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

The germline encoding of a non-immune immunoglobulin M (IgM) molecule in mammals was experimentally 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 expressed in any non-developmental tissue. Although ovariectomy and castration result in uncontrolled and/or enhanced humoral and cellular immunity involving increased weights of the spleen and thymus with pronounced B and T cell production, the development of mercaptoethanol-sensitive, complement-binding, 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 non-immune murine anti-A, which is complementary to the trans-species, syngeneic ovarian GalNAc-glycan-bearing glycolipids and distinct from the cross-reactive adaptive anti-A antibody, was strongly downregulated or 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 from the first, genetically as-yet-undefined trans-species <i>O</i>-linked glycosylation of proteins and after depletion of the volatilely expressed “immature” <i>O</i>-GalNAc transferase activities and release from the transiently appearing glycopeptides, provides the A-reactive glycosidic sites. 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 the pronounced occurrence of anti-Tn in the plasma of the human histo (blood) group O, in which the A-allelic, phenotype-specific GalNAc glycosylation of plasma proteins does not occur and not affect the anti-Tn levels.