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The thematic issue of Frontiers in Immunology, entitled “Human Antibodies Against the Dietary Non-Human Neu5Gc-Carrying Glycans in Normal and Pathological States,” benefits from an extensive fundamental review of previous studies on N-glycolylneuraminic acid (Neu5Gc) in humans [(1) for recent review and citations therein] and from studies on anti-Neu5Gc antibodies (A-GcAbs) in Cmah mice that, similar to humans, lack a functional cytidine monophosphate N-acetylneuraminic acid hydroxylase (CMAH), thereby allowing Neu5Gc synthesis (2). Further, “xenosialitis” assumes that the local interaction of A-GcAbs with traces of Neu5Gc residue at the surface of certain human cells may result in a chronic activation of Neu5Gc-displaying cells, which would eventually generate atheroma [for endothelial cells (ECs)] and malignancies (for epithelia) (1, 3). However, not many studies have been performed to date in humans, and these studies have not yet unambiguously demonstrated that A-GcAb-related xenosialitis could contribute to major diseases in humans. This opinion article aims to assess the available evidence-based background of the concept of a deleterious effect of xenosialitis on human diseases, and to suggest alternative working hypotheses for future studies. As previously mentioned, xenosialitis, which is restricted to human pathologies in this opinion article, has been proposed as a “logical” basis for deleterious effects that would result from in situ interactions of A-GcAbs, which are present in human sera and diet-derived Neu5Gc deposits on certain human cells (1). However, this framework assumes the paradox that evolution would have allowed such a dangerous confrontation. Results from studies on Cmah mice have been extensively reviewed (1). However, using CMAH-deficient mice—which do not benefit from the coevolution adaptation that followed the lack of Neu5Gc in humans— poses an issue, as xenosialitis models require exogenous immunizations to elicit A-GcAbs (4, 5), due to the difficulty of “humanizing” the mice with a Neu5Gc-rich diet. In addition, cases of “positive data” arguing for xenosialitis in animal models have required experimental designs that use mice which are prone to spontaneously developing endothelial injuries (5) [see also comments in (6, 7)].

Challenging the Role of Diet-Induced Anti-Neu5Gc Antibodies in Human Pathologies