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 GalNAc glycan of syngeneic ovarian 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 in the course of the early trans-species <i>O</i>-linked glycosylation of proteins and subsequent depletion of volatilely expressed “immature” <i>O</i>-GalNAc transferase activities, which might result in the generation and release of glycan-depleted proteins that by binding sites and reactivity reflect the structure 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.