ENTdoc, I think of the PS as just a target. In the figure I drew the important point is what happens in the macrophage (or DC), which is what would be to the left of the long membrane with the PSR and Fc-gamma-R (FcgR) on it. I am going to try to describe this in detail for others who might be interested. When the PS receptor (PSR) binds to the exposed PS a signal transduction pathway is activated in the macrophage. This pathway results in the expression of genes which code for anti-stimulatory cytokines, as shown in the figure. These cytokines are secreted by the macrophage and then affect other nearby immune cells putting them into a state which is non-stimulatory. This would happen if the macrophage encounters a cell that has undergone a normal death by apoptosis and needs to be removed, i.e. cleaning up the garbage. Now if there were pathogens present and antibodies to them also present then the antibodies would bind to the pathogen. The macrophages then bind to the antibody through their Fc gamma receptors. This activates a different signal transduction pathway which results in a different set of genes being expressed, and then the secretion of pro-stimulatory cytokines. These different cytokines alert the surrounding immune cells that there are pathogens present so to go on the attack. What does that have to do with bavi? Bavi is just an antibody that binds to its target PS. The important point is that the macrophage binds to bavi using its FcgRs which then activate the production of the pro-stimulatory cytokines and cause the activated macrophage to eat whatever is connected to the antibody. When the DCs also do this then they can present antigens to T-cells and lead to development of long-term immunity (natural antibodies against the pathogens or tumor cells). In the figure you can see that both the PSR and the FcgR are present. I show how the signal from both are integrated in the little box and the resulting signal comes out. This shows that the pro-stimulatory signal over-rides the anti-stimulatory signal. Think of many receptors and how the resulting effect depends on a majority of one type of signal or the other. Of course it is not this simple as there are many other such receptor-ligand combinations that can also contribute to the overall resulting signal. So adding bavi can overwhelm the immunosuppressive signal that the PS by itself would trigger in the macrophage, and switch the signal to a pro-stimulatory one, i.e. switching the macrophage from the M2 state to the M1 state. Of course adding bavi will also mean that it will compete with the PSR for binding to PS and so that will also contribute to the net result. Enough bavi could result in competitive inhibition of the PSR binding to PS. If you look at things this way it comes down to turning signals on and off so you just need to find the best way to do that. Using bavi is just utilizing a natural pathway that already exists to activate the immune system. Bavi is working at a fundamental level here and that is why I find it so powerful. I hope I haven't totally confused everyone!
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