"Natural" antibodies and histo-blood groups in biological development with respect to histo-blood group A. A perspective review.

The "inappropriate" A-specific ovarian glycosphingolipids discovered in unfertilized C57BL/10J female mice reflect growth processes, which suggest the activity of embryonic stem cells undergoing genetic polymorphism. And the responding anti-GalNAc antibody represents the first classical "natural" antibody, which was unmasked as a highly specific autoantibody. This murine anti-A is subspecifically distinct from the human antibody, discovering by a broader reactivity growth-dependent, xenoreactive A-specific structures also in non-reproductive murine tissues, where an equivalent of the human AB gene family as a cis AB-gene encodes A-and B glycotransferases. Expression of antigen is known to need always more than its encoded enzyme, and the special mechanism which in the C57BL/10J murine ovarian glycospingolipids blocks the expression of "B" still remains still unknown. A herewith arising postulation of a growth-predominating common biological activity may be supported by findings in rats. The number of A-genes here significantly exceeds those of B and in the Wistar rat the A-antigen is only expressed in the wild type, while B-expression requires the transfer of human B. Nevertheless in transgenic rats, the appearance of "A" still remains more pronounced. The observations lead to reports on animals, which do not show AB transferase production or a respective antigen expression in their normal tissues, but inconcistently display A activity in malignant tumors. And respective examples are delivered by phenotype independent neo expressions of "inappropriate" A-specific structures in human cancer. Although in comparison with epitope deletions they are rare, the ubiquitous "natural" (IgM and IgG) anti-A and anti-B levels, against self and not self, irrespective of the blood group in any normal human sera, may reflect invisible "inappropriate" A-specific growth. The role of the associated (auto) anti-B might be different, because B-neo expressions obviously not occur in cancer, and anti-gal-antibodies are supposed to originate primarily from environmental, cross-reactive stimulation, and beyond their functions in defense are otherwise engaged in physiology. In general natural antibody specificities undergo significant phylogenetical changes within the species. However, the in nature wide-spread "natural" anti-A agglutinin specificities survived or even predominated the long-term evolution from the brown trout up to man and still respond to the biological power, i.e. the products of a CAZY glycosyltransferase 6 (ABO) gene family. It is so hypothesized that both, the murine and human "natural" anti-A antibodies represent examples of a still to be analyzed polyclonal response to a provocative, species-independent evolutionary epitope, which arises or escapes by some enzymatic predominance from the genetical polymorphism in a consistent developmental process.