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. In mouse and man, this molecule most likely gets its complementary footprints or anti-A reactivity 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 its 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-reactivities of anti-A specific immunoglobulins and their pronounced occurrence in the plasma of the human histo (blood) group O, in which phenotype-specific GalNAc glycosylation of plasma proteins does not occur. In the C57BL/10 mouse, all of the tissues expressed the species-specific Forssman<i> </i>reactivity, and further A-like structures were identified in the male and female reproductive and endodermal organs by reaction with innate human anti-A antibody, while the murine anti-A was exclusively inhibited by syngeneic ovarian glycolipids. Moreover, the early ovarian tissue, which represents a last evolutionary and/or developmental location, showed a developmental polymorphism characterized by reactivity to the lectin from <i>Dolichos biflorus</i> and the agglutinin from <i>Helix pomatia </i>indicating the functional involvement of the <i>O</i>-GalNAc-determined mucin-type A-like, Tn and T (Thomsen-Friedenreich) epitopes that signify malignancy when metabolically accumulated and expressed in non-developmental tissues.