Germline encoded anti-A-reactive IgM arising from growth-dependent and aberrant O-GalNAc glycosylations.*

The germline encoding of a mammalian immunoglobulin M (IgM) molecule was experimentally documented for the first time in C57BL/10 mice subjected to an ovariectomy prior to the onset of puberty. The target of this innate antibody is a trans-species developmental antigen that signifies malignancy when accumulating in non-developmental tissues. This murine anti-A antibody, which is complementary to the <i>O</i>-GalNAc glycan expressed by syngeneic ovarian glycolipids, appears serologically identical to the human innate anti-A isoagglutinin. In mouse and man, this molecule most likely gets its complementary footprint from the early growth-dependent, trans-species <i>O</i>-GalNAc glycosylations of proteins and subsequent GalNAc transferase depletions, which complete a cell differentiation process and result in the release of glycan-depleted, complementary proteins that through specific binding sites and reactivity might establish this mechanism and reveal the structure and quality of the volatilely expressed, complementary “lost” glycans. Consequently, these early or first <i>O</i>-GalNAc-glycosylations of proteins, involving serine/threonine residues, are metabolically related to those of the mucin-type, “aberrant” monosaccharide GalNAcα1-<i>O</i>-Ser/Thr-R or Tn antigen and explain the anti-Tn cross-reactivity of anti-A specific immunoglobulins and the pronounced occurrence of cross-reactive anti-Tn antibody in the plasma of human histo (blood) group O. In fact, in the human blood group O, an A-allelic, phenotype-specific GalNAc glycosylation of plasma proteins does not occur and affect the levels of the anti-Tn antibody, which may function as a growth regulator that depending on its levels, initiates the process of growth inhibition through enzyme-substrate competition with subsequent trans-species <i>O</i>-GalNAc-glycosylations and mediates autologous cellular cytotoxicity.