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Neu5Gc, the Pro-inflammatory Human Xeno-Autoantigen

Despicable Me, Universal Studios.
Xeno-autoantigen: a molecule derived from an external source that incorporates into an organism, inducing an immune response against new self antigens.
The consumption of red meat is correlated with increased incidence of carcinomas in humans. One hypothesis proposed from the lab of Professor Ajit Varki at UCSD suggests that the mechanism is due to the consumption of a xeno-autoantigenic sialic acid sugar molecule, Neu5Gc (N-glycolylneuraminic acid).

Luckily for the lion, Neu5Gc is not a xeno-molecule and would not be antigenic. But it is not so for humans.
Madagascar, DreamWorks
.
To fully understand the situation, we’ll need to travel back in time some 3 million years, to find a single pre-Homo sapien organism. This individual acquired an inactivating mutation in the CMAH gene, which encodes for the enzyme responsible for converting Neu5Ac (N-acetylneuraminic acid) to Neu5Gc in the body. Fast forward to today: now all humans carry this identical mutation rendering us all incapable of producing Neu5Gc. The significance of this means that Neu5Gc is now a foreign molecule to the human body. The mutation must have carried some positive effects for the human species, but the mechanisms for this have not been fully characterized.
Most of the red meat that we eat, such as beef, pork, and lamb, contain high amounts of Neu5Gc. The human body then treats Neu5Gc as it would Neu5Ac and incorporates it onto the carbohydrate structures that coat the surface of cells, as well as on many soluble proteins. The presence of Neu5Gc structures are now capable of inducing immune responses, one of which is the production of antibodies against such antigens.
Specifically in humans, consumption of red meat has been linked to increased incidences of cancer of the lung, pancreas, colon, and breast. There have been suggestions that this may be related to proteins that increase cell division and tumor growth, while others point to nitrates in processed meats. Dr. Varki has proposed another alternative: that the low-level inflammatory responses against Neu5Gc is a major contributor in inducing these cancers.

In a recent study1, his group found that Neu5Gc knockout mice, when fed with Neu5Gc-rich foods, had dramatically increased incidence of hepatocellular carcinomas along with the accumulation of Neu5Gc into tissues. The increased carcinoma rate was dependent on the injection of anti-Neu5Gc specific serum, indicating that an antibody-dependent, targeted immune response was required and sufficient to increase the rates of carcinomas by five-fold.

But how can immune responses be pro-cancerous when we know that immune cells can fight cancer? There are several possibilities within our current understanding of immunology. First, sublytic levels of complement deposition can activate survival pathways, such as PI3K/AKT. Secondly, Fcγ receptor engagement by antibodies can polarize macrophages to tumor-promoting M2 phenotypes. Thirdly, intra-tumor antibodies can accelerate chronic inflammation leading to the production of reactive oxygen species, which can cause DNA damage, further facilitating carcinogenesis.

Dr. Varki further proposes that Neu5Gc may play in role in other auto-inflammatory diseases such as atherosclerosis and type 2 diabetes. Much of the evidence does certainly lead us to Neu5Gc as a culprit in human diseases, especially cancer. Does it still make you want to ask: where’s the beef?

The Simpsons, Fox Broadcasting Company.
Listen to our Podcast with Dr. Ajit Varki to learn more about the interconnectivity of Neu5Gc, glycobiology, life, and evolution.

References
  1. A Red Meat-Derived Glycan Promotes Inflammation and Cancer Progression.

Relevant Products:
Anti-Neu5Gc Antibody Kit

Contributed by Dzung Nguyen, PhD.
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