Although human cells express a quasi-infinite number of potential autoantigens, only a limited range of the human “self” antigen library is actually targeted by pathological autoimmunity. Accordingly, the clinical expression of human autoimmunity is essentially restricted to relatively few stereotyped disorders including psoriasis, diabetes, vitiligo, thyroiditis, rheumatoid arthritis and multiple sclerosis. Thus, in the context of autoimmunity, not all “self” antigens are equal with regard to immunogenicity and what could be called “superautoantigens” are more prone to be targeted under pathological conditions.
On this basis, the «brain superautoantigens» theory attempts to provide an explanation to the existence of such superautoantigens by unifying two major concepts that were experimentally demonstrated in the last decades: the notion of physiological autoimmunity, initially put forward by Irun Cohen 25 years ago [1,2], and the demonstration by Michal Schwartz and Jonathan Kipnis that a main role of physiological autoimmunity is to promote cognition [3–6].
In light of these stemming concepts, a re-assessment and synthesis of the recent literature in neurosciences and immunology led to a theoretical model stating that, in homo sapiens, a majority of autoantigens that are targeted in common non-CNS autoimmune diseases are indeed brain autoantigens belonging to the synaptic or myelin compartments . This theoretical framework further points to the co-development and co-evolution of, on one hand, the T-cell receptor (TCR) and antibody repertoires (referred thereafter as immune repertoires) and, on another hand, the neural repertoires i.e the distinct neuronal populations and synaptic circuits supporting cognitive or sensorimotor functions.
It is notably proposed that, during evolution, immune and neural repertoires have exerted a mutual selection pressure which has eventually led to i) a high diversity and sophistication of both immune and neural repertoires in homos sapiens ii) a particular susceptibility of homo sapiens to pathological autoimmunity and neurodegeneration. Experimental arguments supporting this view are exposed below and listed in Table 1.
Table 1: Five data-driven arguments supporting the brain superautoantigens theory. GAD65: Glutamate decarboxylase 65 (GAD2), a synaptic enzyme that catalyzes γ-aminobutyric acid (GABA) synthesis from glutamate, is also the main targeted autoantigen in type I diabetes; AchR: acetycholine receptor is a major autoantigen in myasthenia gravis. HSPA5: heat shock protein family A (Hsp70) member 5 is targeted in rheumatoid arthritis; HSP60 (HSPD1): heat shock protein family D (Hsp60) member 1 is also an autoantigen in rheumatoid arthritis; SnRNPS: Small nuclear ribonucleoproteins are the main autoantigens in systemic lupus erythematous (SLE) and in Sjögren syndrome; gangliosides are autoantigens in Guillain-Barre syndrome; TH: tyrosine hydroxylase is one of the targeted autoantigen in vitiligo; AchE: acetylcholinesterase harbor high similarities with the acetylcholinesterase domain of thyroglobulin, a main autoantigen in Hashimoto’s disease (autoimmune thyroiditis). ASIA: Autoimmune/inflammatory syndrome induced by adjuvants; ALS: amyotrophic lateral sclerosis.
Experimental arguments supporting the brain superautoantigens theory
1) Myelin- and synapse-derived autoantigens harbor specific immunogenic features. From a quantitative point of view, synapses and myelin obviously form two major antigenic compartments of the CNS [8,9]. Most interestingly, there is now compelling evidence that throughout the whole life of an individual human brain plasticity is supported by a high renewal rate of both compartments [10,11]. However, one may argue that, owing to the CNS “immune privilege”, abundance and high renewal do not imply that the immune system is actually exposed to such antigens. Recent findings go again this counterargument and show that CNS antigens may be exposed to the immune system via at least 3 pathways: i) draining to the cervical lymph nodes through the dura mater lymphatic system , ii) phagocytosis by CNS-resident antigen-presenting cells (APCs) notably meningeal APCs [5,13,14], iii) efflux of exosomes from brain to blood [15,16]. Finally, the immunogenicity of brain antigens may be inherently linked to the inflammatory mechanisms supporting the physiological functions exerted by synapses and myelin. Indeed, social behavior, cognition and synaptic plasticity have been shown to require a certain level of physiological inflammation mediated by microglia and/or pro-inflammatory cytokines [17–20].
