Psychoneuroimmunology

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Psycho-neuro-endo-immunology (PNEI) is a specialized field of research that studies the interactions between social psychology, behavior, the brain, and the endocrine and immune system of the body. The term was originally coined by Robert Ader^[1] and Nicholas Cohen at the University of Rochester in 1975. Modern scientific research is demonstrating many of the direct effects of the "mind-body" interplay in all fields of medicine: pediatrics, psychiatry, internal medicine, gastroenterology, obstetrics, gynecology, orthopedics, and cardiology.

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.

Contents 1 Background 2 History 3 Psychoneuroimmunological effects 3.1 Link between stress and disease 3.2 Communication between the brain and immune system 3.3 Communication between neuroendocrine and immune system 3.4 Connections between glucocorticoids and immune system 4 Corticotropin-releasing hormone (CRH) 5 References 6 External links 7 Further reading 8 Areas of study 9 See also

[edit] Background

From the US National Institute of Health^[2]:

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 stroke, 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. 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.

[edit] History

In 1974 Robert Ader 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. Ader coined the phrase Psychoneuroimmunology and wrote the two-volume book Psychoneuroimmunology along with David L. Felten and Nicholas Cohen^[1].

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.

[edit] Psychoneuroimmunological effects

Stress is thought to affect immune function through emotional/behavioral (e.g. anxiety, fear, tension, anger, sadness, uncertainty) biochemical (e.g. serum norepinephrine, epinephrine, and adrenal steroids), and physiological changes (e.g. heart rate, blood pressure; Chrousos & Gold, 1992). Researchers have suggested that these changes are beneficial if they are of limited duration (Chrousos & Gold 1992), but when stress is chronic, the system is unable to maintain equilibrium (i.e. homeostasis, allostasis), and disease results (Cannon, 1914; McEwen, 1993).

Two meta-analyses of this literature show a consistent reduction of immune function in healthy people who are experiencing stress. In the first, Herbert and Cohen (1993) 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, suppressor, and cytotoxic T cells, B cells, and NK cells. They also reported stress-related decreases in NK and T cell function (i.e. NKCC 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, Zorrilla et al. (2001) replicated Herbert and Cohen’s (1993) 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 white blood cells, decreases in number and percentages of total T cells and helper T cells, and decreases in percentages of NK cells and cytotoxic T lymphocytes. They also replicated Herbert and Cohen’s finding of stress-related decreases in NKCC and T cell proliferation to PHA and Con A.

Other examples of stressful life circumstances that are linked to impaired immune system function are as follows:

• Alzheimer's caregivers were more likely to have more severe colds (immune systems were compromised for up to 2 yrs afterwards);
• Exam stress lowers the ability to create antibodies to the flu vaccine;
• Wound healing is much slower in psychologically stressed adults;
• Bereavement was associated with lower lymphocyte proliferation 8 weeks later;
• Divorce was associated with depressed T and NK cell levels;
• Unemployment was associated with reduced lymphocyte responses 9 months later;
• Depression was associated with lower T and NK cell levels.

[edit] 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 (Kapprio, Koskenvuo, & Rita, 1987). 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 (Cohen & Herbert, 1996; Chrousos & Gold, 1992; Glaser & Kiecolt-Glaser, 1994). Potential health consequences are broad, but include rates of infection (Cohen, Tyrrell, & Smith, 1991; Cohen & Williamson, 1991), HIV progression (Leserman, Jackson, Petitto, et al., 1999; Leserman, Petitto, Golden, et al., 2000), and cancer incidence and progression (Kaprio, Koskenvuo, & Rita, 1987; Andersen, Kiecolt-Glaser, & Glaser, 1994; Kiecolt-Glaser, & Glaser, 1999).

[edit] Communication between the brain and immune system

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

[edit] 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.

[edit] 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.

[edit] 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 immunsuppression

[edit] References

1. ^ Robert Ader at the University of Rochester - His page contains references to his recent papers on Psychoneuroimmunology.
2. ^ Functional Links between the Immune System, Brain Function and Behavior

• Dr Deborah Hodgson (2006) Psychoneuroimmunology, University of Newcastle

Kiecolt-Glaser Jan K. "Stress, personal relationships, and immune function: health implications." Brain, Behavior and Immunity. 13.1 (Jan 1999): 61-72. PMID: 10371678. Dhabhar Firdaus S. "Stress-induced augmentation of immune function--the role of stress hormones, leukocyte trafficking, and cytokines." Brain, Behavior and Immunity 16.6 (Dec 2002):785-98. PMID: 12480507

• Proceedings of the International Society of Psychoneuro-endocrinology (Brooklyn, NY June 22-25, 1970) Ford D. H. ;"Influence of hormones on the nervous system".

