Vaccine for the mind

Abstract

Stressful episodes or chronic stress can shape our brain, leaving behind their biochemical signature on the neural tissue parenchyma. Mitigating such detrimental effects on the central nervous system (CNS) would be advantageous for coping with stress. While the underlying mechanisms that facilitate this response are still a mystery, recent studies demonstrate that boosting specific components of circulating immunity can potentially enhance our ability to deal with stressors. Yet, the fact that the adaptive arm of the immune system is largely excluded from directly interacting with the healthy CNS raises a key question as to how these cells exert their beneficial effects. Boosting immunity against self by active immunization with CNS-derived peptides was shown to reduce anxiety levels and to modulate hippocampal plasticity. These effects correlate with increased immune surveillance at the borders of the brain; specifically, at the choroid plexus (CP), an epithelial layer that resides at the junction between the blood circulation, and the brain and plays a key role in maintaining and restoring brain homeostasis, regulating cerebrospinal-fluid (CSF) production and neurotropic factors composition. Here, we suggest that immunomodulation of this site by active immunization could protect against stressful episodes, thereby providing a therapeutic, as well as preventive, vaccine for the mind against stress and depression.

Keywords: :

• BDNF
• CNS
• PTSD
• choroid plexus
• depression
• immunity
• inflammation
• mental disorders
• stress
• vaccination

It is well accepted that a previous mildly stressful experience strengthens resilience to a subsequent stressor. In contrast, severely stressful conditions or chronic stress can cause either posttraumatic stress disorder (PTSD) or depression. The biggest enigma relates to the underlying mechanisms; do they involve pure mental/psychological, or physiological pathways? If the mechanisms are physiological, what is their nature? Stressful conditions activate the brain and result in changes in neurotransmitter homeostasis. Such a shift in neurotransmitter balance results in a local response within the brain that involves activated microglia and astrocytes and may lead to an unwanted vicious cycle of toxicity, unless resolved on time.¹ Recent studies suggest that among the mechanisms that are required for facilitating local parenchymal resolution, and restoration of homeostasis/allostasis, are those that take place at the interface between the brain and the circulating immune cells.^2-4 Such mechanisms are essential for an adequate response by the brain to positive activities or negative episodes. Thus, the role of circulating immune cells is to provide, through a remote effect, an additional resolving mechanism, beyond the local neural ones, for ensuring restoration of equilibrium. If such mechanisms are absent, the brain remains activated, and thus any subsequent episodes elicit a disproportionate response. Accordingly, mechanisms that are involved in containing stressful episodes need not require erasing the memory of the episodes, but must mitigate its negative biochemical signature on the brain. If this is the case, one could envision vaccination strategies as a preventative and therapeutic treatments against mental episodes, just as we use immunization to provide protection against an infection.

The Immune System Beyond Host Defense

The primary function of the immune system has long been considered to be host defense. Thus, it was believed that the major task of the adaptive immune system in host defense is to discriminate between self and non-self. However, a decade ago, our research group discovered the importance of self-reactive T cells in the repair of the central nervous system (CNS) following acute injury.⁵ This protective capacity of autoimmune cells was further shown in several models of CNS pathologies including mechanical injury,^6,7 Alzheimer’s disease,⁸ Parkinson disease,^9,10 Amyotrophic lateral sclerosis,¹¹ and imbalances in neurotransmitter levels.¹² In addition to the role of circulating immune cells in CNS repair, adaptive immune cells were found to be key players in maintenance of CNS plasticity under non-pathological conditions, including neurogenesis and spatial learning/memory.^2,13-15 The involvement of circulating immunity in maintenance of CNS plasticity has raised a key question regarding the capacity of the same cells to buffer mental stress.

Adaptive Immunity in Coping With Mental Stress

Following a stressful episode, immune surveillance is increased in most tissues, and is mainly mediated by stress hormones, such as the glucocorticoids.¹⁶ Because of its unique anatomical structure, in which it is sealed by barriers, and due to its immunological features, the brain was commonly considered as an immune privileged site; nevertheless, stress was found by our team to be associated with enhanced leukocyte recruitment to the brain, in contrast to the prevailing dogma that stress activates trafficking of circulating immune cells to almost all tissues, excluding the brain.³ Since the brain is the primary organ to be affected by psychological stress, as well as the central organ that is responsible for orchestrating the complex stress response, we proposed that the increase in immune surveillance is part of the brain’s ability to cope with stress. Indeed, mice in which stress-induced lymphocyte trafficking is enhanced, exhibit improved ability to cope with stress, and hippocampal brain-derived neurotrophic factor (BDNF) is restored to pre-stress levels.³ These results supported our hypothesis that a stressful experience enhances lymphocyte trafficking to the CNS as a physiological mechanism for maintenance and restoration of homeostasis, and suggested viewing adaptive immunity, in the context of mental stress, as a physiological psychotropic defense mechanism that might be amenable to preventative as well as therapeutic boosting.¹⁷

Immune Memory to Self-Antigens Underlies the Physiological Mechanism of Resilience to Mental Stress