2) Major autoantigens targeted in non-CNS autoimmune disorders belong to the synaptic compartment. Major autoantigens identified in non-CNS autoimmune pathologies are highly expressed in the CNS synaptic compartment under developmental or post-developmental conditions. Below is a non-exhaustive list of such autoantigens, also shown in Table 2 and detailed elsewhere :
GAD65 also known as GAD2 (glutamate decarboxylase) is the main autoantigen in diabetes type 1 and is a crucial enzyme of the GABAergic system.
AchR (acetylcholine receptor), the main autoantigen in myasthenia gravis is a receptor to acetycholine, a neurotransmitter crucially involved in memory and behavior.
HSPA5 (heat shock protein family A member 5) also known as BiP or GRP78 is a major autoantigen in rheumatoid arthritis [21,22] and a component of the synaptic glutamate receptor complex .
HSP60 (heat shock protein family D member 1) is a mitochondrial chaperone molecule targeted in autoimmune vasculitis [24,25]. A high density of mitochondria is observed in synaptic boutons  and mitochondria play an important role in the control of synaptic neurotransmitter release [27,28]. Accordingly, mutations in HSP60 (also named HSPD1) are responsible for autosomal recessive spastic paraplegia 13 .
snRNPs (small nuclear ribonucleoproteins) are core components of the spliceosome machinery and the main autoantigens toward which anti-ribonucleotide antibodies are directed in systemic lupus erythematous (SLE) and Sjögren’s syndrome . Several of these targeted snRNPs were found to physically associate with RNA-binding proteins that are abundant in synapses and/or play important roles in cognition or motor fonctions (Cf infra). This is notably the case for SMN (survival of motor neuron) a protein involved in the cytoplasmic assembly of snRNPs before their import in the nucleus . However, the demonstration of snRNPS in the synaptic compartment is still lacking.
hRNPs (heterogenous nuclear proteins) form RNA/protein complexes participating to the control of RNA metabolism. Autoantibodies against hRNPs were demonstrated in SLE, Sjogren syndrome, rheumatoid arthritis . In neurons, specific families of RNAs, including non-coding RNAs such as hRNPs, are exported toward axon terminals, dendrites and synapses in structures called RNA granules (or ribonucleoprotein particles). The involvement of synaptic hRNPs in synaptic plasticity has been clearly demonstrated [33,34].
Ribosomal proteins are targeted by both pathological autoimmunity in SLE patients  and physiological autoimmunity in healthy individuals . Genuine ribosomes are abundant in the synaptic compartment and allow the local synthesis of proteins involved in neurotransmission and synaptic plasticity [37,38].
Collagen IV and laminins, two major components of basement membranes, are the main autoantigens in anti-glomerular basement membrane glomerulonephritis, Goodpasture’s disease and several autoimmune skin disorders [39,40]. Recent evidence indicates that synapses are embedded in an extracellular matrix microenvironment, in which collagen IV and laminins are not only abundant, but critically involved in synapse morphogenesis and synaptic remodeling [41,42].
TH (tyrosine hydroxylase), a major enzyme of the dopamine synthesis pathway in neurons is also essential to melanin synthesis and is targeted by autoantibodies in vitiligo .
MCHR1, melanin-concentrating hormone receptor 1 (MCHR1), another identified autoantigen in vitiligo , is expressed by a subpopulation of CNS neurons and its ligand, MCH, is indeed a neuropeptide regulating energy balance, sleep and mood [45,46].
AchE (acetylcholinesterase) catabolizes acetylcholine and is essential to the proper functioning of the cholinergic system involved in major cognitive tasks such as learning and memory. Interestingly, during autoimmune thyroiditis (Hashimoto’s disease), antibodies directed against thyroglobulin (TG) recognize an acetylcholinesterase domain that is indispensable to both the immunogenicity of TG and its function [47,48].
