Trans-species “A-like” and human blood group A-phenotype-specific GalNAc-glycosylations as they relate to the formation of natural anti-A isoagglutinin and cross-reactive anti-Tn.
Creators: name: Arend, Peter
Publisher: name: figshare
Year: 2016
Subjects: subject: 60802 Animal Cell and Molecular Biology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Developmental Biology
subject: 60305 Evolution of Developmental Systems

description: The multiple trans-species, genetically as-yet-undefined functions of “A-like” <i>O</i>-GalNAc-Ser/Thr glycosylations<sup>1-3</sup>, which<sup> </sup>dominate the early carbohydrate metabolism of vertebrates, are different from the species-intrinsic and human phenotype-determining A-allelic enzyme proteins and/or functions being expressed only after formation of the zygote. The volatilely expressed “A-like” <i>O</i>-GalNAc glycans are structurally related to and likely imply metabolic relationships with the mucin-type monosaccharide GalNAcα1-<i>O</i>-Ser/Thr, also referred to as the Tn antigen, whose accumulation in non-developmental tissues is a marker of malignancy, and which is thus called an “aberrant” glycosylated molecule. Historically, the “A-like” Tn antigen or “T nouvelle” was named upon its discovery reported in 1957<sup>4</sup> to emphasize its distinction from the functionally similar T (Thomsen-Friedenreich) antigen, reported in 1930<sup>5</sup>. Early <i>O</i>-glycan expressions, which may be observed during germ cell development and embryonic stem cell differentiations, are characterized by extremely short half-lives<sup>6</sup><sup>,</sup><sup>7</sup>, and their enzyme depletions most likely cause the release of characteristic <i>O</i>-glycan-depleted, complementary proteins, such as secretory IgM that is not restricted to B cells and might reveal the structure of the volatilely expressed, “lost” <i>O</i>-glycans through germline-specific serine residues. This non-immune anti A-reactive IgM is disctinct from the innate anti-B; it has not undergone clonal selection and must be differentiated from innumerable, adaptive anti-A/B cross-specificities. Indeed, the cryptic “A-like” and/or aberrant structures may be detected by “natural” anti A and/or anti-T antibodies that are among the anti-glycan moieties present in plasma of animals including humans<sup>8</sup>, in whom the levels of anti-T antibodies are highly dependent on the ABO(H) blood group and primarily are expressed through cross-reactivities with anti-A isoagglutinin<sup>9</sup><sup>,</sup><sup>10</sup>; although monoclonal antibodies have specifically been raised against the Tn structure(s)<sup>11</sup><sup>,</sup><sup>12</sup>, a “naturally-occurring” anti-Tn has not been described. After generation of the zygote, the complex construction of the human ABO phenotypes is accomplished in the trans-cisterna and vesicles of the Golgi apparatus through the membrane-bound, human-specific A-allelic alpha-1-3-<i>N</i>-acetylgalactosaminyl transferase T2 and B-allelic alpha-1,3-<i>galactosyl-transferase, </i>encoded on chromosome 9, in epistatic cooperation with the transferases FUT1 and FUT2, encoded on chromosome 19. These membrane-located <i>N</i>-linked glycosylations are associated with soluble enzyme versions, exerting identical specificities through <i>O</i>-linked glycosylations of mucoepithelial cells and plasma proteins, most likely involving conserved serine residues on the variable region of secretory immunoglobulins, and thus independent of clonal selection, reduce or exclude the formation of phenotype- or self-reactive anti-A/B reactivities<sup>13</sup>.The polyreactivity of the secretory “natural” IgM molecule is assumed to be provided by hydrophilic amino acids, and serine residues in particular, represent the appropriate target<i> </i>for<i> O</i>-GalNAc glycosylation. Indeed, the characteristic lack of <i>O</i>-glycans and the presence of serine residues on the secretory IgM, which has emerged from a cell adhesion molecule (CAM), strongly argue for a broken linkage to a volatilely expressed, developmental <i>O</i>-GalNAc glycan and for the proposed mechanism of ontogenetic IgM modulation. This mechanism may explain the anti-Tn cross-reactivity of anti-A-specific IgM or isoagglutinin and the pronounced occurrence of both anti-A and cross-reactive anti-Tn specificities in plasma of blood group O(H) individuals, in which their levels are not affected by A-allelic glycosylation. In fact, while in the phenotype AH individual the polyreactivity of IgM is impaired through A-specific glycosidic reduction or exclusion of anti-A and Tn cross-reactivity, in the phenotype OH individual, these reactivities may contribute to a potential survival advantage, as recently has been discussed for the overall risk of developing cancer when compared with individuals of non-OH blood groups<sup>14</sup><sup>,</sup><sup>15</sup>.