Human heterophile antibodies that agglutinate animal erythrocytes are known to 
detect the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc). This 
monosaccharide cannot by itself fill the binding site (paratope) of an antibody 
and can also be modified and presented in various linkages, on diverse 
underlying glycans. Thus, we hypothesized that the human anti-Neu5Gc antibody 
response is diverse and polyclonal. Here, we use a novel set of natural and 
chemoenzymatically synthesized glycans to show that normal humans have an 
abundant and diverse spectrum of such anti-Neu5Gc antibodies, directed against a 
variety of Neu5Gc-containing epitopes. High sensitivity and specificity assays 
were achieved by using N-acetylneuraminic acid (Neu5Ac)-containing probes 
(differing from Neu5Gc by one less oxygen atom) as optimal background controls. 
The commonest anti-Neu5Gc antibodies are of the IgG class. Moreover, the range 
of reactivity and Ig classes of antibodies vary greatly amongst normal humans, 
with some individuals having remarkably large amounts, even surpassing levels of 
some well-known natural blood group and xenoreactive antibodies. We purified 
these anti-Neu5Gc antibodies from individual human sera using a newly developed 
affinity method and showed that they bind to wild-type but not Neu5Gc-deficient 
mouse tissues. Moreover, they bind back to human carcinomas that have 
accumulated Neu5Gc in vivo. As dietary Neu5Gc is primarily found in red meat and 
milk products, we suggest that this ongoing antigen-antibody reaction may 
generate chronic inflammation, possibly contributing to the high frequency of 
diet-related carcinomas and other diseases in humans.