Gangliosides are the main autoantigens in autoimmune demyelinating polyneuropathy (Guillain-Barre syndrome) and are also highly abundant on the outer layer of neuronal membranes [49,50]. Gangliosides are involved in multiple important neuronal functions including the regulation of glutamate receptor trafficking in the postsynaptic membrane . Moreover, human mutations in ganglioside biosynthetic enzymes are responsible for autosomic disorders that translates into intellectual disability and, less frequently, epilepsy .
3) Cognitive alterations are frequently observed in patients suffering from non-CNS autoimmune diseases. Various levels of cognitive alterations have been demonstrated in a large range of non-CNS autoimmune diseases including systemic lupus erythematous (SLE) [52,53], Sjögren’s syndrome [54,55], psoriasis [56,57], Crohn’s disease [58,59], Hashimoto’s thyroiditis [60,61] and rheumatoid arthritis [62–64].
4) In CNS autoimmune disorders, myelin and synapses are the most frequently targeted antigenic compartments. Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease and also the most frequent autoimmune condition targeting the CNS. Myelin antigens and in particular myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) are considered as the main target autoantigens in MS [65,66]. Besides MS, the landscape of CNS autoimmunity essentially comprises a whole of rare autoimmune synaptopathies that, in most cases, express as paraneoplastic syndromes and target receptors to neurotransmitters .
5) “Incidental” autoimmunity essentially targets myelin- or synapse-derived autoantigens. The term “Incidental” autoimmunity designates here autoimmune pathologies that are secondary to identifiable events such as neoplasms (paraneoplastic syndromes), vaccination (autoimmune/autoinflammatory syndrome induced by adjuvants [ASIA]), or microbial infections (post-streptococcal glomerulonephritis and Guillain-Barre syndrome secondary to Campylobacter jejuni infection). It is striking to observe that most of these incidental autoimmune disorders clinically express as neurological pathologies and are targeting myelinic and/or synaptic autoantigens. An example is given by the adverse effects that followed the vaccination campaign against influenza virus H1N1 in 2009: the only autoimmune manifestation identified so far has been a narcoleptic syndrome that associates with the presence of circulating autoantibodies directed against distinct neuronal populations involved in the regulation of sleep and wakefulness .
Table 2: Major autoantigens targeted in non-CNS autoimmune disorders belong to the synaptic compartment. GAD65: glutamate decarboxylase 65 (GAD2), a synaptic enzyme that catalyzes γ-aminobutyric acid (GABA) synthesis from glutamate; AchR: acetycholine receptor. HSPA5: heat shock protein family A (Hsp70) member 5; HSP60 (HSPD1): heat shock protein family D (Hsp60) member 1; snRNPS: small nuclear ribonucleoproteins; hnRNPS: heterogenous nuclear ribonucleoproteins; TH: tyrosine hydroxylase; MCHR1: melanin-concentrating hormone receptor 1; AchE: acetylcholinesterase; SLE: systemic lupus erythematous. a: HSPA5 is a major component of the synaptic glutamate receptor complex. b: HSP60 is a mitochondrial chaperone molecule; a high density of mitochondria is observed in synaptic boutons and mitochondria play an important role in the control of synaptic neurotransmitter release; accordingly, mutations in HSP60 (HSPD1) are responsible for autosomal recessive spastic paraplegia 13. c: ribosomes are enriched synaptic boutons and in the postsynaptic compartment, allowing local synthesis of proteins involved in neurotransmission and synaptic plasticity. d: In neurons, snRNPs (small nuclear ribonucleoproteins) are protein interactants of RNA-binding proteins playing a crucial role in cognition and/or motor functions; these include FRMP (fragile X mental retardation protein), SMN (survival of motor neurons) and ELAVL1(ELAV like RNA binding protein 1). A variant of the snRN gene TROVE2 (the Ro60-coding gene) is associated with specific memory skills. e: hnRNPS are abundant in the pre-synaptic and post-synaptic compartments of neurons and have been involved in synaptic plasticity. f: Thyroglobulin, a main autoantigen in Hashimoto’s disease, bears an acetylcholinesterase domain that is essential to both immunogenicity and functions of thyroglobulin. f: gangliosides are highly abundant on the outer layer of neuronal membranes and are involved in multiple neuronal functions including trafficking of glutamate receptors in the postsynaptic membrane; human mutations in ganglioside biosynthetic enzymes are responsible for autosomic disorders that translates into intellectual disability and, less frequently, epilepsy.
