Complementary innate (anti-A-specific) IgM emerging from ontogenic O-GalNAc-transferase depletion: (Innate IgM complementarity residing in ancestral antigen completeness).

Abstract The murine and the human genome have global properties in common. So the murine anti-A-specific complementary IgM and related human innate isoagglutinin represent developmental, 2-mercaptoethanol-sensitive, complement-binding glycoproteins, which do not arise from any measurable environmentally-induced or auto- immune response. The murine anti-A certainly originates from a cell surface- or cell adhesion molecule, which in the course of germ cell development becomes devoid of O-GalNAc-transferase and is released into the circulation. In human sera the enzyme occurs exclusively in those of blood group A- and A B subjects, while in group O(H) an identically encoded protein lets expect an opposite function and appears in conjunction with a complementary anti-A reactive glycoprotein. Since O-glycosylations rule the carbohydrate metabolism in growth and reproduction processes, we propose that the ancestral histo-(blood)-group A molecule arises in the course of O-GalNAc-glycosylations of glycolipids and protein envelops at progenitor cell surfaces. Germ cell development postulates embryonic stem cell fidelity, which is characterised by persistent production of α-linked O-GalNAc-glycans. They are determined by the A-allele within the human, “complete” histo (blood) group A B (O) structure that in early ontogeny is hypothesised to be synthesised independently from the final phenotype. The structure either passes “completely” through the germline, in transferase-secreting mature tissues becoming the “complete” phenotype A B , or disappears in exhaustive glycotransferase depletion from the differentiating cell surfaces and leaves behind the “incomplete” blood group O-phenotype, which has released a transferase- and O-glycan-depleted, complementary glycoprotein (IgM) into the circulation. The process implies, that in humans the different blood phenotypes evolve from a “complete” A B (O) molecular complex in a distinct enzymatic and/or complement cascade suggesting O-glycanase involvements. While the murine and human oocyte zona pellucida express identical O-glycans, the human phenotype O might be explainable by the kinetics of the murine ovarian O-GalNAc glycan synthesis and the complementary anti-A released in parallel. The maturing murine ovary may provide insight into encoding of the physiologically superior α-linked GalNAc ancestral epitope that becomes essential in reproduction as well as in tissue renewal events. According to recent reports, O-GalNAc-transferase-determined blood group A suggests superiority in human female fertility and was called even “protective”. So the minor fertility of blood-group-O females may reside in a critical timing in developmental shifting of enzyme functions affecting the formation of GalNAc-determined hormone receptors on the way to maturation. Experiments that had inserted an oocyte genome into a somatic one to generate pluripotent stem cells, might elucidate a developmental dilemma by testing oocytes from different blood group A B donors donors. Perhaps they will unmask the molecular basis of an evolutionary trend, while stem cell generation itself capitalises on the enzymatically-advantaged, lineage-maintaining (histo) blood group A-allele, which guaranties ancestral functional completeness.