Direct immunergic neurotransmission theory
Since antibody synthesis is probably one of the most versatile activity of our organism, able to connect our body with the external environment and protect us by any harmful stimuli, we hypothesized that antibodies could also act as mediators between “periphery” and “centre” as direct immunergic neurotransmitters. Obviously, it is difficult to think they could be classical neurotransmitters, since vesicles of antibodies at the synaptic knob have never been observed. However, as it happens for other substances implicated in non-adrenergic-non-cholinergic neurotransmission[5,7,57], we have supposed that they may directly interact with synaptic membrane receptors in order to evocate or inhibit neuronal action potentials.
The direct immunergic hypothesis differs from the indirect one because in the latter antibodies are responsible only for their interference with the action of a “classic” neurotransmitter. In the direct immunergic hypothesis of neurotransmission, antibodies are directly responsible for the releasing of a neurotransmitter (with excitatory or inhibitory function), or they are directly able to evoke a postsynaptic potential by their binding to a neuronal receptor.
In support of this theory, we considered that in patients with systemic lupus erythematosus (SLE) part of the autoantibodies that target dsDNA are able to cross-react with different subunits of the NMDA receptor (NMDAR)[89] producing a spectrum of symptoms comprising cognitive impairment, emotional imbalance, anxiety and, in some cases, seizures and psychosis[99]. It has been shown that anti-NMDAR binding may function as modulator when neuron has activated synapse, probably by increasing the channel open-state duration regulated by glutamate. Different effects have also been documented in relation to antibody titers. Lower or discontinuous titers seemed to produce only electrophysiological changes in NMDAR-mediated synaptic transmission, while higher titers induced neuronal stress and neurotoxicity[89]. Antibodies that target NMDAR are also responsible for the most common type of autoimmune encephalitis, in which they are generally at high titers[100-102] and in patients with no history of SLE. Antibodies targeting CNS receptors and involved in neurotransmission alterations have been documented in several works[45,90,100,101].
Growing evidences that link presence of autoimmunity and psychic status could be an interesting support to our hypothesis that a direct immunergic modulation of neurotransmission is present in healthy individuals. Autoantibodies in low titers are present also in physiologic conditions like many other cytokines and mediators of inflammation. The presence of autoimmune phenomena in psychiatric patients is documented, and on the other side patients with autoimmune diseases frequently have psychiatric symptoms as comorbidities[103-108]. Psychiatric disorders are linked to an augmented inflammatory status, giving support to a tight connection between nervous and immune systems[109-111]. In addition to anti-NMDAR, other antibodies that bind voltage-gate potassium channels have been found in association with psychosis in patients with autoimmune encephalitis[112].
The challenging issue that needs to be clarified is if a different spectrum of disease (or the border between physiologic and pathologic conditions) is related to antibody titers rather than different kinds of circulating antibodies. According to our theory, we think that quantitative rather than qualitative characteristic in antibody production could make the difference between physiologic and pathologic conditions because a basal interaction between neurons and antibodies may be as necessary as basal interaction between other molecules (e.g. cytokines, opioids, brain peptides, etc…) and the nervous system[113,114].