Brain superautoantigens and the co-development/co-evolution model
There is now compelling evidence that TCR and antibody repertoires are by nature polyspecific and that immune responses against “self” antigens are consubstantial to immune responses against “non-self” antigens [70–75]. A major advantage conferred by physiological autoimmunity is thus to provide an immune repertoire directed against cross-reactive “non-self” antigens. In particular, autoreactive T-cell clones were found to exert key functions in the adaptive immune responses directed against “non-self” antigens expressed by infectious agents [73–75].
Figure 1: Co-development of the neural and immune repertoires. The co-development/co-evolution model proposes that at the scale of an individual, exposure of brain superautoantigens to the immune system is responsible for: i) the generation of cognition-promoting self-reactive T-cell clones that favor the elaboration, maintenance and/or reinforcement of neural repertoires ii) a continuous stimulation and education of the immune repertoires allowing larger and finest adaptive immune responses against “non self” or “altered self” antigens (expressed for instance by tumors). In a given individual, physiological immunization against brain superautoantigens would fluctuate overtime and would be dictated by genetics, immune inputs and brain activity (including mood and mental state, cognition and completion of sensorimotor programs).Neural repertoires essentially shaped by brain activity continuously fuels the immune system with brain superautoantigens, providing thus a major educational and stimulating input to the adaptive immune system.
On this basis, the co-development/co-evolution model  proposes that at the scale of an individual, exposure of the immune system to brain superautoantigens is responsible for: i) the generation of cognition-promoting self-reactive T-cell clones that favor the elaboration, maintenance and/or reinforcement of neural repertoires ii) a continuous stimulation and education of the immune repertoires allowing larger and finest adaptive immune responses against “non self” or “altered self” antigens (expressed for instance by tumors), (Figure 1).
Figure 2: Co-evolution of the neural and immune repertoires. The co-development/co-evolution model proposes that during evolution, neural and immune repertoires may have exerted mutual selection pressures in a species-specific manner. In one hand, immune repertoires against brain superautoantigens would have favored the emergence of neural repertoires expressing brain superautoantigens. On the other hand, neural repertoires expressing brain superautoantigens would have favored the emergence of immune repertoires directed against brain superautoantigens. As a result, evolution of the immune and nervous systems, the two main systems allowing sensing and adaptation to the external environment would have been, at least in part, endogenously-driven.
The co-development/co-evolution model also envisions connections between neural and immune repertoires as a driving force of evolution (Figure 2). In this scheme, the now classical co-evolution theory  proposing that “two species may exert a mutual selection pressure that benefit to both species across evolution”, is oriented in an alternate way stating that “neural and immune repertoires may exert a mutual selection pressure that benefits to both repertoires and to the host across evolution”. More specifically, it is proposed that during evolution, neural and immune repertoires may have exerted mutual selection pressures in a species-specific manner.
In one hand, immune repertoires against brain superautoantigens would have favored the emergence of neural repertoires expressing brain superautoantigens. On the other hand, neural repertoires expressing brain superautoantigens would have favored the emergence of immune repertoires directed against brain superautoantigens. As a result, the immune and nervous systems, i.e the two main systems allowing the external environment to be sensed of and adapted to would have been shaped, at least in part, by internal cues (Figure 2).
