Characterization of the Hanganutziu-Deicher (Serum-Sickness) Antigen as Gangliosides Containing N-Glycolylneuraminic Acid

Merrick, Jason R. W.; Zadarlik, K.; Milgrom, Felix

doi:10.1159/000232140

Cited by 127 publications

(90 citation statements)

References 6 publications

(7 reference statements)

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“…Overall characteristics of cohort A As shown in Figure 1A, the 889 patients in cohort A were retained from an initial cohort of 1,370 first graft recipients treated with ularly, of the Neu5Gc antigen, coined as the "serum sickness antigen" (12,(14)(15)(16). Humans cannot synthesize the sialic acid Neu5Gc (glycolyl form of neuraminic acid) from the acetylated form, Neu5Ac, following the mutation of the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) (17,18).…”

Section: Introduction Resultsmentioning

confidence: 99%

Rabbit antithymocyte globulin–induced serum sickness disease and human kidney graft survival

Couvrat-Desvergnes¹,

Salama²,

Berre³

et al. 2015

Journal of Clinical Investigation

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Section: Introduction Resultsmentioning

confidence: 99%

Rabbit antithymocyte globulin–induced serum sickness disease and human kidney graft survival

Couvrat-Desvergnes¹,

Salama²,

Berre³

et al. 2015

Journal of Clinical Investigation

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“…Neu5Gc bound to horse serum glycoconjugates was later found to be the dominant epitope recognized by Hanganutziu-Deicher (HD) Abs, which were typically detected by their ability to agglutinate animal erythrocytes (8,9). HD Abs and HD Ags were then discovered in the sera and tissues of cancer patients (10).…”

Section: Effects Of Natural Human Antibodies Against a Nonhuman Sialimentioning

confidence: 99%

Effects of Natural Human Antibodies against a Nonhuman Sialic Acid That Metabolically Incorporates into Activated and Malignant Immune Cells

Nguyen

Tangvoranuntakul

Varki

2005

The Journal of Immunology

136

144

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Humans are genetically incapable of producing the mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc), due to an inactivating mutation in the enzyme synthesizing it. Despite this, human cells and tissues appear capable of metabolically incorporating Neu5Gc from exogenous sources, including dietary red meat and dairy products. All normal humans studied are now shown to have circulating Abs against Neu5Gc, with marked differences in isotype levels. The question arises whether such Abs can adversely affect Neu5Gc-expressing human cells or tissues. In this study, we show that although normal human PBMC do not incorporate Neu5Gc during in vitro incubation, activated T cells do. Primary human leukemia cells and human leukemic cell lines are even more efficient at incorporation. Human sera containing naturally high levels of anti-Neu5Gc IgG Abs (hereafter abbreviated GcIg) deposited complement on Neu5Gc-expressing leukemic cells and activated T cells, but not on normal cells. The binding of GcIg resulted in complement-mediated cytotoxicity, which was inhibited by heat inactivation. Low anti-Neu5Gc IgG-containing human sera did not mediate any of these effects. Mixed killing assays confirmed the 15-fold selective killing of leukemic cells over PBMC by GcIg following Neu5Gc feeding. This approach could potentially serve as novel way to target malignant cells for death in vivo using either natural Abs or anti-Neu5Gc Abs prepared for this purpose. Further studies are needed to determine whether deposition of natural GcIg and complement can also target healthy proliferating immune cells for death in vivo following incorporation of dietary Neu5Gc.

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“…Although Neu5Gc is a major Sia in most mammals (including our closest evolutionary relatives, the great apes) (8), it is thought to be absent in healthy humans (1)(2)(3). Indeed, humans generate immune responses against i.v.-administered molecules carrying Neu5Gc, e.g., the ''serum sickness'' reaction to equine antithymocyte globulin therapy (9,10). These findings are explained by a human-specific inactivating mutation in the CMAH gene (11)(12)(13)) that occurred Ϸ2.5 million to 3 million years ago (14).…”

mentioning

confidence: 99%

Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid

Tangvoranuntakul

Gagneux

Díaz

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

543

586

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Humans are genetically unable to produce the sialic acid N-glycolylneuraminic acid (Neu5Gc), because of a mutation that occurred after our last common ancestor with great apes. Although Neu5Gc is presumed absent from normal humans, small amounts have been claimed to exist in human tumors and fetal meconium. We have generated an antibody with high specificity and avidity for Neu5Gc. Fetal tissues, normal adult tissues, and breast carcinomas from humans showed reactivity to this antibody, primarily within secretory epithelia and blood vessels. The presence of small amounts of Neu5Gc was confirmed by MS. Absent any known alternate pathway for its synthesis, we reasoned that these small amounts of Neu5Gc might originate from exogenous sources. Indeed, human cells fed with Neu5Gc incorporated it into endogenous glycoproteins. When normal human volunteers ingested Neu5Gc, a portion was absorbed and eliminated in urine, and small quantities were incorporated into newly synthesized glycoproteins. Neu5Gc has never been reported in plants or microbes to our knowledge. We found that Neu5Gc is rare in poultry and fish, common in milk products, and enriched in red meats. Furthermore, normal humans have variable amounts of circulating IgA, IgM, and IgG antibodies against Neu5Gc, with the highest levels comparable to those of the previously known anti-␣-galactose xenoreactive antibodies. This finding represents an instance wherein humans absorb and metabolically incorporate a nonhuman dietary component enriched in foods of mammalian origin, even while generating xenoreactive, and potentially autoreactive, antibodies against the same molecule. Potential implications for human diseases are briefly discussed.

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Characterization of the Hanganutziu-Deicher (Serum-Sickness) Antigen as Gangliosides Containing N-Glycolylneuraminic Acid

Cited by 127 publications

References 6 publications

Rabbit antithymocyte globulin–induced serum sickness disease and human kidney graft survival

Rabbit antithymocyte globulin–induced serum sickness disease and human kidney graft survival

Effects of Natural Human Antibodies against a Nonhuman Sialic Acid That Metabolically Incorporates into Activated and Malignant Immune Cells

Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid

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