Introduction to psychoneuroimmunology

Psychoneuroimmunology (PNI) investigates the relations between the psychophysiological and immunophysiological dimensions of living beings. PNI brings together researchers in a number of scientific and medical disciplines, including psychology, the neuroscience, immunology, physiology, pharmacology, psychiatry, behavioral medicine, infectious diseases, and rheumatology.

The profound interest of PNI is in interactions between the nervous and immune systems, and the relation between behavior and health. Despite the protean approach to research, the outcome common to all research endeavors is the discovery of new information, or novel evidence, which contributes to the continuing and cumulative generation of knowledge.

It deals with, among other things, the physiological functioning of the neuroimmune system in states of both health and disease; malfunctions of the neuroimmune system in disorders (autoimmune diseases, hypersensitivities, immune deficiency), the physical, chemical and physiological characteristics of the components of the neuroimmune system in vitro, in situ, and in vivo.

PNI also involves endocrinology and is sometimes referred 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, 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 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.

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

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". Ader had discovered that the immune system of rats can be conditioned to respond to external stimuli unrelated to immune function. 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 and the drug Cytoxan which induces nausea and suppresses the immune system. Ader was surprised to discover that after conditioning, just feeding the rats saccharine-laced water was sufficient to suppress the immune system of the rats. 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 Felton went on to write the groundbreaking two-volume 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 neuropeptides are present on both the cell walls of the brain and in the immune system. The discovery by Pert, et all. that neuropeptides and neurotransmitters are also on cell walls of the immune system shows a close association with emotions and suggests that emotions and health are deeply interdependent. Showing that the immune and endocrine systems are modulated not only by the brain but by the central nervous system itself has had an enormous impact on how we understand 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, is 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
While the lay person can believe in a mind-body connection, the PNI researcher 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-10 (IL-10), Interleukin-12 (IL-12), Interferon-gamma (IFN-Gamma) and tumor necrosis factor alpha (TNF-alpha) can affect the brain. Immune cells called macrophages, which are the first on the scene of any infection, 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.

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 :


 * the acute-phase reaction
 * the sickness syndrome
 * 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 hypersensativity and chronic infections.

Chronic secretion of stress hormones, glucocorticoids (GCs) and catecholamines (CAs), as a result of disease, may reduce the affect 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.

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. 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. Potential health consequences are broad, but include rates of infection HIV progression  and cancer incidence and progression

Stress is thought to affect immune function through emotional and/or behavioral manifestations such as anxiety, fear, tension, anger and sadness and physiological changes heart rate, blood pressure. sweating. Researchers have suggested that these changes are beneficial if they are of limited duration, 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.

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, 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 phytohemaglutinin [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, 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.
 * 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 pyschoneuroimmunological process. Antidepressants have also been shown to suppress TH1 upregulation.

Tricyclic and dual serotonergic-noradrenergic reuptake inhibition by SNRIs (or SSRI-NRI combinations), have also shown analgesic properties additionally. 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.

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. 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.

Recommended Reading

 * Berczi and Szentivanyi (2003) NeuroImmune Biology, Elsevier, ISBN 0-444-50851-1 (Written for the highly technical reader)
 * Goodkin, Karl, and Adriaan P. Visser, (eds), Psychoneuroimmunology: Stress, Mental Disorders, and Health, American Psychiatric Press, 2000, ISBN 0-88048-171-4, technical.
 * Ransohoff, Richard, et al (eds), Universes in Delicate Balance: Chemokines and the Nervous System, Elsevier, 2002, ISBN 0-444-51002-8
 * Robert Ader, David L. Felten, Nicholas Cohen, Psychoneuroimmunology, 4th edition, 2 volumes, Academic Press, (2006), ISBN 0-12-088576-X