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 in connection with the subsequent transferase depletions, which result in the formation and release of glycan-depleted proteins that through specific binding sites and reactivity might establish this mechanism and reveal the structure and quality of the volatilely expressed “lost” glycans. Consequently, these <i>O</i>-GalNAc-glycosylations of proteins, involving serine/threonine residues, are either identical or metabolically related with 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 and depending on its levels, initiate the process of growth inhibition through enzyme-substrate competition with subsequent trans-species <i>O</i>-GalNAc-glycosylations. <br>