Психонейроиммунология: Психика, Нерв жүйесі және Иммунитеттің өзара әрекеттесуі

Area of study within psychosomatic medicine

Psychoneuroimmunology (PNI), also referred to as psychoendoneuroimmunology (PENI) or psychoneuroendocrinoimmunology (PNEI), is the study of the interaction between psychological processes and the nervous and immune systems of the human body. It is a subfield of psychosomatic medicine. PNI takes an interdisciplinary approach, incorporating psychology, neuroscience, immunology, physiology, genetics, pharmacology, molecular biology, psychiatry, behavioral medicine, infectious diseases, endocrinology, and rheumatology. 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.

Interest in the relationship between psychiatric syndromes or symptoms and immune function has been a consistent theme since the beginning of modern medicine. Claude Bernard, a French physiologist of the Muséum national d'Histoire naturelle (National Museum of Natural History in English), formulated the concept of the milieu interieur in the mid 1800s. In 1865, Bernard described the perturbation of this internal state: " there are protective functions of organic elements holding living materials in reserve and maintaining without interruption humidity, heat and other conditions indispensable to vital activity. Sickness and death are only a dislocation or perturbation of that mechanism" (Bernard, 1865). Walter Cannon, a professor of physiology at Harvard University coined the commonly used 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 beast, such as anxiety, distress, or rage, was accompanied by total cessation of movements of the stomach (Bodily Changes in Pain, Hunger, Fear and Rage, 1915). These studies looked 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. Hans Selye, a student of Johns Hopkins University and McGill University, and a researcher at Université de Montréal, experimented with animals by putting them under different physical and mental adverse conditions and noted that under these difficult conditions the body consistently adapted to heal and recover. Several years of experimentation that formed the empiric foundation of 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 individuals, including lower numbers of lymphocytes and poorer antibody response to pertussis vaccination, compared with nonpsychiatric control subjects. In 1964, George F. Solomon, from the University of California in Los Angeles, and his research team coined the term "psychoimmunology" and published a landmark paper: "Emotions, immunity, and disease: a speculative theoretical integration."

In 1975, Robert Ader and Nicholas Cohen, at the University of Rochester, advanced PNI with their demonstration of classic conditioning of immune function, and they subsequently coined the term "psychoneuroimmunology". 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 saccharin laced water (the conditioned stimulus) and the drug Cytoxan, which unconditionally induces nausea and taste aversion and suppression of immune function. Ader was surprised to discover that after conditioning, just feeding the rats saccharin 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 the 1970s, Hugo Besedovsky, Adriana del Rey and Ernst Sorkin, working in Switzerland, reported multi directional immune neuro endocrine interactions, since they show that not only the brain can influence immune processes but also the immune response itself can affect the brain and neuroendocrine mechanisms. They found that the immune responses to innocuous antigens triggers an increase in the activity of hypothalamic neurons and hormonal and autonomic nerve responses that are relevant for immunoregulation and are integrated at brain levels (see review). On these bases, they proposed that the immune system acts as a sensorial receptor organ that, besides its peripheral effects, can communicate to the brain and associated neuro endocrine structures its state of activity. (more references in The discovery that neuropeptides and neurotransmitters act directly upon the immune system shows their close association with emotions and suggests mechanisms through which emotions, from the limbic system, 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 affected the understanding of 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.

There are 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 dysregulation is highlighted by increased risks across diverse conditions and diseases. For example, stressors can produce profound health consequences. In one epidemiological study, 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 cancer incidence and progression, and high rates of infant mortality.

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,

In one of the earlier PNI studies, which was published in 1960, subjects were led to believe that they had accidentally caused serious injury to a companion through misuse of explosives. Since then decades of research resulted in two large meta analyses, which showed consistent immune dysregulation 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 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, 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). A study done by the American Psychological Association did an experiment on rats, where they applied electrical shocks to a rat, and saw how interleukin 1 was released directly into the brain. Interleukin 1 is the same cytokine released when a macrophage chews on a bacterium, which then travels up the vagus nerve, creating a state of heightened immune activity, and behavioral changes. More recently, there has been increasing interest in the links between interpersonal stressors and immune function. For example, marital conflict, loneliness, caring for a person with a chronic medical condition, and other forms on interpersonal stress dysregulate immune function.

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

Glucocorticoids and catecholamines influence immune cells. Hypothalamic Pituitary Adrenal axis releases the needed hormones to support the immune system. Activity of the immune system is correlated with neurochemical/neuroendocrine activity of brain cells.

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, SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine, dopamine and cannabinoid 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. 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. 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. The endocannabinoid system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery. Data suggest that the endocannabinoid system in cortical and subcortical structures is differentially altered in an animal model of depression and that the effects of chronic, unpredictable stress (CUS) on CB1 receptor binding site density are attenuated by antidepressant treatment while those on endocannabinoid content are not. The increase in amygdalar CB1 receptor binding following imipramine treatment is consistent with prior studies which collectively demonstrate that several treatments which are beneficial to depression, such as electroconvulsive shock and tricyclic antidepressant treatment, increase CB1 receptor activity in subcortical limbic structures, such as the hippocampus, amygdala and hypothalamus. And preclinical studies have demonstrated the CB1 receptor is required for the behavioral effects of noradrenergic based antidepressants but is dispensable for the behavioral effect of serotonergic based antidepressants. 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.