• Proceedings of the 16th World Congress on Psychosomatic Medicine, held in Goteborg, Sweden on August 24-29, 2001

Sivik, T. (Editor), with D. Byrne (Editor), D. R. Lipsitt (Editor), C. N. Christodoulou (Editor), H. Dienstfrey (Editor)"Psycho- Neuro- Endocrino- Immunology (PNEI)"

• Lorente, L., J. A. Aller & G. J. Arias, "Psycho-neuro-immune-endocrine system: a three-phase-old response" (Journal of Internal Medicine Volume 239 Issue 1 Page 83 - January 1996)

• Pert, Candace B. "Molecules Of Emotion: The Science Behind Mind-Body Medicine" (Scribner; 1st Touchstone Ed edition (February 17, 1999))

Kaprio, J., Koskenvuo, M., and Rita, H. (1987). Mortality after bereavement: a prospective study of 95,647 widowed persons. American Journal of Public Health 77(3), 283-7. Chrousos, G. P. and Gold, P. W. (1992). The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267(Mar 4), 1244-52. Glaser, R. and Kiecolt-Glaser, J. K. (1994). Handbook of Human Stress and Immunity. San Diego: Academic Press. Cohen, S., Tyrrell, D. A., and Smith, A. P. (1991). Psychological stress and susceptibility to the common cold. The New England Journal of Medicine 325(9), 606-12. Cohen, S. and Williamson, G. M. (1991). Stress and infectious disease in humans. Psychological Bulletin 109(1), 5-24. Leserman, J., Jackson, E. D., Petitto, J. M., Golden, R. N., Silva, S. G., Perkins, D. O., Cai, J., Folds, J. D., and Evans, D. L. (1999). Progression to AIDS: the effects of stress, depressive symptoms, and social support. Psychosomatic Medicine 61(3), 397-406. Leserman, J., Petitto, J. M., Golden, R. N., Gaynes, B. N., Gu, H., Perkins, D. O., Silva, S. G., Folds, J. D., and Evans, D. L. (2000). Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS. The American Journal of Psychiatry 157(8), 1221-8. Andersen, B. L., Kiecolt-Glaser, J. K., and Glaser, R. (1994). A biobehavioral model of cancer stress and disease course. American Psychologist 49(5), 389-404. Kiecolt-Glaser, J. K. and Glaser, R. (1999). Psychoneuroimmunology and cancer: fact or fiction? European Journal of Cancer 35, 1603-7. Herbert, T. B., & Cohen, S. (1993). Stress and immunity in humans: A meta-analytic review. Psychosomatic Medicine, 55, 364-379. Zorrilla, E. P., Luborsky, L., McKay, J. R., Rosenthal, R., Houldin, A., Tax, A., McCorkle, R., Seligman, D. A., & Schmidt, K. (2001). The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behavior and Immunity, 15(3), 199-226.

[edit] External links

• Neuroimmunology, The Medical School, Birmingham University - Dr Abid Karim
• Online Resources Psychoneuroimmunology, Neuroimmunomodulation
• Online Resources Psychoneuroimmunology
• Azar, Beth "Father of PNI reflects on the field's growth: Robert Ader finds the rise in popularity of psychoneuro-immunology gratifying and frightening" (American Psychology Association Monitor, Vol 30, 6 1999)

[edit] Further reading

• Berczi and Szentivanyi (2003) NeuroImmune Biology, Elsevier, ISBN 0-444-50851-1 (Written for the highly technical reader)
• Mind-Body Medicine: An Overview, US National Institutes of Health, Center for Complementary and Alternative Medicine
• #↑  Robert Ader, David L. Felten, Nicholas Cohen , Psychoneuroimmunology, 3rd edition, 2 volumes, Academic Press, (2001) , ISBN 0-12-044314-7
• 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
• Sternberg (2001) The Balance Within, The Science Connecting Health and Emotions, Freeman, ISBN 0-7167-4445-7 (Written for the general public)

[edit] Areas of study

[edit] See also

• Neuroimmune System
• Immune system
• Immunology
• Neurology
• Psychosomatic illness