Background

Neural targets that control thermogenesis, behavior, sleep, and mood can be affected by pro-inflammatory cytokines which are released by activated macrophages and monocytes during infection. Within the central nervous system production of cytokines has been detected as a result of brain injury, during viral and bacterial infections, and in neurodegenerative processes.

From the US National Institute of Health:^[1]

“Despite the brain’s status as an immune privileged site, an extensive bi-directional communication takes place between the nervous and the immune system in both health and disease. Immune cells and neuroimmune molecules such as cytokines, chemokines, and growth factors modulate brain function through multiple signaling pathways throughout the lifespan. Immunological, physiological and psychological stressors engage cytokines and other immune molecules as mediators of interactions with neuroendocrine, neuropeptide, and neurotransmitter systems. For example, brain cytokine levels increase following stress exposure, while treatments designed to alleviate stress reverse this effect.

“Neuroinflammation and neuroimmune activation have been shown to play a role in the etiology of a variety of neurological disorders such as stroke, Parkinson’s and Alzheimer’s disease, multiple sclerosis, pain, and AIDS-associated dementia. However, cytokines and chemokines also modulate CNS function in the absence of overt immunological, physiological, or psychological challenges. For example, cytokines and cytokine receptor inhibitors affect cognitive and emotional processes. Recent evidence suggests that immune molecules modulate brain systems differently across the lifespan. Cytokines and chemokines regulate neurotrophins and other molecules critical to neurodevelopmental processes, and exposure to certain neuroimmune challenges early in life affects brain development. In adults, cytokines and chemokines affect synaptic plasticity and other ongoing neural processes, which may change in aging brains. Finally, interactions of immune molecules with the hypothalamic-pituitary-gonadal system indicate that sex differences are a significant factor determining the impact of neuroimmune influences on brain function and behavior.”

Recent research demonstrates that reduction of lymphocyte populations can impair cognition in mice, and that restoration of lymphocytes restores cognitive abilities. ^[2]

Epigenetics of Neuroimmunology

Overview

Epigenetic medicine encompasses a new branch of neuroimmunology that studies the brain and behavior. This new branch has already provided unique insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. This new study is leading to the discovery of environmental stressors that dictate initiation of specific neurological disorders and specific disease biomarkers. The goal of this is to “promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cells ^[3].” Understanding epigenetic medicine is important to understanding possible future pharmacological treatments. Many of the immediate gaps in knowledge are attributed to basic lack of understanding of gene expression and regulation and are thus the limiting factors for creating advanced treatments or cures to many diseases. To better understand these processes, neuroimmunological experiments are being created and tested to once and for all amass a more complete anthology of knowledge pertaining to the complex interactions between the nervous and immune systems along with that of gene expression. While some disorders may affect the nervous and immune systems independently of one another, it is impossible to truly understand neuroimmnulogical science without a complex understanding of how each system works independently and also how they work together.

Neural stem cell fate

Several studies have shown that regulation of stem cell maintenance and the subsequent fate determinations are quite complex. The complexity of determining the fate of a stem cell can be best understood by knowing the “circuitry employed to orchestrate stem cell maintenance and progressive neural fate decisions ^[4].” Neural fate decisions include the utilization of multiple neurotransmitter signal pathways along with the use of epigenetic regulators. The advancement of neuronal stem cell differentiation and glial fate decisions must be orchestrated timely to determine subtype specification and subsequent maturation processes including myelination ^[5].

Neurodevelopmental Disorders

Neurodevelopmental disorders result from impairments of growth and development of the brain and nervous system and lead to many disorders. Examples of these disorders include Asperger syndrome, traumatic brain injury, communication, speech and language disorders, genetic disorders such as fragile-X syndrome, Down syndrome, epilepsy, and fetal alcohol syndrome. Studies have shown that autism spectrum disorders (ASDs) may in fact be due to basic disorders of epigenetic regulation ^[6]. Other neuroimmunological research has shown that deregulation of correlated epigenetic processes in ASDs can alter gene expression and brain function without causing classical genetic lesions which are more easily attributable to a cause and effect relationship ^[7]. These findings are some of the numerous recent discoveries in previously unknown areas of gene misexpression.

