Evolution of the human ABO polymorphism by two complementary selective pressures.

The best-known example of terminal-glycan variation is the ABO histo-blood group polymorphism in humans. We model two selective forces acting on histo-blood group antigens that may account for this polymorphism. The first is generated by the invasion of opportunistic bacterial or other pathogens that interact with the epithelial-mucosal surfaces. The bacteria adapt to the microenvironments of common host phenotypes and so create frequency-dependent selection for rarer host alleles. The second is generated by intracellular viruses, and accounts for the observed differentials between the ABO-phenotype frequencies. It is thought that viruses acquire histo-blood group structures as part of their envelope from their previous host. The presence of host antigens on the viral envelope causes differential transmission of the virus between host types owing to the asymmetric action of ABO natural antibodies. Our model simulations show that these two forces acting together can account for the major features of the ABO polymorphism in humans.

Comparing antigen-independent mechanisms of T cell regulation.

Key features of the kinetics of T lymphocyte proliferative responses are remarkably insensitive to the nature of the antigenic stimulus. This consistency suggests the presence of an antigen-independent mechanism regulating T cell clonal expansion. Knowledge of such a mechanism could allow us to modulate T helper cell (CD4+) and cytotoxic T cell (CD8+) responses more effectively. Using a simple mathematical model of T cell proliferation and death, we investigate a variety of plausible mechanisms and compare the model predictions to experimental data from the literature. We find that irrespective of the details of the mechanism, rates of apoptosis must progressively increase to control a T cell response. If apoptosis is mediated by cell-cell contact this alone is sufficient to regulate both (CD4+) and (CD8+) T cell responses. Proliferation of both T cell subsets can also be regulated by an internal programme, by cytokine signalling, or by an APC-mediated route. To regulate (CD8+) T cells these mechanisms must change both apoptosis and division rates, and this change must occur with time not division number.