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Human Antibodies Against Non-Human Neu5Gc-carrying Glycans in Normal and Pathologic States

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While most mammals commonly express the two forms of sialic acids, N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), humans cannot synthesize Neu5Gc due to a loss-of-function mutation in the CMAH gene which encodes the enzyme responsible for its synthesis. Consequently, Neu5Gc is ...

While most mammals commonly express the two forms of sialic acids, N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), humans cannot synthesize Neu5Gc due to a loss-of-function mutation in the CMAH gene which encodes the enzyme responsible for its synthesis. Consequently, Neu5Gc is immunogenic in humans, leading to the generation of antibodies against various presentations of Neu5Gc-glycans. These antibodies appear in the first months of life and coincide with dietary feeding of Neu5Gc antigens (e.g. red meat and baby formulas containing cow’s milk).

Co-existence of Neu5Gc and anti-Neu5Gc antibodies in humans may have detrimental consequences, and in recent years, a considerable amount of fundamental information on this subject has been accumulated. This new knowledge covers various aspects of Neu5Gc chemistry, biology and associated effects on human health including: 1. Synthesis of natural and artificial antigenic Neu5Gc-epitopes; 2. The evolutionary and biological outcomes of the loss of Neu5Gc in humans, and their effects on receptor recognition (i.e. by sialic acid immunoglobulin-like lectins; Siglecs); 3. The nature and kinetics of anti-Neu5Gc antibody responses in humans, and 4. Their role in various human diseases. Diet-derived Neu5Gc can be absorbed by human cells and can be found at very low levels on the surface of endothelial cells and of oncogenic epithelial cells. This unique situation results in the expression of a non-self molecule in the context of self, coined as a ‘xeno-autoantigen’. Together with circulating anti-Neu5Gc ‘xeno-autoantibodies’ a peculiar “physiological” condition of chronic antibody exposure may result in in situ chronic inflammation, termed xenosialitis, eventually contributing to various human diseases.

Nevertheless, the mechanisms underlying the roles of anti-Neu5Gc antibodies in human pathologies are largely unexplored. Indeed, most current investigations focus on several unresolved theoretical and fundamental questions directly related to a possible deleterious role of anti–Neu5Gc antibodies in humans. However their effects in autoimmune diseases or following exposure to treatment with animal-derived biotherapeutics or bio-devices remain poorly understood. Recently, new studies have shed at least some light in that respect, including a possible role for a repertoire shifted to anti-Neu5Gc antibodies in human patients treated with Neu5Gc-containing cells, tissues, or molecules.

In this Research Topic, we aim to focus on the possible pathological role of anti-Neu5Gc antibodies that are elicited either through exposure to Neu5Gc-containing foods or artificially through treatment with animal-derived substances and to therefore advance studies of various pathologies that could result from such an immune conflict.


Keywords: Neu5Gc, N-acetylneuraminic acid, N-glycolylneuraminic acid, CMAH


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