Accordingly, the co-development/co-evolution model predicts that: i) in terms of diversity, immune and neural repertoires have followed a parallel evolution across species, ii) cognition-promoting autoimmunity is quantitatively and qualitatively scaled to the level of complexity that each species exhibits with regard to cognitive functions and iii) genes and/or genomic regulatory mechanisms involved in the diversification of both immune and neural repertoires have had a major evolutionary impact. Regarding this later point, independently from the emergence of new synapse- or myelin-related genes, it could be proposed that mechanisms allowing a proper exposure of brain superautoantigens to the immune system have exerted a major leverage evolutionary force. Several of these putative mechanisms are presented in Figure 3.
Figure 3: Exposure of the immune system to brain superautoantigens. Exposure of the immune system to brain superautoantigens may be achieved via 4 pathways that converge toward antigen presenting cells : i) draining of brain superautoantigens to the cervical lymph nodes through the dura mater lymphatic system, ii) draining of brain superautoantigens in the meningeal spaces and presentation by meningeal antigen-presenting cells (APCs), iii) efflux of brain superautoantigens from brain to blood via exosomes, iv) endogenous expression of brain superautoantigens by APCs. Illustrations were obtained by modifications of figures published in open source articles [90–93].
Recent findings further connect immunity to human cognitive functions
Several recently published papers further illustrate the link between immunity and cognition in humans. In particular, while Ro60 is recognized as a major autoantigen in SLE and Sjogrën syndrome, a variant of the Ro60-encoding gene, TROVE2, was found to associate with higher emotional memory capacity in healthy human subjects . In the discussion section, the authors pointed to the intriguing observation that a high incidence of autoimmune disorders was observed in patients suffering from post-traumatic stress syndrome .
Ro60 belongs to the family of small nuclear ribonucleoproteins that are involved in RNA splicing and, besides Ro60, comprises other “self” antigens targeted in autoimmunity. Interestingly, the assembly of snRNPs in the cytoplasm requires a protein called survival of motor neuron (SMN)  which is highly expressed in neurons and exert major roles in motor functions .
Moreover, at least 2 snRNPs targeted by autoimmunity physically interact with RNA-binding proteins that play major roles in the CNS: the La autoantigen Ssb, which binds FRMP (fragile X mental retardation protein) and the small non-coding RNA called Y RNA (also named RNY1) which binds ELAVL1 (ELAV like RNA binding protein 1) protein also known as HuR .
Altogether, these findings indicate that snRNPS are possibly brain superautoantigens. In another recent study, an epigenetic immune signature of cortical thickness and memory performance was identified in the blood cells of healthy young adults . Although markers of physiological autoimmunity were not explored in this study, one may propose that systemic analyses of antibody or TCR repertoires would provide cues on the molecular mechanisms linking blood immune cells and cortical neurons. Finally, human umbilical cord plasma was shown to exert major rejuvenation effects on the synaptic plasticity and hippocampal-dependent cognition of aged mice . Again, the role exerted by natural autoantibodies in this experimental setting deserves further exploration.
Conclusions and clinical implications
Establishing a molecular connection between neural and immune repertoires holds several potentially important implications with regard to physiology, pathology and, possibly, evolution. In particular, that immune and neural repertoires co-develop and co-maintain implies that physiological fluctuations of the immune status may shape our mental state. This may notably occur via a modulation of the number and/or cytokine profile of T-cells that physiologically home the brain and recognize brain superautoantigens.
It also implies that, conversely, brain activity, a term being used here in its broadest sense, continuously fuels the immune system with brain superautoantigens and provides thus a major educational and stimulating input to the adaptive immune system (Figure 1). In this view, brain superautoantigens and microbiota-derived antigens may exert complementary functions. With regard to pathology, admitting that immune and neural repertoires are mutually nourishing throughout the whole life of an individual should lead to a pathophysiological re-assessment of conditions usually considered as purely immunological (autoimmune disorders) or purely neurological (autism, schizophrenia, neurodegenerative diseases).
