From Serum Sickness to Xenosialitis: Past, Present, and Future Significance of the Non-human Sialic Acid Neu5Gc

The description of serum sickness more than a century ago in humans transfused with animal sera eventually led to identification of a class of human antibodies directed against glycans terminating in the common mammalian sialic acid N-Glycolylneuraminic acid (Neu5Gc), hereafter called Neu5Gc-glycans. The detection of such glycans in malignant and fetal human tissues initially raised the possibility that it was an oncofetal antigen. However, serumsickness antibodies were also noted in various human disease states. These findings spurred further research on Neu5Gc, and the discovery that it is not synthesized in the human body due to a human-lineage specific genetic mutation in the enzyme CMAH. However, with more sensitive techniques Neu5Gc-glycans were detected in smaller quantities on certain human cell types, particularly epithelia and endothelia. The likely explanation is metabolic incorporation of Neu5Gc from dietary sources, especially red meat of mammalian origin. This incorporated Neu5Gc on glycans appears to be the first example of a xeno-autoantigen, against which varying levels of xeno-autoantibodies are present in all humans. The resulting chronic inflammation or xenosialitis may have important implications in human health and disease, especially in conditions known to be aggravated by consumption of red meat. In this review, we will cover the early history of the discovery of serum sickness antibodies, the subsequent recognition that they were partly directed against Neu5Gc-glycans, the discovery of the genetic defect eliminating Neu5Gc production in humans, and the later recognition that this was not an oncofetal antigen but the first example of a xeno-autoantigen. Further, we will present comments about implications for disease risks associated with red meat consumption such as cancer and atherosclerosis. We will alsomention the potential utility of these anti-Neu5Gc-glycan antibodies in cancer immunotherapy and provide some suggestions and perspectives for the future. Other reviews in this special issue cover many other aspects of this unusual pathological process, for which there appears to be no other described precedent.