Neurodegenerative Disorders

Increasing evidence suggests that neurodegenerative diseases are mediated by erroneous epigenetic mechanisms. Neurodegenerative diseases include Huntington’s disease and Alzheimer’s disease. Neuroimmunological research into these diseases has yielded evidence including the absence of simple Mendelian inheritance patterns, global transcriptional dysregulation, multiple types of pathogenic RNA alterations, and many more ^[8]. In one of the experiments, a treatment of Huntington’s disease with histone deacetylases (HDAC), an enzyme that removes acetyl groups from lysine, and DNA/RNA binding anthracylines that affect nucleosome positioning, showed positive effects on behavioral measures, neuroprotection, nuclesome remodeling, and associated chromatin dynamics ^[9]. Another new finding on neurodegenerative diseases involves the overexpression of HDAC6 suppresses the neurodegenerative phenotype associated with Alzheimer’s disease pathology in associated animal models ^[10]. Other findings show that additional mechanisms are responsible for the “underlying transcriptional and post-transcriptional dysregulation and complex chromatin abnormalities in Huntington’s disease ^[11].”

Neuroimmunological Disorders

The nervous and immune systems have many interactions that dictate overall body health. The nervous system is under constant monitoring from both the adaptive and innate immune system. Throughout development and adult life, the immune system detects and responds to changes in cell identity and neural connectivity ^[12]. Deregulation of both adaptive and acquired immune responses, impairment of crosstalk between these two systems, as well as alterations in the deployment of innate immune mechanisms can predispose the central nervous system (CNS) to autoimmunity and neurodegeneration ^[13]. Other evidence has shown that development and deployment of the innate and acquired immune systems in response to stressors on functional integrity of cellular and systemic level and the evolution of autoimmunity are mediated by epigenetic mechanisms ^[14]. Autoimmunity has been increasingly linked to targeted deregulation of epigenetic mechanisms, and therefore, use of epigenetic therapeutic agents may help reverse complex pathogenic processes ^[15]. Multiple sclerosis (MS) is one type of neuroimmunological disorder that affects many people. MS features CNS inflammation, immune-mediated demyelination and neurodegeneration, and may represent an emerging class of epigenetic disorders ^[16].

Major Themes of Research

The interaction of the CNS and immune system are fairly well known. Burn-induced organ dysfunction using vagus nerve stimulation has been found to attenuate organ and serum cytokine levels. Burns generally induce abacterial cytokine generation and perhaps parasympathetic stimulation after burns would decrease cardiodepressive mediator generation. Multiple groups have produced experimental evidence that support proinflammatory cytokine production being the central element of the burn-induced stress response ^[17]. Still other groups have shown that vagus nerve signaling has a prominent impact on various inflammatory pathologies. These studies have laid the groundwork for inquiries that vagus nerve stimulation may influence postburn immunological responses and thus can ultimately be used to limit organ damage and failure from burn induced stress.

Basic understanding of neuroimmunological diseases has changed significantly during the last ten years. New data broadening the understanding of new treatment concepts has been obtained for a large number of neuroimmunological diseases, none more so than multiple sclerosis, since many efforts have been undertaken recently to clarify the complexity of pathomechanisms of this disease. Accumulating evidence from animal studies suggests that some aspects of depression and fatigue in MS may be linked to inflammatory markers ^[18].

Research into the link between smell, depressive behavior, and autoimmunity has turned up interesting findings including the facts that inflammation is common in all of the diseases analyzed, depressive symptoms appear early in the course of most diseases, smell impairment is also apparent early in the development of neurological conditions, and all of the diseases involved the amygdale and hippocampus. Better understanding of how the immune system functions and what factors contribute to responses are being heavily investigated along with the aforementioned coincidences.

Future Directions

The nervous system and immune system require the appropriate degrees of cellular differentiation, organizational integrity, and neural network connectivity. These operational features of the brain and nervous system may make signaling difficult to duplicate in severely diseased scenarios. There are currently three classes of therapies that have been utilized in both animal models of disease and in human clinical trials. These three classes include DNA methylation inhibitors, HDAC inhibitors, and RNA-based approaches. DNA methylation inhibitors are used to activate previously silenced genes. HDACs are a class of enzymes that have a broad set of biochemical modifications and can affect DNA demethylation and synergy with other therapeutic agents. The final therapy includes using RNA-based approaches to enhance stability, specificity, and efficacy, especially in diseases that are caused by RNA alterations. Emerging concepts concerning the complexity and versatility of the epigenome may suggest ways to target genomewide cellular processes. Other studies suggest that eventual seminal regulator targets may be identified allowing with alterations to the massive epigenetic reprogramming during gametogenesis. Many future treatments may extend beyond being purely therapeutic and may in fact be determined to be preventative perhaps in the form of a vaccine. Newer high throughput technologies when combined with advances in imaging modalities such as in vivo optical nanotechnologies may give rise to even greater knowledge of genomic architecture, nuclear organization, and the interplay between the immune and nervous systems.

