A Mouse Model for Dietary Xenosialitis

Ma, Fang; Deng, Liwen; Secrest, Patrick; Shi, Linda Z.; Zhao, June; Gagneux, Pascal

doi:10.1074/jbc.m116.739169

Cited by 19 publications

(11 citation statements)

References 63 publications

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“…Mammals make anti-sperm antibodies when directly exposed to sperm (72). Major human sperm antigens include, highly sialylated GPI-anchored glycoproteins such as CD52 (73, 74), which in males that have a functional CMAH allele, carry Neu5Gc (75). Theoretically, immunization of females homozygous for the loss-of-function allele of Cmah could occur via insemination by males that have Neu5Gc-bearing sperm.…”

Section: Evolutionary Mechanisms For the Fixation Of Loss-of-functionmentioning

confidence: 99%

Absence of Neu5Gc and Presence of Anti-Neu5Gc Antibodies in Humans—An Evolutionary Perspective

Altman

Gagneux

2019

Front. Immunol.

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The glycocalyx of human cells differs from that of many other mammals by the lack of the sialic acid N-glycolylneuraminic acid (Neu5Gc) and increased abundance of its precursor N-acetylneuraminic acid (Neu5Ac). Most humans also have circulating antibodies specifically targeting the non-human sialic acid Neu5Gc. Recently, several additional mammalian species have been found to also lack Neu5Gc. In all cases, loss-of-function mutations in the gene encoding the sialic acid-modifying enzyme CMAH are responsible for the drastic change in these species. Unlike other glycan antigens, Neu5Gc apparently cannot be produced by microbes, raising the question about the origin of these antibodies in humans. Dietary exposure and presentation on bacteria coating themselves with Neu5Gc from the diet are distinct possibilities. However, the majority of the non-human species that lack Neu5Gc do not consume diets rich in Neu5Gc, making it unlikely that they will have been immunized against this sialic acid. A notable exception are mustelids (ferrets, martens and their relatives) known for preying on various small mammal species rich in Neu5Gc. No studies exist on levels of anti-Neu5Gc antibodies in non-human species. Evolutionary scenarios for the repeated, independent fixation of CMAH loss-of-function mutations at various time points in the past include strong selection by parasites, especially enveloped viruses, stochastic effects of genetic drift, and directional selection via female immunity to paternal Neu5Gc. Convergent evolution of losses of the vertebrate-specific self-glycan Neu5Gc are puzzling and may represent a prominent way in which glycans become agents of evolutionary change in their own right. Such change may include the reconfiguration of innate immune lectins that use self-sialic acids as recognition patterns.

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Section: Evolutionary Mechanisms For the Fixation Of Loss-of-functionmentioning

confidence: 99%

Absence of Neu5Gc and Presence of Anti-Neu5Gc Antibodies in Humans—An Evolutionary Perspective

Altman

Gagneux

2019

Front. Immunol.

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“…We hypothesize that sperm sialic acids and female-expressed Siglecs may modulate the leukocytic reaction and promote sperm survival within the female reproductive tract. Indeed, a recent report has shown that sialic acids on sperm are protective against phagocytosis by macrophages, ex vivo (25). To begin to address this, we investigated sialic acid-dependent interactions between sperm and isolated neutrophils in vitro.…”

mentioning

confidence: 99%

The female reproductive tract contains multiple innate sialic acid-binding immunoglobulin-like lectins (Siglecs) that facilitate sperm survival

Tecle¹,

Reynoso²,

Wang

et al. 2019

Journal of Biological Chemistry

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“…This mechanism was demonstrated in human-like Cmah null mice (44, 46). On the other hand, a random CMAH mutation may simply have become fixed in a small group of individuals who eventually gave rise to modern humans.…”

Section: Humans Cannot Synthesize Neu5gcmentioning

confidence: 81%

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

2019

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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.

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A Mouse Model for Dietary Xenosialitis

Cited by 19 publications

References 63 publications

Absence of Neu5Gc and Presence of Anti-Neu5Gc Antibodies in Humans—An Evolutionary Perspective

Absence of Neu5Gc and Presence of Anti-Neu5Gc Antibodies in Humans—An Evolutionary Perspective

The female reproductive tract contains multiple innate sialic acid-binding immunoglobulin-like lectins (Siglecs) that facilitate sperm survival

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

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