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 or threonine residues ( O ‐Gal NA c‐Ser/Thr‐R) does not occur in bacteria, the O ‐Gal NA c glycan‐bearing ovarian glycolipids, discovered in C57 BL /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 ‐Gal NA c 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 Gal NA c 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 Gal NA c α 1‐ 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 Gal NA c 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.