The term “Neuroimmune co-pathology” could be proposed to depict the co-involvement of the immune and neural repertoires in such pathologies (Figure 4). In this view, autism and schizophrenia could result from dual neurodevelopmental and immunodevelopmental alterations connected by a pathological immunization against brain superautoantigens.
Figure 4: Neuroimmune co-pathologies. The term “Neuroimmune co-pathology” is proposed to depict pathologies during which neural and immune repertoires are concurrently altered via a process of pathological immunization against brain superautoantigens. Such a pathological immunization may result from an altered brain activity and/or an altered immune status in genetically predisposed individuals. Neuroimmune co-pathologies may notably include autism, schizophrenia, organ-specific autoimmune diseases and neurodegenerative disorders.
Similarly, autoimmune conditions may stem from neurodevelopmental dysfunctions leading to a non-physiological exposure of brain superautoantigens to the immune system. Of note, while the emergence of pathological immune repertoires against brain superautoantigens would represent a key event in neuroimmune co-pathologies, the maintenance or expansion of a physiological immune repertoire against brain superautoantigens would prevent or delay the clinical outcome of neuro-immune co-pathologies. Thus, while altered brain activity may contribute to trigger pathological autoimmunity (Figure 4), brain superautoantigens may also represent a molecular support to innovative therapeutic approaches based on brain-mediated modulation of adaptive immunity. In this regard, future studies should be designed to identify the immune- and brain-related parameters supporting respectively physiological vs pathological autoimmunity against brain superautoantigens.
Finally, one has to underscore that several proteins whose misfolding is associated with (and possibly cause) neurodegeneration harbor features of brain superautoantigens. These include the proteins tau, amyloid beta and alpha-synuclein which are respectively involved in Alzheimer’s disease (tau, amyloid beta) and Parkinson’s disease (alpha-synuclein). In fact, not only previous reports demonstrated natural autoantibodies against tau , amyloid beta  or alpha-synucluein  in healthy individuals but, depending on the context, autoimmune responses against such proteins were shown to either ameliorate or aggravate clinical outcomes in animal models of neurodegeneration [85–88]. Neurodegenerative disorders are thus likely to form an important share of the neuroimmune co-pathologies.
The notion of brain superautoantigens and the co-development/co-evolution model from which it stems offers a theoretical frame for the study of physiological and pathophysiological interactions between the nervous and immune systems. Although largely speculative at this stage, this model may also point to the role exerted by the “internal environment” of each species in shaping neurological and immunological abilities to sense and adapt to the external environment. Such an endogenously-driven adaptation to the external environment would notably explain why many current species have largely different levels of sophistication of their immune and nervous systems although having had the same time to evolve under a similar external environment .
Many thanks to Prof. Irun Cohen from the Weizmann Institute for the so fruitful talks we had, his encouragements, great kindness and open mindedness.
Serge Nataf, MD, PhD – Bank of Tissues and Cells, Lyon University Hospital (Hospices Civils de Lyon), CarMeN Laboratory, INSERM 1060, INRA 1397, INSA Lyon, Université Claude Bernard Lyon-1, Lyon, F-69000, France; Tel: 33 4 72 11 76 67; email: firstname.lastname@example.org
List of Non-Standard Abbreviations
GAD65: glutamate decarboxylase 65 (GAD2), AchR: acetycholine receptor, HSPA5: heat shock protein family A (Hsp70) member 5; HSP60 (HSPD1): heat shock protein family D (Hsp60) member 1; snRNPS: small nuclear ribonucleoproteins; hnRNPS: heterogenous nuclear ribonucleoproteins TH: tyrosine hydroxylase; ASIA: autoimmune/inflammatory syndrome induced by adjuvants; ALS: amyotrophic lateral sclerosis; TCR: T-cell receptor; APC: antigen-presenting cell; MBP: myelin basic protein; MOG: myelin oligodendrocyte glycoprotein. FRMP: fragile X mental retardation protein; ELAVL1: ELAV like RNA binding protein 1; SMN: survival of motor neuron.
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