Early ovariectomy reveals the germline encoding of the “natural” mammalian anti-A-reactive IgM reflecting developmental malignancy.

The germline encoding of a mammalian immunoglobulin M (IgM) molecule was documented for the first time as a result of the specifically timed ovariectomy of C57BL/10 mice. The target of this innate antibody involves a trans-species developmental antigen that signifies malignancy when accumulating in non-developmental tissues. While ovariectomy and castration result in uncontrolled immunity with pronounced B and T cell production, the non-immune anti-A reactivity in murine plasma was not enhanced after an ovariectomy that was performed in C57BL/10 mice prior to the onset of puberty. This murine anti-A, which is complementary to the GalNAc glycan of syngeneic ovarian glycolipids and distinct from adaptive anti-A antibody did not appear in plasma of animals ovariectomized at the age of 20 days. In mouse and man, this molecule most likely gets its complementary footprint during the early trans-species <i>O</i>-linked glycosylations of proteins in connection with subsequent or simultaneous depletion of volatilely expressed “immature” <i>O</i>-GalNAc transferase activities, which might involve the generation and release of glycan-depleted proteins that by binding sites and reactivity reflect the structure and quality of the disappeared glycan. Consequently, these volatilely expressed non-somatic <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 pronounced occurrence of anti-Tn in plasma of the human histo (blood) group O, in which the A-allelic, phenotype-specific GalNAc glycosylation of plasma proteins does not occur and affect the anti-Tn levels.