding protected the parasites from FcγR-dependent phagocytosis of VAR2CSA(+) IEs, but it did not affect IE adhesion to chondroitin sulfate A or lead to C1q deposition on IEs. Taken together, our results indicate that the VAR2CSA affinity for nonspecific IgM has evolved to allow placenta-sequestering P. falciparum to evade acquired protective immunity without compromising VAR2CSA function or increasing IE susceptibility to complement-mediated lysis. Furthermore, functionally important PfEMP1 epitopes not prone to IgM masking are likely to be particularly important targets of acquired protective immunity to P. falciparum malaria.
恶性疟原虫疟疾是主要的死亡和严重发病原因之一。它的毒力与其通过克隆抗原变异和感染红细胞（IE）的组织特异性黏附逃避宿主免疫的能力有关。恶性疟原虫红细胞膜蛋白 1（PfEMP1）家族是这两者的核心。在这里，我们提出了一种以前未记录的恶性疟原虫逃避机制的证据：非特异性 IgM 掩盖 PfEMP1 特异性 IgG 表位。非特异性 IgM 与表达 PfEMP1 蛋白 VAR2CSA（参与胎盘疟疾发病机制和保护性免疫）的寄生虫感染的红细胞结合，阻止了随后人类单克隆 IgG 对该 PfEMP1 变体的 Duffy 结合样（DBL）结构域 DBL3X 和 DBL5ε 的特异性结合。引人注目的是，一种针对 VAR2CSA 的单克隆抗体，该抗体结合在这些结构域外，并且可以抑制 IE 与特定 VAR2CSA 受体硫酸软骨素 A 的黏附，不受影响。非特异性 IgM 结合保护寄生虫免受 FcγR 依赖性吞噬 VAR2CSA(+)IE，但它不影响 IE 与硫酸软骨素 A 的黏附，也不会导致 C1q 在 IE 上沉积。总之，我们的研究结果表明，VAR2CSA 对非特异性 IgM 的亲和力已经进化，使胎盘定殖的恶性疟原虫能够逃避获得性保护性免疫，而不会损害 VAR2CSA 的功能或增加 IE 对补体介导的裂解的敏感性。此外，不太容易受到 IgM 掩盖的功能性重要 PfEMP1 表位可能是获得性保护性免疫恶性疟原虫疟疾的特别重要的靶标。