Our work led us to propose that successful resolution of a stressful experience elicits immunological memory, which makes subsequent coping efforts more efficient. We experimentally distinguished between the cognitive memories of past experiences and stress-induced immunological memory, by artificially inducing only immune memory in the form of a vaccination with a self-antigen prior to exposure to stressful episodes. Thus, mice that were inoculated with a CNS-derived peptide before their exposure to predator odor showed reduced anxiety levels and reduced acoustic startle response, as well as enhanced recovery of hippocampal BDNF.³ As a corollary, tolerance to CNS-specific antigens reduces coping ability in response to stress.¹⁸ Moreover, prolonged stressful experience, as well as chronic stress, leading to immune tolerance, results in reduced resilience to future stressful episodes. In light of these results, it is possible that the poor ability to cope with chronic stress and the resulting depression is the outcome of suppression of the immune response that develops under chronic mild stress.¹⁹ In contrast, immunization with a CNS-related antigen ameliorates depressive behavior and enhances hippocampal BDNF levels and neurogenesis.²⁰

Immunity That Protects the Mind Resides at the Active Junction Between the Immune System and the Brain: The Choroid Plexus

Nevertheless, the mystery remains regarding how circulating immune cells can affect the healthy brain when they are excluded from interacting with the neuronal parenchyma. The CNS is shielded from circulating immunity by two primary barriers; the blood-brain barrier (BBB), tightly sealed under physiological conditions with its surrounding glia limitans, and the blood-cerebrospinal (CSF) barrier (BCSFB), comprised of the epithelial lining of the choroid plexus (CP). The main role attributed to the CP is the production of the cerebrospinal fluid, providing the brain with a nutritive metabolic milieu, and forming a protective mechanical cushion. However, recent studies showed that this epithelial tissue, whose position enables exposure to both inner (parenchymal) and outer (from the circulation) signals, is a key player in maintaining brain homeostasis.^21-23

The CP regulates the CSF levels of numerous neurotropic factors, including BDNF,²⁴ vascular endothelial growth factor (VEGF)²⁵ and insulin-like growth factor-1 (IGF-1),²⁶ three key peptides shown to be essential for maintaining hippocampal plasticity²⁷ and are required for the neuronal parenchyma in handling mental stress.²⁸ In addition, during acute mental stress, T cells were shown to accumulate at the CP, along with an increase in the epithelial expression of the adhesion molecule, intercellular adhesion molecule-1 (ICAM-1).³ Similar induction of ICAM-1 was found at the CP in response to glucocorticoid administration, correlating with the organ-specific increased immune surveillance seen in response to stress outside the CNS.²⁹

Current studies in our laboratory indicate the CD4⁺ T cell clones that reside in the CP under physiological conditions are CNS-specific and are of an effector memory phenotype (Baruch et al., manuscript in revision), suggesting a constant immune-epithelium dialogue taking place in this compartment, affecting the brain from its borders. Taken together with the fact that CNS-specific T cells were shown to regulate hippocampal BDNF levels,¹⁴ a key player in hippocampal resilience to chronic stress,³⁰ we suggest that their beneficial effects are mediated through an CP epithelium-T cell dialogue. Thus, obliteration of the parenchymal stress signature can be achieved through CP-derived factors that arrest microglial activity and thereby up-regulate supportive factors (e.g., IGF-1) and reduce cytotoxic factors (e.g. TNF-α),³¹ and via the ability of the circulating T cells to facilitate recruitment of monocyte-derived macrophages,³² which locally arrest microglial toxicity.^32-35

Our finding that the naïve CP retains a broad repertoire of CD4⁺ T cell clones that recognize CNS antigens, and the fact that the CP retains specialized antigen presenting cells (APCs), Flt3⁺ dendritic cells,³⁶ which can actively present self-antigens and stimulate T cells, support their effector function in this compartment. Following recognition and reactivation by their cognate antigens, these cells will either enter the CSF or remain at the stroma of the CP,^37,38 excreting their effects remotely from the neuronal parenchyma. Importantly, we view this epithelium-T cell dialogue to be critically dependent on the correct balance of the adaptive immune response, orchestrated by T helper and regulatory cells and their derived cytokines.

Vaccine for the Mind

We propose that the active life-long dialogue between circulating immunity and the neuronal parenchyma, needed for maintaining cognitive ability and resilience to stress, takes place at the BCSFB, with the choroid plexus epithelium as the mediator. Accordingly, we suggest that immunomodulation of this site by vaccination could protect against a stressful episode, and thereby prevent deviation of brain homeostasis. One strategy to potentially achieve this response is immunization. Vaccination with CNS-specific antigens can be problematic, as such immunization can potentially trigger an overwhelming inflammatory autoimmune response; this risk can be avoided by using lower affinity agonists (“altered peptide ligands”), which induce a non-pathogenic immune response.⁶ Indeed, we have previously shown that T cell–based vaccination with myelin-derived altered peptides can confer resilience to psychological stress, affecting hippocampal plasticity and neurotropic balance.¹⁷ We propose that this increase in peripheral self-recognizing helper T cells is reflected within the CP compartment, helping to activate the epithelium to produce the factors that are needed to support the CNS. We expect that such factors do not erase the cognitive memories of a stressful experience and are not meant to do so, but rather facilitate erasing their biochemical signature, which is manifested, in part, by chronic or dysregulated activation of microglia.^39,40 Thus, immunomodulation of the CP via the peripheral immune system in order to restore CNS homeostasis may provide a novel preventative and therapeutic vaccine for the mind against the deleterious effects of emotional or mental stress.

Disclosure of Potential Conflicts of Interest

There are no potential conflicts of interest.

Acknowledgments

We thank Dr. Shelley Schwarzbaum for editing the manuscript. M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology, and is supported by an ERC Advanced Research Award.