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</sup><sup>-</sup><sup>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<sup>6</sup><sup>-</sup><sup>8</sup> and embryonic stem cell differentiations, are characterized by extremely short half-lives<sup>9</sup><sup>,</sup><sup>10</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 but also arises from epithelial cells<sup>11</sup><sup>,</sup><sup>12</sup>, and might reveal the structure of the volatilely expressed, “lost” <i>O</i>-glycans through germline-specific serine/threonine 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>13</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>14</sup><sup>,</sup><sup>15</sup>; although monoclonal antibodies have specifically been raised against the Tn structure(s)<sup>16</sup><sup>,</sup><sup>17</sup>, a “naturally-occurring” anti-Tn has not been described. After the 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-galactosyl-transferase<i>, </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 also through <i>O</i>-glycosylations of mucoepithelial cells and plasma proteins, most likely involving the serine/threonine 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-H and A/B reactivities<sup>18</sup>. The polyreactivity of the secretory “natural” IgM molecule is assumed to be provided by hydrophilic amino acids, and serine/threonine residues on the V regions<sup>19</sup> in particular, represent the appropriate target<i> </i>for<i> O</i>-GalNAc glycosylation. Indeed, the characteristic lack of <i>O</i>-glycan and the presence of serine/threonine 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 support the proposed mechanism of an ontogenetic, glycosidic IgM modulation; such a „broken” linkage may be documented through the presence of <i>O</i>-GalNAc glycan-bearing glycolipids in differentiating, normal murine ovarian tissue and the complementary, non-immune IgM in plasma<sup>6-8</sup>. 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 anti-A and Tn reactivities may potentially contribute to a survival advantage when compared with the individuals of non-OH blood groups for the recently discussed overall risk of developing cancer<sup>20</sup><sup>,</sup><sup>21</sup>.