The correlation between immune function, psychopathology and personality.

1. The correlation between immune function, psychopathology and personality. By Timothy R. Test, Sr., Ph.D. National College Everest College of Phoenix

2. Stress, stressors, stressed-out Much progress has been made in the field of psychoneuro-endocrinology within the past decades in expounding and understanding the effects of hormones on proper brain development, how the brain ages, and diseases of the brain. One of its most intriguing topics is how the brain is impacted by stress.

3. Stress, stressors, stressed-out continued Heuser & Lammers posit that psychological and experimental factors are the stressors that have the most impact for human beings. Therefore, “a definition of stress more focused on the central nervous system consists in the view of stress as alterations in psychological homeostatic processes.” Examples of these types of stressors include withholding of rewards, and the anticipation of punishment (not the punishment itself).

4. Stress, stressors, stressed-out continued The brain controls the interpretation of what is stressful as well as the behavioral and physiological responses that are produced. Brief periods of controllable stress do not have a large impact on physical or mental health. Heuser & Lammerspoint out though, that “a lack of control and uncertainty can produce a chronic state of distress that is believed to enhance vulnerability to stress-related disorders.”

5. Stress, stressors, stressed-out continued The stress system coordinates the adaptive response of the organism to real or perceived stressors. The main components of the stress system are the hypothalamic–pituitary–adrenal (HPA) loop and the limbs of the locus ceruleusnorepinephrine/autonomic (LC/NE) pathways, which appear to be synergistic. The catecholaminesfacilitate the availability of energy to vital organs. Glucocorticoids from the adrenals function as “antistress” hormones that help “to contain or shut down the neural defensive reactions” that are brought on by stress.

6. The Pituitary-Adrenal Axis: POMC Peptides (ACTH, b-Endorphin) and Glucocorticoids The release of CRH from neurons in the paraventricular hypothalamus (PVN) or the hypothalamus provides the major signal that regulates the pituitary-adrenal axis. When released into the portal blood vessels, CRH causes the anterior pituitary corticotrophs to release ACTH, and stimulates synthesis of POMC (Pro-opiomelanocortin,the precursor to ACTH) as well as other peptides. CRH release is modulated by many different neurotransmitters, neuromodulators, hormones, peptides, and cytokines, and as such this system is very complex

7. HPA-AXIS Corticotropin-releasing hormone (CRH) Adrenocorticotropic hormone (corticotropin)

8. The Pituitary-Adrenal Axis: POMC Peptides (ACTH, b-Endorphin) and Glucocorticoids Continued The CRH effect on the pituitary is increased by AVP (Arginine vasopressin), whereas CRH is inhibited by opiates CRH release is increased by neurotransmitters such as acetylcholine, norepinephrine, and serotonin, while it is inhibited by GABA (γ-Aminobutyric acid ) and gaseous neuromodulator nitric oxide CRH release is increased by neuropeptide Y and certain cytokines while it is inhibited by Substance P. Estrogen increases the release of CRH and inhibits the glucocorticoid negative-feedback effect

9. The Pituitary-Adrenal Axis: POMC Peptides (ACTH, b-Endorphin) and Glucocorticoids Continued ACTH decreases antibody production in response to antigen, interferes with macrophage-mediated tumoricidal activity, and suppresses cytokine production. Depending on the dosage and other factors prior to the stimulation with mitogens, ACTH has the capability to either increase or decrease the proliferation of lymphocytes. CRH has been found in other tissues and this peripheral CRH is capable of inducing the expression of POMC in leukocytes much like it does in the pituitary

10. The Pituitary-Adrenal Axis: POMC Peptides (ACTH, b-Endorphin) and Glucocorticoids Continued CRH can also promote the release of cytokines such as (interleukin) IL-1 and IL-6 from monocytes which then act on the lymphocytes to promote POMC-derived peptides. Glucocorticoids have the capability of blocking these actions. Leukocytes have the capacity to mimic HPA influences locally. b-Endorphin and other opioid peptides also seem capable of either enhancing or suppressing immune response.

11. The Pituitary-Adrenal Axis: POMC Peptides (ACTH, b-Endorphin) and Glucocorticoids Continued Insufficient adrenal function results in elevated white blood cells. Animals that had their adrenals removed were observed to have an enlarged thymus. Research has shown that stress or noxious stimulation results in adrenals that are enlarged and atrophied the thymus. Glucocorticoids act by shutting off activated immune response in order to prevent damage from an immune response that is unregulated.

12. The Pituitary-Adrenal Axis: POMC Peptides (ACTH, b-Endorphin) and Glucocorticoids Continued The effects of glucocorticoids are not unidirectional and require a prolonged exposure to relatively high levels before becoming suppressive. Glucocorticoids are affected by the level of corticosteroid-binding globulin in the circulation, and makes the glucocorticoids less available to intracellular receptors. When the glucocorticoid binding to intracellular receptors occur in sufficient numbers to alter the expression of specific genes, then suppression will start to take place.

