Absorption, metabolic incorporation, and inflammation engendered by the non-human sialic acid, N-glycolylneuraminic acid.

摘要

All human adults have circulating antibodies against N-glycolylneuraminic acid (Neu5Gc), a sialic acid that can't be produced in humans. However, dietary Neu5Gc (particularly from red meat) can be metabolically incorporated into human tissues and expressed on self glycans, as if made endogenously. We hypothesize that dietary Neu5Gc (xenoantigen) and Neu5Gc-specific antibodies (xenoautoantibodies) interact in a mechanism generating chronic inflammation, perhaps contributing to human-specific risk of diseases associated with red meat consumption.;Chapter 2 presents evidence that supports a role for dietary Neu5Gc as the source of human tissue Neu5Gc through a gastrointestinal study of dietary Neu5Gc in the Neu5Gc-deficient Cmah-/- mouse model. In this model, Neu5Gc-containing glycoproteins are digested by intestinal enterocytes and trafficked through the blood to the liver and other peripheral tissues. Long term feeding of Neu5Gc-containing glycoproteins leads to tissue incorporation in a human-like pattern, establishing this feeding paradigm as a means to mimic the human condition in vivo.;Appendix I presents studies aimed at generating a human-like Neu5Gc-specific antibody response in mouse. Although humans develop spontaneous Neu5Gc-specific antibodies early in life, Cmah-/- mice need to be immunized. Several immunization strategies are compared, but erythrocyte ghost- and mucin-based antigens have attractive properties. This section also presents work towards control immunizations, as well as discussing important aspects about detecting immune responses at the bench.;Chapter 3 demonstrates incorporation of dietary Neu5Gc in human vasculature, a site that interacts with circulating Neu5Gc-specific antibodies to generate chronic inflammation in humans. In vitro studies show that Neu5Gc-specific antibodies generate inflammation in vascular endothelium exhibiting Neu5Gc incorporation.;Chapter 4 synthesizes information from Chapters 2 and 3 and Appendix I in a mouse model of atherosclerosis where groups were defined by dietary Neu5Gc and Neu5Gc immunization. Initial studies indicate that Neu5Gc-specific antibodies negatively correlate with atherosclerosis, potentially disagreeing with results from Chapter 3 and suggesting an unexplored role(s) for Neu5Gc in lesion pathophysiology. Alternatively, the erythrocyte ghost immunization may not mimic the human condition, which could underlie this unexpected result.