Development of the immunergic neurotransmission theory
Evolution has led our body to conjugate efficacy and economy for the simplest coordination between organs and systems. Thus, we could advance the hypothesis that antibodies may operate in a multilevel modality, including the possibility that they may act as neurotransmitters as well as it happens for other molecules in the brain.
In fact, research is clarifying that molecules implicated in the network between nervous, endocrine, and immune systems are redundant. Briefly, a neurotransmitter should be synthesized and stored in nerve terminals, released by a calcium-dependent mechanism, and then inactivated by enzymes in the synaptic cleft and/or by neuronal re-uptake; properties of neurotransmitters have been furnished many years ago by Eccles and other researchers[52-54]. But this approach to neurotransmission is schematic, and does not represent the real complexity of neural interconnections as well as their linkage with hormonal and immune systems. First, it does not take into account the mounting importance of astroglial modulation of neurotransmission, started to be clarified only in the last fifteen years[55-58]. Then, the last twenty years has seen the raise of serotoninergic, histaminergic, purinergic, nitrergic, gamma-aminobutyric acid (GABA)-ergic, cannabinergic, tachykininergic, enkephalinergic, and endorphinergic neurotransmission systems as fundamental typologies of communication in central and peripheral neurons, and receptors for these neurotransmitters are also expressed on lymphocytes and other immune cells[59-67].
Along with these developments in the understanding of the neuro-immune network mediators, interesting are the advancements in the comprehension of the role of the blood-brain barrier (BBB). Though BBB crossing remains a hard challenge for intravenously administered monoclonal antibodies[68], increasing evidences are showing that there may be a passage of natural antibodies through the BBB, or the recruitment of B cells within it, allowing antibodies to interact with the nervous system tissues[69-75].
Basing on these assumptions, we developed an immunergic hypothesis of neurotransmission involving antibody interactions within the nervous system. Experimental results show that B cells, once differentiated in plasma cells, are able to produce antibodies either within or outside the nervous system[72,73,75]. It seems that antibodies may act as direct or indirect neurotransmitters, though the supposition of an indirect immunergic neurotransmission can be supported by a greater amount of evidences.