13. The Pituitary-Adrenal Axis: POMC Peptides (ACTH, b-Endorphin) and Glucocorticoids Continued Glucocorticoids have an inhibitory effect on proinflammitory cytokines such as interferon IFN-y, Granulocyte-macrophage colony-stimulating factorGM-CSF, IL-1, IL-2, IL-3, IL-6, IL-12, and tumor necrosis factor TNF- a as well as histamine, prostaglandins, and leukotrienes. Because glucocorticoids do not seem to affect IL-4, they can promote a shift from Th1 to Th2 predominance. Glucocorticoids prevent an accumulation of leukocytes at inflammation sites. glucocorticoids alter the response of leukocytes that diminishes antigen presentation and inflammation while promoting antibody synthesis by acting on the expression of cytokines, adhesion molecules, and receptors on leukocytes.

14. Stress, stressors, stressed-out continued The adaptive responses are the short activation of the HPA system. The maladaptive responses are often caused by the overproduction of stress hormones as well as the inability to terminate HPA activation. A person in chronic stress can cause sustained increases in glucocorticoids, and in the case of humans, cortisol. In certain cases, a chronic adaptation to a stressor can cause the HPA system to become tonically inhibited. Heuser & Lammers posit that stressors that result in the activation of corticotropin-releasing hormone (CRH) release from paraventricular neurons in the hypothalamus also result in elevated glucocorticoid (GC) levels. A cessation of activation by CRH can cause lower levels of GC. The hippocampus, via the binary glucocorticoid receptors system, regulates the overall activity of the HPA system.

15. Hippocampus

16. The hormonal stress response When an individual experiences psychological or physical stress, the parvocellularneurons of the paraventricularhypothalamus (PVN) produce increased amounts of CRH and vasopressin (VP). CRH and VP are then released into portal vessels, and this activates secretion of corticotropin (ACTH) from the corticotrophsof the anterior pituitary cells. “ACTH itself enters the circulating blood and stimulates the secretion of glucocorticoids (cortisol in humans and corticosteronein rats) from the cortex of the adrenal glands.”

17. The hormonal stress response continued What the authors call a ‘compensatory’ increase in CRH mRNA expression in PVN has been observed in mature and developing rats following stress-induced CRH secretion. Glucocorticoids suppress this compensatory enhancement of CRH mRNA expression in PVN in order to shut down the stress response and returns the individual to a state of homeostasis. This increase of glucocorticoid secretion is vital for an individual in order to adapt to stress. If an individual has an excessive exposure or prolonged exposure to glucocorticoids, the effects may be hazardous because of the effects it has on the CNS and other organs.

18. Stress, glucocorticoid receptors andthe hippocampus The hippocampus is one of the most important brain areas that regulates stress response and also affected by stress.* There is a rich concentration of glucocorticoid receptors including type I (mineralocorticoid) and type II (glucocorticoid) in the hippocampus. Type I receptors regulate the basal activity of the HPA system. * Type II receptors have a lower affinity for glucocorticoids than type I receptors and they play a more important role in modulation of HPA functions during high release of glucocorticoids during acute stress. * *Taken directly from the article

19. Stress, glucocorticoid receptors andthe hippocampus continued The hippocampus modulates glucocorticoid release through inhibitory effects on the HPA system. The hippocampus has an important role in integrating neurohumoral, and neurochemical responses to stress. Glucocorticoids have a wide range of effects on the hippocampus, which helps regulate cognitive functions such as information processing. Normal GC concentrations are vital for proper synaptic transmission and the maintenance of neuronal viability of the different hippocampal subfields. Studies have shown chronic elevation of corticosteroid levels leads to neurodegeneration or suppressed neurogenesis in the hippocampus. Direct glucocorticoid exposure results in decreased dendritic branching, alterations in synaptic terminal structure, a loss of neurons, and an inhibition of neuronal regeneration in the dentate gyrus.

20. Stress, glucocorticoid receptors andthe hippocampus continued These effects of glucocorticoids are exerted through disruption of cellular metabolism and by increasing the vulnerability of hippocampal neurons to a variety of insults, including endogenously released excitatory amino acids. Moreover, depletion of corticosteronecould induce apoptosis in granule cells of the dentate gyrus. The structural changes of hippocampal neurons after chronic absence or chronic overexposure to corticosteroids indicate that steroid-dependent expression of genes is of crucial importance for hippocampal integrity. The results of these studies have profound implications for several neuropsychiatric diseases, especially depression and posttraumatic stress disorder. Several studies found a significant reduction in hippocampal volume in depressed patients.

21. Glucocorticoid receptors and HPA system regulation The ability of the glucocorticoid negative feedback system to limit the production of GC during stress can be impaired by early life stress, history of chronic emotional/physical stress and older age. A nonstressed HPA system is characterized by an increased variance mostly due to a wide circadian variation, with distant morning zeniths and evening nadirs, a discrete but small lunch-induced GC peak and an appropriate suppression of the afternoon GC concentrations in response to low-dose dexamethason.

