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).

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/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 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.