The main interests of PNI are the interactions between the nervous and immune systems and the relationships between mental processes and health. PNI studies, among other things, the physiological functioning of the neuroimmune system in health and disease; disorders of the neuroimmune system (autoimmune diseases; hypersensitivities; immune deficiency); and the physical, chemical and physiological characteristics of the components of the neuroimmune system in vitro, in situ, and in vivo.

PNI may also be referred to as psychoendoneuroimmunology (PENI).

History

Interest in the relationship between psychiatric syndromes or symptoms and immune function has been a consistent theme since the beginning of modern medicine.

Walter Cannon, a professor of physiology at Harvard University, looked at the need for mental and physical balance throughout the organism and coined the term, Homeostasis in his book The Wisdom of the Body,1932, from the Greek word homoios, meaning similar, and stasis, meaning position.

In his work with animals Cannon observed that any change of emotional state in the animal, such as anxiety, distress, or rage, was accompanied by total cessation of movements of the stomach. These studies into the relationship between the effects of emotions and perceptions on the autonomic nervous system, namely the sympathetic and parasympathetic responses that initiated the recognition of the freeze, fight or flight response. His findings were published from time to time in professional journals, then summed up in book form in The Mechanical Factors of Digestion, published in 1911. Dr. Cannon’s seminal work, Bodily Changes in Pain, Hunger, Fear and Rage was published in 1915.

Picking up on Cannon’s work was Hans Selye. Selye experimented with animals putting them under different physical and mental adverse conditions and noted that under these conditions the body consistently adapted to heal and recover. Several years of experimentation that formed the empiric foundation of Dr. Selye’s concept of the General Adaptation Syndrome. This syndrome consists of an enlargement of the adrenal gland, atrophy of the thymus, spleen and other lymphoid tissue, and gastric ulcerations.

Selye describes three stages of adaptation, including an initial brief alarm reaction, followed by a prolonged period of resistance and a terminal stage of exhaustion and death. This foundational work led to a rich line of research on the biological functioning of glucocorticoids.^[2]

Mid 20th century studies of psychiatric patients reported immune alterations in psychotic patients, including numbers of lymphocytes ^[3][4] and poorer antibody response to pertussis vaccination, compared with nonpsychiatric control subjects.^[5] In 1964 George F. Solomon et all. coined the term “psychoimmunology” and published a landmark paper: “Emotions, immunity, and disease: a speculative theoretical integration.”^[6]

Birth of psychoneuroimmunology

In 1975 Robert Ader and Nicholas Cohen at the University of Rochester advanced PNI with their demonstration of classic conditioning of immune function, and coined the term “psychoneuroimmunology”.^[7][8] Ader was investigating how long conditioned responses (in the sense of Pavlov’s conditioning of dogs to drool when they heard a bell ring) might last in laboratory rats. To condition the rats, he used a combination of saccharine-laced water (the conditioned stimulus) and the drug Cytoxan which unconditionally induces nausea and taste aversion and suppression of the immune system. Ader was surprised to discover that after conditioning, just feeding the rats saccharine-laced water was associated with the death of some animals and he proposed that they had been immunosuppressed after receiving the conditioned stimulus. Ader (a psychologist) and Cohen (an immunologist) directly tested this hypothesis by deliberately immunizing conditioned and unconditioned animals, exposing these and other control groups to the conditioned taste stimulus, and then measuring the amount of antibody produced. The highly reproducible results revealed that conditioned rats exposed to the conditioned stimulus were indeed immunosuppressed. In other words, a signal via the nervous system (taste) was affecting immune function. This was one of the first scientific experiments that demonstrated that the nervous system can affect the immune system.

In 1981 David Felten, then working at the Indiana University of Medicine, discovered a network of nerves leading to blood vessels as well as cells of the immune system. The researchers also found nerves in the thymus and spleen terminating near clusters of lymphocytes, macrophages and mast cells, all of which help control immune function. This discovery provided one of the first indications of how neuro-immune interaction occurs.

Ader, Cohen and Felten went on to edit the groundbreaking book Psychoneuroimmunology in 1981, which laid out the underlying premise that the brain and immune system represent a single, integrated system of defense. An updated fourth edition was released in 2006.

