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

echanism 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, which is complementary to the GalNAc glycan expressed by syngeneic ovarian glycolipids and distinct from cross-reactive adaptive anti-A antibody, did not appear in the plasma of animals subjected to ovariectomy at the age of 20 days. 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 blood group O, an A-allelic, phenotype-specific GalNAc glycosylation of plasma proteins does not occur and affect the reactivity of the anti-Tn antibody, which may occur in appearance as a growth regulator and depending on its level, initiates the process of growth inhibition through substrate competition with subsequent trans-species <i>O</i>-GalNAc-glycosylations.