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

Abstract

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, “serum sickness” 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 also mention 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.

Human species-specific loss of CMP- N -acetylneuraminic acid hydroxylase enhances atherosclerosis via intrinsic and extrinsic mechanisms

“…We have already shown that this novel form of antibodymediated inflammation can potentiate cancer progression in the human-like Cmah-null mouse model (29). Based on these and previous observations we have suggested that xenosialitis may also help explain the increased risk of cancer and CVD epidemiologically associated with human red meat consumption (30).…”

“…With regard to the xenosialitis phenom-enon, further work is also necessary to determine the exact pathways by which Neu5Gc is taken up into tissues, and potential approaches to prevent or eliminate such incorporation are being explored. The current findings indicate that this unique example of inflammation driven by a metabolically incorporated dietary glycan (30) is pathologically relevant and may be involved in other inflammation-driven diseases that are known to be associated with red meat consumption, including carcinomas (25), which also appear to be rare in chimpanzees (46). and maintained in the UCSD vivarium according to Institutional Review Board guidelines for the care and use of laboratory animals.…”

“…The obvious question arising from such experimental mouse studies is whether circulating anti-Neu5Gc antibodies correlate with CVD risk in human population studies. We are currently exploring this possibility (43) but are also aware of the numerous complicating variables in humans, such as the varying amount and unknown bioavailability of Neu5Gc from dietary red meat, the amount of Neu5Gc loading in tissues, the complex and variable polyclonal antibody profiles of individual humans, the skewed distribution of antibody levels within populations, and the variability of concurrent inflammatory conditions (30). Also, given that CMAH deletion results in variable loss of a major cellsurface molecule (Neu5Gc) and a corresponding increase in the precursor Neu5Ac throughout the body, it is not surprising that there is no single dominant mechanistic explanation for the striking phenotypic changes found in this study; rather, there are multiple interactive mechanisms (Fig.…”

Association between Neu5Gc carbohydrate and serum antibodies against it provides the molecular link to cancer: French NutriNet-Santé study

“…It is a nine-carbon negatively charged monosaccharide that can be synthesized by most mammals and found at the tips of carbohydrate chains (glycans), glycoproteins, and glycolipids [ 6 ]. Humans cannot synthesize Neu5Gc due to a deletion in the CMAH gene that encodes the cytidine 5′-monophosphate-Neu5Ac hydroxylase [ 7 ]. Yet, dietary Neu5Gc can be consumed then incorporated at low levels onto human cell surfaces, particularly in cancer, consequently displaying a broad assortment of immunogenic Neu5Gc-glycans [ 6 , 8 ].…”

“…Yet, dietary Neu5Gc can be consumed then incorporated at low levels onto human cell surfaces, particularly in cancer, consequently displaying a broad assortment of immunogenic Neu5Gc-glycans [ 6 , 8 ]. In fact, all humans examined thus far have a diverse collection of polyclonal anti-Neu5Gc antibodies [ 7 , 9 , 10 ]. Thus, circulating anti-Neu5Gc antibodies continuously encounter Neu5Gc-containing epitopes on human tissues and have been proposed to lead to xenosialitis [ 11 ], which in mice have been shown to exacerbate cancer [ 11 , 12 ] and cardiovascular disease [ 13 ].…”