In 1985, research by neuropharmacologist Candace Pert revealed that neuropeptide-specific receptors are present on the cell walls of both the brain and the immune system.^[9][10] The discovery by Pert et al. that neuropeptides and neurotransmitters act directly upon the immune system shows their close association with emotions and suggests mechanisms through which emotions and immunology are deeply interdependent. Showing that the immune and endocrine systems are modulated not only by the brain but also by the central nervous system itself has had an enormous impact on how we understand emotions, as well as disease.

Contemporary advances in psychiatry, immunology, neurology and other integrated disciplines of medicine has fostered enormous growth for PNI. The mechanisms underlying behaviorally induced alterations of immune function, and immune alterations inducing behavioral changes, are likely to have clinical and therapeutic implications that will not be fully appreciated until more is known about the extent of these interrelationships in normal and pathophysiological states.

The Immune-Brain Loop

PNI research is looking for the exact mechanisms by which specific brainimmunity effects are achieved. Evidence for nervous system–immune system interactions exists at several biological levels.

The immune system and the brain talk to each other through signaling pathways. The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system “talk to each other” and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the Hypothalamic-pituitary-adrenal axis (HPA axis) and the sympathetic nervous system (SNS). The activation of SNS during an immune response might be aimed to localize the inflammatory response.

The body’s primary stress management system is the HPA axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body’s cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases. HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines.

Molecules called pro-inflammatory cytokines, which include interleukin-1 (IL-1), Interleukin-2 (IL-2), interleukin-6 (IL-6), Interleukin-12 (IL-12), Interferon-gamma (IFN-Gamma) and tumor necrosis factor alpha (TNF-alpha) can affect the brain. Immune cells including macrophages, create these molecules and experiments showed that they can act directly inside the brain by creation of microglia and astrocytes (both types of glial cells) to trigger a sickness response. Cytokines are also locally produced in the brain, especially in the hypothalamus, thus contributing to the development of behavioural effects.^[11]

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis. Like the stress response, the inflammatory reaction is crucial for survival. Systemic inflammatory reaction results in stimulation of four major programs^[12]:

• the acute-phase reaction
• Sickness behavior
• the pain program
• the stress response

These are mediated by the HPA axis and the SNS. Common human diseases such as allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro-inflammatory versus anti-inflammatory and T helper (Th1) versus (Th2) cytokine balance.

Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disease, in addition to autoimmune hypersensitivity and chronic infections.

Chronic secretion of stress hormones, glucocorticoids (GCs) and catecholamines (CAs), as a result of disease, may reduce the effect of neurotransmitters, including serotonin, norepinephrine and dopamine, or other receptors in the brain, thereby leading to the dysregulation of neurohormones. Under stimulation, norepinephrine is released from the sympathetic nerve terminals in organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released norepinephrine, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells.

Glucocorticoids also inhibit the further secretion of corticotropin-releasing hormone from the hypothalamus and ACTH from the pituitary (negative feedback). Under certain conditions stress hormones may facilitate inflammation through induction of signaling pathways and through activation of the Corticotropin-releasing hormone.

These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health, developing into a “systemic anti-inflammatory feedback” and/or “hyperactivity” of the local pro-inflammatory factors which may contribute to the pathogenesis of disease.

This systemic or neuro-inflammation and neuroimmune activation have been shown to play a role in the etiology of a variety of neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease, multiple sclerosis, pain, and AIDS-associated dementia. However, cytokines and chemokines also modulate central nervous system (CNS) function in the absence of overt immunological, physiological, or psychological challenges.^[13]

Psychoneuroimmunological effects

There is now sufficient data to conclude that immune modulation by psychosocial stressors and/or interventions can lead to actual health changes. Although changes related to infectious disease and wound healing have provided the strongest evidence to date, the clinical importance of immunological disregulation is highlighted by increased risks across diverse conditions and diseases.

Link between stress and disease

Stressors can produce profound health consequences. In one epidemiological study, for example, all-cause mortality increased in the month following a severe stressor – the death of a spouse.^[14] Theorists propose that stressful events trigger cognitive and affective responses which, in turn, induce sympathetic nervous system and endocrine changes, and these ultimately impair immune function ^{[15] [16]}. Potential health consequences are broad, but include rates of infection ^{[17] [18]} HIV progression ^{[19] [20]} and cancer incidence and progression.^{[21] [22] [23]}

Stress is thought to affect immune function through emotional and/or behavioral manifestations such as anxiety, fear, tension, anger and sadness and physiological changes such as heart rate, blood pressure, and sweating. Researchers have suggested that these changes are beneficial if they are of limited duration^[24], but when stress is chronic, the system is unable to maintain equilibrium or homeostasis.

