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Cmah mutation showed no endogenous Neu5Gc (Hedlund et al., 2007). Absent an alternate pathway for Neu5Gc synthesis, the sugar must enter from external sources. Indeed, cultured human cells express Neu5Gc because of uptake and metabolic incorporation from animal products in the medium (e.g., FCS) (Tangvoranuntakul et al., 2003; Bardor et al., 2005). This process involves macropinocytosis, delivery to the lysosome, and export of free Neu5Gc to the cytosol via the sialin transporter (Bardor et al., 2005). Once Neu5Gc reaches the human cytosol, it is a molecular “Trojan horse.” Differing by only one oxygen atom from endogenous Neu5Ac and having been eliminated only recently in evolutionary time, Neu5Gc is handled by human biochemical pathways as if it were native. Indeed, one can feed Neu5Gc to human cells and make them look like NHH cells (Bardor et al., 2005; Nguyen et al., 2005).

Classic studies showed that chickens generate a strong IgY antibody response against Neu5Gc (Malykh et al., 2001). Using a more specific version of such polyclonal antibodies and adding mass spectrometry to be certain (Hedlund et al., 2008), we confirmed the presence of Neu5Gc in human tumors and in fetal tissues (Tangvoranuntakul et al., 2003). Surprisingly, we also found smaller amounts in normal human tissues (Tangvoranuntakul et al., 2003). The likely explanation is a dietary origin. Voluntary Neu5Gc ingestion studies confirmed that humans could indeed take up Neu5Gc (Tangvoranuntakul et al., 2003).

ANTI-Neu5Gc ANTIBODIES IN HUMANS ARE OF BROAD AND HIGHLY VARIABLE SPECIFICITIES

Why should it matter that human tissues express small amounts of Neu5Gc derived from dietary sources? Although human biochemical pathways do not see Neu5Gc as foreign, it is detected as such by the immune system. Thus, contrary to prior work that used limited methodologies, we find anti-Neu5Gc antibodies circulating in all normal humans. In fact, some individuals have very high levels (Padler-Karavani et al., 2008), including complement-fixing IgGs capable of activating and/or killing cells expressing Neu5Gc (Nguyen et al., 2005). In this situation, a xeno-antigen can become metabolically incorporated into tissues, even while it is detected as being foreign by B cells. Thus, we call Neu5Gc a “xeno-autoantigen” in humans (Pham et al., 2009).

LIMITED DISTRIBUTION OF Neu5Gc IN FOODS AND DISEASE RISKS ASSOCIATED WITH RED MEAT

Because Sias are not found in plants, and Neu5Gc is not synthesized by microbes, the dietary source of Neu5Gc must be foods of animal



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