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)

Abstract

While native blood group A-like glycans have not been demonstrated in prokaryotic microorganisms as a source of human “natural” anti-A isoagglutinin production, and metazoan eukaryotic N-acetylgalactosamine O-glycosylation of serine or threonine residues (O-GalNAc-Ser/Thr-R) does not occur in bacteria, the O-GalNAc glycan-bearing ovarian glycolipids, discovered in C57BL/10 mice, are complementary to the syngeneic anti-A-reactive immunoglobulin M (IgM), which is not present in animals that have undergone ovariectomy prior to the onset of puberty. These mammalian ovarian glycolipids are complementary also to the anti-A/Tn cross-reactive Helix pomatia agglutinin (HPA), a molluscan defense protein, emerging from the coat proteins of fertilized eggs and reflecting the snail-intrinsic, reversible O-GalNAc glycosylations. The hexameric structure of this primitive invertebrate defense protein gives rise to speculation regarding an evolutionary relationship to the mammalian nonimmune, anti-A-reactive immunoglobulin M (IgM) molecule. Hypothetically, this molecule obtains its complementarity from the first step of protein glycosylations, initiated by GalNAc via reversible O-linkages to peptides displaying Ser/Thr motifs, whereas the subsequent transferase depletion completes germ cell maturation and cell renewal, associated with loss of glycosidic bonds and release of O-glycan-depleted proteins, such as complementary IgM revealing the structure of the volatilely expressed “lost” glycan carrier through germline Ser residues. Consequently, the evolutionary/developmental first glycosylations of proteins appear metabolically related or identical to that of the mucin-type, potentially “aberrant” monosaccharide GalNAcα1-O-Ser/Thr-R, also referred to as the 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 antibody in plasma from humans with histo-blood group O. In fact, A-allelic, phenotype-specific GalNAc glycosylation of plasma proteins does not occur in human blood group O, affecting anti-Tn antibody levels, which may function as a growth regulator that contributes to a potential survival advantage of this group in the overall risk of developing cancer when compared with non-O blood groups.

In mouse and man, the complementarity of the nonimmune anti-A/Tn cross-reactive IgM most likely occurs in a process of rapid glycosylations/deglycosylations, called “single cycle event”, which causes the release of an antibody molecule that displays a predetermined breaking point through the hydroxyl (–OH) functional group of terminal serine/threonine residues. The germline encoded anti-Tn cross-reactivity of the anti-A-specific isoagglutinin and the pronounced occurrence of anti-Tn reactivity in plasma from humans with histo (blood) group O(H), could contribute to the potential, currently discussed survival advantage of this group in the overall risk of developing cancer when compared with non-O blood groups.

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