The theory described in this section has been conceived by Dr. Stefano Mancini during his studies on the functioning of antibody response. The term “immunergic neurotransmission” has been coined by Dr. Stefano Mancini, refering to the action of the antibodies as neurotransmitters.

Dr. Mancini wants to thank those who helped him in this work:

Dr. Francesco Mariani

Prof. Luca Roncucci

Dr.ssa Claudia Degli Esposti

Dr. Ronny Cicola.

Have a nice reading!

Antibodies as Neurotransmitters: A Theory for the Understanding of the Complexity of Neuroimmune Crosstalk and Whole Body Homeostasis.

Introduction

Since the Nobel prize winner Niels K. Jerne suggested the possibility that immune system is regulated by an intricate network of interacting molecules (idiotype network theory, 1976), immune system has not only been interpreted as the self/non-self recognizing apparatus, but also as a gateway by which homeostasis perturbation can result in immune reactivity or immune tolerance[1,2].

Immune system is regulated at many levels by interactions between hormones[3,4], brain peptides[5,6,7], cytokines[8,9], chemokines[10,11], vitamins[12-14], inflammatory mediators[15,16], and a great number of receptors (including Toll-like receptors[17,18] and others[19-22]). The complexity of this tight communication between systems influences different patterns of activation and response of our immune system. The levels of activity of these connections are reciprocal and multidirectional, as it has been documented in many research works since the late 1980s[23-25].

Today, studies addressed in elucidating which antibodies are directed to which antigens and the impact antibodies have in the development of different diseases are exponentially growing, with the implementation of new methods and techniques[26]. This approach is producing a plethora of new antibodies that researchers are trying to characterize in a statistical relationship with different clinical conditions. Anyway, we must admit that for a large part of cases the significance of the presence of circulating antibodies remains poorly understood. In many clinical or experimental situations, antibody production seems inevitably to remain an “epiphenomenon” (i.e. cross-reactivities without a clear role). For an overview of the problematics regarding circulating antibody significance we suggest a selection of the literature[27-39].

Our plasma cells produce a lot of antibodies and if the sense of antibody production were only the interaction with non-self, it would be excessively dispersive for the economy of the individuals and would not be in accordance with the growing evidence of an immune system subjected to genetic and evolutionally selected pattern of antibody reactivity[40-43]. Only in few cases, presence of autoantibodies may predict the development of pathological conditions[29-31] or its course in the years[32,33,36]. On the other side, circulating antibody significance and role are yet showing contrasting evidences[27,34,35,37]. The presence and permanence of myriads of different antibodies following infectious diseases, vaccinations, cancers, pollutant exposures, etc... or even in apparently healthy subjects remains a fascinating conundrum[38,39,44-49]. Finally, the production of antibodies in patients with autoimmune diseases treated with biological therapies (i.e. TNF-alpha blocker monoclonal antibodies, and others) is a paradoxical event that has not yet a clear explanation[50,51].

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.

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].

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].

Concluding remarks

It has been documented by many researches how body homeostasis is the result of the close, continuous, and multidirectional dialogue between nervous, endocrine, and immune systems. In the last decade, enormous progresses have been made into the clarification of the neuroimmune crosstalk, with particular emphasis on the role of neurotransmitters, brain peptides and hormones, due to their ability to spread to, and be shared by, tissues and cells involved in the neuroimmune modulation[3-7,11,22,113-120].

Since recent studies are showing that BBB is a dynamic structure and could also be crossed by antibodies[69-71,90], or there could be an intrathecal synthesis of immunoglobulins[72-75], we hypothesized that the pool of molecules involved in neuroimmune crosstalk could be expanded by the comprehension of antibodies into a circuitry that we have called immunergic neurotransmission, summarized in Figure 1. Our hypothesis is based on the evidence that many pathologic conditions are characterized by an increased synthesis of antibodies for which cross-reactivity between the “periphery” and the “centre” is very frequent. Moreover, significance of the presence of these antibodies is uncertain in many conditions, sometimes affects healthy individuals, and thus is still object of debate[89-95,103].

In conclusion, we hope that our theory, that obviously needs effective experimental proofs, may be a contribution to the development of a new research approach in which antibody production is not a simple response to non-self, but a complex effect of human evolution towards a system fully integrated in the neuroimmune dialogue.

Figure 1.

A schematic overview of the factors involved in neuroimmune crosstalk is illustrated. Antibodies are at the top of the pyramid that represents neuroimmune activation and regulation. Cytokines, brain peptides, hormones, and the other inflammation mediators have a pivotal role in regulating integrated processes between environment (antigens), nervous tissues, and immune cells that ultimately lead to antibody production. In our immunergic neurotransmission hypothesis, antibodies could be in turn the effectors that close in a certain manner the neuroimmune circuit.

Abbreviations: APC: antigen presenting cells, IFNs: interferons, ILs: interleukins, NT: neurotransmission, TLR: Toll-like receptors.

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