Immune changes in response to very brief stressors have been a central theme in the last decade of PNI research, but older literature also provides early illustrations. In a study published in 1960, subjects were led to believe that they had accidentally caused serious injury to a companion through misuse of explosives.^[25]

Two meta-analyses of the literature show a consistent reduction of immune function in healthy people who are experiencing stress.

In the first meta-analysis by Herbert and Cohen in 1993,^[26] they examined 38 studies of stressful events and immune function in healthy adults. They included studies of acute laboratory stressors (e.g. a speech task), short-term naturalistic stressors (e.g. medical examinations), and long-term naturalistic stressors (e.g. divorce, bereavement, caregiving, unemployment). They found consistent stress-related increases in numbers of total white blood cells, as well as decreases in the numbers of helper T cells, suppressor T cells, and cytotoxic T cells, B cells, and Natural killer cells (NK). They also reported stress-related decreases in NK and T cell function, and T cell proliferative responses to phytohaemagglutinin [PHA] and concanavalin A [Con A]. These effects were consistent for short-term and long-term naturalistic stressors, but not laboratory stressors.

In the second meta-analysis by Zorrilla et al. in 2001,^[27] they replicated Herbert and Cohen’s meta-analysis. Using the same study selection procedures, they analyzed 75 studies of stressors and human immunity. Naturalistic stressors were associated with increases in number of circulating neutrophils, decreases in number and percentages of total T cells and helper T cells, and decreases in percentages of Natural killer cell (NK) cells and cytotoxic T cell lymphocytes. They also replicated Herbert and Cohen’s finding of stress-related decreases in NKCC and T cell mitogen proliferation to Phytohaemagglutinin (PHA) and Concanavalin A (Con A).

Communication between the brain and immune system

• Stimulation of brain sites alters immunity (stressed animals have altered immune systems).
• Immune cells produce cytokines that act on the CNS.
• Immune cells respond to signals from the CNS.

Communication between neuroendocrine and immune system

• Glucocorticoids and catecholamines influence immune cells.^[28]
• Endorphins from pituitary & adrenal medulla act on immune system.
• Activity of the immune system is correlated with neurochemical/neuroendocrine activity of brain cells.

Connections between glucocorticoids and immune system

• Anti-inflammatory hormones that enhance the organisms response to a stressor.
• Prevent the overreaction of the body own defense system.
• Regulators of the immune system.
• Affect cell growth, proliferation & differentiation.
• Cause immunosuppression.
• Suppress cell adhesion, antigen presentation, chemotaxis & cytotoxicity.
• Increase apoptosis.

Corticotropin-releasing hormone (CRH)

Release of corticotropin-releasing hormone (CRH) from the hypothalamus is influenced by stress.

• CRH is a major regulator of the HPA axis/stress axis.
• CRH Regulates secretion of Adrenocorticotropic hormone (ACTH).
• CRH is widely distributed in the brain and periphery
• CRH also regulates the actions of the Autonomic nervous system ANS and immune system.

Furthermore, stressors that enhance the release of CRH suppress the function of the immune system; conversely, stressors that depress CRH release potentiate immunity.

• Central mediated since peripheral administration of CRH antagonist does not affect immunosuppression.

Pharmaceutical advances

Glutamate agonists, cytokine inhibitors, vanilloid-receptor agonists, catecholamine modulators, ion-channel blockers, anticonvulsants, GABA agonists (including opioids and cannabinoids), COX inhibitors, acetylcholine modulators, melatonin analogs (such as Ramelton), adenosine receptor antagonists and several miscellaneous drugs (including biologics like Passiflora edulis) are being studied for their psychoneuroimmunological effects.

For example, SSRI’s, SNRI’s and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a psychoneuroimmunological process.^[29][30][31] Antidepressants have also been shown to suppress TH1 upregulation.^{[32][33][34][35][36]}

Tricyclic and dual serotonergic-noradrenergic reuptake inhibition by SNRIs (or SSRI-NRI combinations), have also shown analgesic properties additionally.^[37][38] According to recent evidences antidepressants also seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing Interferon-beta (IFN-beta) release or augmenting NK activity in depressed patients.^[39]

These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psychoneuroimmunological approach may be required for optimal pharmacotherapy in many diseases.^[40] Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.^[41]

Extrapolating from the observations that positive emotional experiences boost the immune system, Roberts speculates that intensely positive emotional experiences —sometimes brought about during mystical experiences occasioned by psychedelic medicines—may boost the immune system powerfully. Research on salivary IgA supports this hypothesis, but experimental testing has not been done.