Glycobiology Advance Access published online on July 31, 2008
Glycobiology, doi:10.1093/glycob/cwn072
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Diversity in Specificity, Abundance and Composition of Anti-Neu5Gc Antibodies in Normal Humans: Potential Implications for Disease
* Glycobiology Research and Training Center and Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Department of Chemistry, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA
Glycobiology Research and Training Center and Department of Pathology, University of California at San Diego, La Jolla, CA 92093, USA
Address correspondence to: Ajit Varki, 9500, Gilman Drive, University of California, San Diego, La Jolla, CA 92093-0687, Tel: 858-534-2214. Fax: 858-534-5611, a1varki{at}ucsd.edu
Received on May 27, 2008; accepted on July 28, 2008
Human heterophile antibodies that agglutinate animal erythrocytes are known to detect the non-human 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 varies 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 show 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.
Key words: Antibodies / Cell surface molecules / Human / Neu5Gc / Sialic acids
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