Effects of Natural Human Antibodies against a Nonhuman Sialic Acid That Metabolically Incorporates into Activated and Malignant Immune Cells

Abstract

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.

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

“…Human sera contain naturally high levels of anti-N-glycolyl gangliosides antibodies even of IgG isotype (6,44), which only induce complement-mediated mechanism in leukemia cells (7). Our results suggest that this NGcGM3-mediated cell death seems to be a particular property of 14F7 variable region.…”

“…N-glycolyl sialic acid differs by an additional oxygen atom to the Nacetyl moiety and is not detected in healthy human tissues due to a genetic deletion in the CMP-N-acetyl hydroxylase enzyme that catalyze the biosynthesis conversion of Nacetyl to N-glycolyl sialic acid (4). However, the N-glycolyl variant can be detected in some human tumors and fetal tissues (3,5), where is known to be immunogenic (6,7). Free N-glycolyl sialic acid can be metabolically incorporated into human carcinoma cells by fluid pinocytosis and lysosomal sialic acid transporter (8).…”

Diversity in cell surface sialic acid presentations: implications for biology and disease

“…38 Meanwhile, healthy humans have significant and differing levels of circulating antiNeu5Gc antibodies. 38,39 Our current hypothesis is that chronic inflammation related to this antigen-antibody reaction could be facilitating both carcinogenesis and atherogenesis.…”

Detection of the dietary xenoglycan N-glycolylneuraminic acid (Neu5Gc) and anti-Neu5Gc antibodies within reproductive tracts of male and female infertility subjects

“…This has been reported in both human tumors such as breast, colon, and skin cancers [10] and normal tissues including secretory epithelium and blood vessels [9]. Moreover, most humans have circulating anti-Neu5Gc antibodies [9,11] targeting this xenoglycan in serum [9,12]. Levels of anti-Neu5Gc antibodies vary among different individuals, but it has been suggested that chronic exposure to Neu5Gc and incorporation of this xenoglycan combined with circulating anti-Neu5Gc antibodies can promote chronic inflammatory states contributing to various diseases [14] including some of the diseases associated Hanganutziu-Deicher antibodies, which are reactive against Neu5Gc [13,14].…”