Early ovariectomy reveals the germline encoding of natural anti-A- and Tn-cross-reactive immunoglobulin M (IgM) arising from developmental O -GalNAc glycosylations. (Germline-encoded natural anti-A/Tn cross-reactive IgM)

  • Peter Arend
  • Cancer Medicine, June 2017, Wiley
  • DOI: 10.1002/cam4.1079

The human natural anti-A isoagglutinin dissolves from trans-species, germline Tn antigen

What is it about?

The human natural anti-A isoagglutinin, which arises most pronouncedly in blood group O(H) individuals, seems identical to the germline-encoded anti-A/Tn cross-reactive non-immune IgM molecule and might represent the authentic complementary protein to the native Tn carbohydrate structure, which occurs during every normal growth in volatile expressions. Innate antibodies remain involved in controlling the growth processes, from which they arise, and the Tn (serologically A-like) epitope and its complementary non-immune anti-A/Tn cross-reactive IgM most likely act, via a reversible oxygen bridge, as a functional unity in growth regulation. This principle may be clarified by lower metazoans, such as Helix pomatia, whose anti-A/Tn agglutinin has emerged from the coat proteins of fertilized eggs, while reflecting the snail-intrinsic reversible O-GalNAc glycosylations; the hexameric structure of this primitive invertebrate defense protein gives rise to speculation regarding an evolutionary relationship to the mammalian nonimmune, anti-A-reactive immunoglobulin M (IgM) molecule. In fact, the female C57BL/10 mouse demonstrates the developmental connection of reproduction and primitive immunological defense, in which similarly to Helix pomatia agglutinin, the anti-A/Tn cross-reactive, non-immune protein or ancestral immunoglobulin M is complementary to O-GalNAc-carrying ovarian glycolipids and is released into the plasma after completion of germ cell maturation. Finally, this murine anti-A antibody demonstrates identical serological reaction patterns to human innate anti‐A isoagglutinin.

Why is it important?

The evolution of the human ABO(H) blood group system clearly discriminates against the non-O blood groups A and B, with regard to immunity via impairment of the non-immune IgM polyreactivity due to A and B phenotypic, glycosidic accommodation, while in addition, these groups are excluded from the adaptive production of immunoglobulins against prokaryotic A/B cross-reactive antigenic structures due to clonal selection. Malignant growth does not occur in lower metazoans, such as snails, but in higher organisms appears to be favored by the more complex metabolic pathways and higher number of mutations, associated with the progress of species and phenotype diversity.


Peter Arend

The formation of the serologically histo (blood) group A-like (ABO(H) blood group independent) structure GalNAc1α-O-Ser/Thr-R, also referred to as the Tn (T "nouvelle") antigen, implies the first step of protein glycosylation occurring in all metazoan eukaryotes, and characterizes the embryogenic stem cell fidelity in germ cell transformation and cell renewal. Thus, this A-like epitope does not represent a tumor antigen per se but occurs as a developmental structure, which in healthy organisms preferably becomes detectable in fast growing tissues, such as the ovary during the course of puberty, but when accumulated in non-reproductive tissues on different peptide backbones may signify malignancy. This means accumulation of a primarily normal developmental structure due to a malignant metabolic jam, caused by various, finally unknown origins. Although a native, naturally-occurring or specific anti-Tn, which does not cross-react with natural anti-A antibodies, has not yet been detected, monoclonal anti-Tn-specific antibodies have been constructed in several laboratories. Consequently, respective complementary and various Tn-epitopes are conceivable to occur during tumor growth. The serologically A-like, trans-species Tn epitope must be differentiated from the human-specific, classic blood group A phenotype, constructed in epistatic cooperation via the functions of the A allele located on chromosome 9, with the functions of the H and Se loci on chromosome 19 at 19q13.3 that encode the fucosyltransferases 1 (FUT1) and FUT2 and ultimately promote the synthesis of the ABO(H) epitopes on red cells, mucoepithelial cells, secretions and plasma proteins. It must be emphasized, that the blood group ABO(H) phenotype formation finally occurs on both cell membranes and plasma proteins and occurs by means of membrane-bound and soluble glycotransferases. This implies that the cell surfaces and plasma proteins are identically glycosylated, and while anti-self reactivity thereby is reduced or excluded, innate immunity is affected via phenotypically "adapted" IgM glycosylation. Thus, future research and bioengineering efforts should focus much more on the properties and role of plasma proteins and their functional unity with cell membrane processes. We need more expanded molecular-immunological explanations for the currently discussed survival advantage of the human histo (blood) group O(H), which represents the most common blood group worldwide

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