Indirect immunergic neurotransmission theory
Since the early 1970s, studies demonstrated that antibodies directed toward synaptosomal antigens exist, are inducible, and may affect permeability to neurotransmitters[76,77]. Anyway, BBB was considered a membrane interposed between humoral immunity and neurons, except for some inflammatory conditions in which breakage of BBB was observed[78]. Recent researches demonstrate that BBB is a dynamic structure interposed between blood torrent and nervous structures, influenced by several factors in physiologic and pathologic conditions[79-84]. Interestingly, variations in BBB permeability have been documented after many kind of stimuli, including antibodies themselves[85-90]. This may suggest that antibodies are implicated in the regulation of neuronal activity.
Moreover, clues for an immunergic indirect neurotransmission could be suggested by considering new insights into the pathogenesis of myasthenia gravis (MG), and some other autoimmune disorders of synaptic transmission[90]. MG is characterized by the presence of autoantibodies directed to nicotinic acetylcholine receptors (nAchR) at the postsynaptic neuromuscular junction, with the effect to interfere with cholinergic activation of muscular contraction (so it is a peripheral disease of the neuromuscular transmission). Initially, these autoantibodies seemed to be specific for neuromuscular junctions, but nowadays reports of multilevel interaction are emerging[91]. In particular, there are growing evidences of cross-reaction between nAchR antibodies and other epitopes localized in the central nervous system. Cross-reactivity between antibodies in MG and neuromyelitis optica (NMO) has been reported[92,93]. In these cases, aquaporin-4 (AQP4) water channel auto-antigen is involved, and frequently symptoms are not limited to optic nerve and spinal cord, but also tend to appear as demyelinating disorders of the central nervous system. This cross-reactivity is interesting for the fact that it links peripheral with central nervous system, with passage of autoantibodies inside the brain[92].
These autoantibodies, likewise others seen in several conditions[89,90,94,95], are particularly able to interfere with neuronal transmission and signal homeostasis within the brain, also acting through glial cells and interfering with different excitatory or inhibitory pathways; again, they are associated with enhancing of BBB permeability[87,88,90,96]. These evidences led us to think that a feedback control between immune and nervous system mediated by antibodies could exist. A feedback in which antibodies, along with cytokines and hormones, could play a role in neurotransmission modulation between the “periphery” and the “centre”.
If we take into account that a basal natural autoimmunity is present in healthy people[27], we may suppose that antibody interactions with neurotransmission could be a homeostatic factor for individuals. In other words, antibodies may act as signalling molecules able to connect immune and nervous systems through the modulation of neurotransmission, interacting with different nervous structures. The disruption of this homeostasis may be provoked by the action of particular pathogens in specific neuroendocrine situations, and/or by profound antigenic stimulation due to neoplastic diseases. This could also explain in part a major incidence of immune dysregulation in women, due to higher levels in estrogens which have been associated to different pattern of neurotransmission with respect to men[97,98].