Germline encoded, anti-Tn/cross reactive anti-A, polyreactive IgM

What is it about?

New interpretations: Native blood group A-like glycans have not been demonstrated in prokaryotic microorganisms as a source of "natural" human anti-A isoagglutinin production, and metazoan eukaryotic N-acetylgalactosamine O-glycosylation of serine or threonine residues (O-GalNAc-Ser/Thr-R) does not spontaneously occur in bacteria. The O-GalNAc glycan-containing ovarian glycolipids discovered in C57BL/10 mice are complementary to syngeneic anti-A-reactive immunoglobulin M (IgM), which is absent in animals that have undergone ovariectomy prior to the onset of puberty. These mammalian ovarian glycolipids are also complementary to the anti-A/Tn cross-reactive Helix pomatia agglutinin (HPA), a molluscan defense protein derived from the coat proteins of fertilized eggs and reflecting the snail's intrinsic reversible O-GalNAc glycosylations. The hexameric structure of this primitive invertebrate defense protein suggests an evolutionary relationship with the mammalian non-immune, anti-A-reactive immunoglobulin M (IgM) molecule. Hypothetically, this molecule derives its complementarity from the first step of protein glycosylation initiated by GalNAc via reversible O-linkages to peptides bearing Ser/Thr motifs, while the subsequent transferase depletion completes germ cell maturation and cell renewal, associated with the loss of glycosidic bonds and the release of O-glycan-depleted proteins, such as the complementary IgM, which reveals the structure of the transiently expressed "lost" glycan carrier through germline Ser residues. Consequently, the evolutionary/developmental first glycosylations of proteins appear to be metabolically related or identical to that of the mucin-type, potentially "aberrant" monosaccharide GalNAcα1-O-Ser/Thr-R, also called Tn (T "nouvelle") antigen, and explain the anti-Tn cross-reactivity of human innate or "natural" anti-A-specific isoagglutinin and the pronounced occurrence of cross-reactive anti-Tn antibodies in the plasma of humans with histo-blood group O(H). Originally created for “Early ovariectomy reveals the germline encoding of natural anti-A- and Tn-cross-reactive immunoglobulin M (IgM) arising from developmental O-GalNAc glycosylations. (Germline-encoded natural anti-A/Tn cross-reactive IgM)”, Cancer Medicine, DOI: 10.1002/cam4.1079, PMCID: PMC5504323

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Photo by Anton Darius on Unsplash

Photo by Anton Darius on Unsplash

Why is it important?

New interpretations: Hypothetically, the Tn/A-like molecule derives its complementarity from the first step of protein glycosylation initiated by GalNAc via reversible O-linkages to peptides bearing Ser/Thr motifs, while the subsequent transferase depletion completes germ cell maturation and cell renewal, associated with the loss of glycosidic bonds and the release of O-glycan-depleted proteins, such as the complementary IgM, which reveals the structure of the transiently expressed "lost" glycan carrier through germline Ser residues. Consequently, the evolutionary/developmental first glycosylations of proteins appear to be metabolically related or identical to that of the mucin-type, potentially "aberrant" monosaccharide GalNAcα1-O-Ser/Thr-R, also called Tn (T "nouvelle") antigen, and explain the anti-Tn cross-reactivity of human innate or "natural" anti-A-specific isoagglutinin and the pronounced occurrence of cross-reactive anti-Tn antibodies in the plasma of humans with histo-blood group O(H). Originally created for “Early ovariectomy reveals the germline encoding of natural anti-A- and Tn-cross-reactive immunoglobulin M (IgM) arising from developmental O-GalNAc glycosylations. (Germline-encoded natural anti-A/Tn cross-reactive IgM)”, Cancer Medicine, DOI: 10.1002/cam4.1079, PMCID: PMC5504323

Perspectives