Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid

Abstract

Humans are genetically unable to produce the sialic acid N-glycolylneuraminic acid (Neu5Gc), because of a mutation that occurred after our last common ancestor with great apes. Although Neu5Gc is presumed absent from normal humans, small amounts have been claimed to exist in human tumors and fetal meconium. We have generated an antibody with high specificity and avidity for Neu5Gc. Fetal tissues, normal adult tissues, and breast carcinomas from humans showed reactivity to this antibody, primarily within secretory epithelia and blood vessels. The presence of small amounts of Neu5Gc was confirmed by MS. Absent any known alternate pathway for its synthesis, we reasoned that these small amounts of Neu5Gc might originate from exogenous sources. Indeed, human cells fed with Neu5Gc incorporated it into endogenous glycoproteins. When normal human volunteers ingested Neu5Gc, a portion was absorbed and eliminated in urine, and small quantities were incorporated into newly synthesized glycoproteins. Neu5Gc has never been reported in plants or microbes to our knowledge. We found that Neu5Gc is rare in poultry and fish, common in milk products, and enriched in red meats. Furthermore, normal humans have variable amounts of circulating IgA, IgM, and IgG antibodies against Neu5Gc, with the highest levels comparable to those of the previously known anti-␣-galactose xenoreactive antibodies. This finding represents an instance wherein humans absorb and metabolically incorporate a nonhuman dietary component enriched in foods of mammalian origin, even while generating xenoreactive, and potentially autoreactive, antibodies against the same molecule. Potential implications for human diseases are briefly discussed.

Evolution of human-chimpanzee differences in malaria susceptibility: Relationship to human genetic loss of N -glycolylneuraminic acid

“…To determine the relative importance of Sia-specificity, we experimentally changed the Sia profile while keeping the glycophorin protein backbone constant. Human cells growing in human serum express only Neu5Ac but can metabolically incorporate free Neu5Gc from the medium and eventually express it on their membrane glycoconjugates (41,46,47). The human erythroleukemia cell line K562 is known to express GYPA (48), and we found that it also expresses glycophorin C [both were detected by specific antibody staining and flow cytometry (data not shown)].…”

A Sialylated Glycan Microarray Reveals Novel Interactions of Modified Sialic Acids with Proteins and Viruses

“…Glycan 20, which is an ␣2-6 monosialylated derivative of NA2, bound RCA-I before and after neuraminidase, although binding was not enhanced after neuraminidase treatment. RCA-I bound weakly to ␣2-6-sialylated lactose and LNnT (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), unlike the corresponding ␣2-3-sialylated lactose and LNnT (41-57), which were not bound. Although most sialic acid derivatives moderately decreased RCA-I binding to NA2, ␣2-6-sialylation with Neu5Ac8Me (19) and Neu5Gc9Ac (25) greatly inhibit RCA-I binding.…”

Simple Capillary Electrophoresis–Mass Spectrometry Method for Complex Glycan Analysis Using a Flow-Through Microvial Interface

“…8,10,44,53,60 Even though Neu5Gc is a common sialic acid in most mammals, it has been demonstrated to be absent in healthy humans and only small amounts have been found in some tumors and meconium. 61 The CE-MS method succeeded in detecting this heterogeneity of acidic monosaccharides without removing the sialic acid from the glycan chain by acid hydrolysis as it has been commonly reported. 8,53,62 As reviewed lately, the LC-MS detection of sialic acids and its heterogeneous subtypes is challenging.…”