Effects of natural human antibodies against a nonhuman sialic acid that metabolically incorporates into activated and malignant immune cells
Effects of natural human antibodies against a nonhuman sialic acid that metabolically incorporates into activated and malignant immune cells
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DOI：
10.4049/jimmunol.175.1.228
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发表时间：
2005-07-01
影响因子：
4.4
通讯作者：
Varki, A
中科院分区：
文献类型：
--
作者：
Nguyen, DH;Tangvoranuntakul, P;Varki, A
由于合成 N-乙醇酰神经氨酸 (Neu5Gc) 的酶发生失活突变，人类在遗传上无法产生哺乳动物唾液酸 N-乙醇酰神经氨酸 (Neu5Gc)。尽管如此，人类细胞和组织似乎能够通过代谢吸收来自外源的 Neu5Gc，包括膳食红肉和乳制品。现在研究的所有正常人都显示出具有针对 Neu5Gc 的循环抗体，但同种型水平存在显着差异。问题是这样的抗体是否会对表达 Neu5Gc 的人类细胞或组织产生不利影响。在这项研究中，我们表明，尽管正常人 PBMC 在体外孵育期间不掺入 Neu5Gc，但活化的 T 细胞却掺入了 Neu5Gc。原代人白血病细胞和人白血病细胞系的掺入效率更高。含有天然高水平抗 Neu5Gc IgG Ab（以下简称 GcIg）的人血清将补体沉积在表达 Neu5Gc 的白血病细胞和活化的 T 细胞上，但不会沉积在正常细胞上。 GcIg 的结合导致补体介导的细胞毒性，这种毒性可通过热失活来抑制。含有低抗 Neu5Gc IgG 的人血清不会介导任何这些效应。混合杀伤试验证实，在 Neu5Gc 喂养后，GcIg 对白血病细胞的选择性杀伤作用是 PBMC 的 15 倍。这种方法有可能成为使用天然抗体或为此目的制备的抗 Neu5Gc 抗体在体内靶向恶性细胞死亡的新方法。需要进一步的研究来确定天然 GcIg 和补体的沉积是否也可以在饮食中掺入 Neu5Gc 后靶向健康增殖的免疫细胞导致体内死亡。
Humans are genetically incapable of producing the mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc), due to an inactivating mutation in the enzyme synthesizing it. Despite this, human cells and tissues appear capable of metabolically incorporating Neu5Gc from exogenous sources, including dietary red meat and dairy products. All normal humans studied are now shown to have circulating Abs against Neu5Gc, with marked differences in isotype levels. The question arises whether such Abs can adversely affect Neu5Gc-expressing human cells or tissues. In this study, we show that although normal human PBMC do not incorporate Neu5Gc during in vitro incubation, activated T cells do. Primary human leukemia cells and human leukemic cell lines are even more efficient at incorporation. Human sera containing naturally high levels of anti-Neu5Gc IgG Abs (hereafter abbreviated GcIg) deposited complement on Neu5Gc-expressing leukemic cells and activated T cells, but not on normal cells. The binding of GcIg resulted in complement-mediated cytotoxicity, which was inhibited by heat inactivation. Low anti-Neu5Gc IgG-containing human sera did not mediate any of these effects. Mixed killing assays confirmed the 15-fold selective killing of leukemic cells over PBMC by GcIg following Neu5Gc feeding. This approach could potentially serve as novel way to target malignant cells for death in vivo using either natural Abs or anti-Neu5Gc Abs prepared for this purpose. Further studies are needed to determine whether deposition of natural GcIg and complement can also target healthy proliferating immune cells for death in vivo following incorporation of dietary Neu5Gc.