@Jonathan Edwards
Could you please expand a little bit further on this.
I am not familiar with antibody signaling, nor the need for at least two antibodies to bind to an antigen in order for signaling to commence.
Also, can I ask, is it possible that, even with just one antibody binding to the serotonin molecule, this might disable the molecule, in the sense that this serotonin molecule + antibody might no longer be able to bind to a serotonin receptor and activate the receptor?
If so, then might these anti-serotonin antibodies effectively cause a serotonin deficit in the brain?
In order for an antibody to generate inflammation when it finds, and binds to, its antigen, it has to signal to inflammatory cells through receptors that bind the 'back end' or 'Fc portion' of the antibody. In order to signal when bound to antigen but not when on its own the antibody has to make use of subtle steric/thermodynamic changes rather than just non-covalent chemical binding to a receptor because binding to antigen does not actually change the chemical structure of the back end that binds receptors.
In practice the antibody takes advantage of a phenomenon known as cross-linking. What that means is that if two antibodies are bound to different faces on an antigen molecule, or groups of antibody molecules form a complex meshwork with antigen molecules (every antigen binding at least two antibodies and and the antibodies binding two antigens), then you get a steric arrangement of antibody back ends (Fcs) all close together.
The Fc portion signals by binding to one of two systems. If it is outside the circulation (but not in brain) it can generate inflammation through binding a huge multimeric molecule called complement C1q. C1q has six arms and it at least three bind an antibody Fc it changes shape and activates the complement cascade. This can result in binding and activating complement receptors on macrophages.
The Fc can also bind directly to macrophages through Fc receptors. But again, nothing happens unless several receptors are bound at the same place because of cross-linking of antibodies to an antigen. If three or more Fc receptors (possibly two) are bound by Fcs at the same place a phosphorylating kinase wins out over counteracting phosphatases and intracellular signalling occurs.
So the interesting thing is that for antigens with only 'one face' or one 'epitope' binding to antibody cannot cause inflammation. As to what is required to have two epitopes, that involves unbelievably complicated stereochemical and thermodynamic issues, but there are good reasons for thinking that you cannot get stable binding of two antibodies to a single molecule that is smaller than 500 Daltons and normally not for less than several kiloDaltons - quite a large peptide. So you cannot get cross linking of C1q or Fc receptors and inflammation.
What is not clear from the abstract is whether or not in the paper quoted the suggestion is that the autoantibodies are causing the inflammation. The alternative might be that the inflammation is causing autoantibody formation but I don't know of any reason why that should occur.
One of the problems of clinical immunology is that very few clinicians, or even lab people think through the inflammatory effector pathways. When I moved from working on macrophage physiology to immunology per se I could not find anyone who could explain to me exactly how immune complexes worked. Later I discovered that Keith Peters understood but nobody else had taken much notice. So we had to work out the different inflammatory mechanisms in RA and lupus for ourselves.
The bottom line is that antibody binding to antigen in itself does nothing. Each antibody has a different shape to its antigen binding site. If it bound 5HT all you would get is a slightly different shape again (the 5HT would appear to be part of the overall antibody shape). That new shape might be recognised but the binding would be so local and the antibodies involved so huge that they would almost certainly pull apart immediately under thermal energy.
On the other issue. Antibody can mop up a mediator and cause a deficit of the mediator. That is how the anti-TNF antibody infliximab works. However, neurotransmitters are secreted in very tiny synaptic clefts in brain tissue where antibody levels are very low and only stay in the cleft for a few microseconds. Antibodies can certainly block transmission by binding to transmitter receptors but I doubt there would ever be enough antibody for long enough to mop up a transmitter itself. I may be wrong but I doubt it. And there would be no inflammation.
