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In the Light of Evolution Volume IV: The Human Condition
What Is the Fate of Orally Ingested Neu5Gc?
We need to know mechanisms by which Neu5Gc is absorbed from the human gut and delivered to tissues. Early studies in rodents showed that the fate of ingested Neu5Gc may differ, based on the form in which it is presented (Nöhle and Schauer, 1984). We can now study these issues by feeding Cmah-null mice different forms of Neu5Gc and looking at its fate in the gut, body fluids, and tissues. At this time, we cannot assume that ingestion of a certain amount of Neu5Gc will deliver a corresponding amount to tissues. A related issue is the fate of Neu5Gc during food processing and cooking.
Mechanisms of Anti-Neu5Gc Antibody Induction
We are studying the tempo and mode of appearance of these highly variable antibodies in human samples and the potential mechanisms for their induction, using Cmah-null mice as a model. We also need to address whether Neu5Gc-containing glycans are truly T-cell-independent antigens, whether the antibody response involves a germline V-set domain, and if the antibody-binding pockets undergo affinity maturation. A related issue is whether these antibodies have any positive value (e.g., potentially protecting against enveloped viruses originating from other species).
Prognostic Value of Anti-Neu5Gc Antibodies
The highly variable anti-Neu5Gc antibody response of humans is further complicated because Neu5Gc itself is not the entire epitope recognized (i.e., the underlying glycan structures to which it is attached influences binding specificity). Thus, there are many possible Neu5Gc epitopes, and each human has a different response to each of them (Padler-Karavani et al., 2008). Because some of these epitopes are differentially expressed in different tissues, only some of the antibodies may have pathogenic roles, and the antibody subclasses may also make a difference. Perhaps one or more of these anti-Neu5Gc-antibodies will prove to be a predictive, prognostic, or diagnostic marker for one or more diseases. We are pursuing this possibility using a glycan microarray that contains matched Neu5Gc and Neu5Ac glycans as targets.
Complexity of the “Sialome” in the Cell Surface
The manner in which Sias are presented within the context of a complex cell-surface “landscape” can affect the way they interact with Siabinding proteins (Cohen et al., 2009). In other words, such proteins recognize not only linear glycan sequences but also more complex structures