22. Glucocorticoid receptors and HPA system regulation continued A chronically stressed HPA system and that of older individuals is characterized by a decreased variance. This is mostly due to “evening nadir elevations and morning zenith decreases, a large lunch-induced GC response and an inadequate suppression of afternoon GC levels after overnight dexamethason.” How HPA responds to stress is very dependent on specific psychological factors such as control and predictability. There is evidence that the anticipation of an event is just as strong in terms of activation of the HPA system as the event itself. For example, patients who are phobic show the highest elevation of cortisol on the day prior to being exposed to the phobic stimuli.

23. Stress allostasis and aging “Allostasis refers to the process of re-establishing homeostasis in the face of challenge. It is the process of achieving stability through change and refers in part to the process of increasing sympathetic and HPA activity to promote adaptation and to re-establish homeostasis.” It encompasses an individual’s ability to anticipate, adapt or cope with impeding future events.

24. Stress allostasis and aging continued When allostatic systems remain active they can cause wear and tear on tissues and accelerate pathophysiology. This is called allostatic load. Examples of this include loss of bone mass in depression associated with elevated levels of glucocorticoids and atrophy of neurons in the hippocampus as a result of recurrent, hypercortisolemicdepression. chronic stress tends to enhance the magnitude to responses to subsequent presentations of either the same or novel stressors. Chronic stress has been found to induce a sensitization of the HPA system that is not identifiable under “resting” conditions. This will manifest when a novel acute stressor is imposed.

25. Stress earlier in life and its impact on future health: anxiety disorders and PTSD Recent research has linked repeated, severe activations of the HPA system and physiological and cognitive functions For example the authors point to the GCs act on the hippocampus and amygdala to disrupt episodic memory. During development, proper function of both the activation and the ‘shut-off’ mechanisms of the HPA loop is essential to allow the individual to cope with acute stress, as well as to allow normal growth and maturational processes. High levels of GCs may have a negative influence on these processes.

26. Stress earlier in life and its impact on future health: anxiety disorders and PTSD continued Studies have shown that early maternal separation or handling of neonatal rats can cause widespread and lifelong changes in various transmitter systems that regulate the stress systems. In humans the relationship between early life events and health in adulthood can be linked to parental influences on the development of neural systems important to the expression of behavioral and endocrine responses to stress.

27. Stress earlier in life and its impact on future health: anxiety disorders and PTSD continued As adults, individuals who were childhood victims of physical or sexual abuse are at significantly greater risk for mental illness, obesity, diabetes, and heart disease. Heuser & Lammers point out that continual emotional neglect, family conflict or harsh, inconsistent discipline increases the risk for depression and anxiety disorders and obesity. Additionally, prenatal stress has been linked to an increased risk for major depression in adulthood. Moreover, research in the last decade has shown that early life stress can contribute to higher risks for PTSD. “In adult PTSD, it is hypothesized that the catecholamine- and HPA-system responses to stress become maladaptive, causing long-term negative consequences.”

28. Stress and depression Heuser & Lammers posit that excess CRH within the CNS may cause a depressive symptom complex consisting of loss of appetite, insomnia and intense anxiety. Clinical studies have shown that hyperactivity of central CRH neuronal activity may be involved in the pathophysiology of depressive disorders. The hypercortisolemia and impaired negative feedback of cortisol on the HPA system observed in melancholic depression can be traced to a primary central CRH hyperdrive. Through observation of the DST which shows a nonsuppression of cortisol following administration of the synthetic glucocorticoid dexamethasone. Paradoxically increased ACTH and cortisol secretion after CRH infusion in dexamethasone-pretreated patients were observed following a combined dexamethasone suppression/CRH stimulation test (DEX/CRH-test).

29. Stress, HPA system and addiction In studies conducted on animals, the dopaminergic transmission in the nucleus accumbenswere facilitated by glucocorticoids and glucocorticoid treatment were found to enhance amphetamine-consumption. In addition, repeated exposure to stress or to psychostimulantdrugs produces a sensitization of mesolimbic dopaminergic neurons. HPA system status also influences responses to psychostimulants. As such, stress and glucocorticoids can be linked to the abuse of drugs under certain conditions.

30. CRH antagonists for treatment of depression and other stress-related disorders “Research has found substantial alterations in central CRH systems brought about by early life stress. Oral administration of the CRH receptor antagonist antalarmin significantly decreased cerebrospinal fluid concentration of CRH, and pituitary–adrenal and autonomic responses to stress as well as inhibiting behaviors indicative of fear and anxiety in adult primates.” “The research group of Florian Holsboer of the Max-Planck-Institute of Psychiatry has recently proven the antidepressant and anxiolytic properties of the selective CRH receptor antagonist R121919 in a clinical trial of depressed patients.”

31. Conclusion The brain is a major target for glucocorticoid hormones by which psychological and physical disorders could be caused. treatment strategies aimed at regulating abnormal levels of glucocorticoids are currently worth further investigation and study. A combination of genetics, early life stress, and ongoing stress may ultimately determine individual stress responsiveness and the manifestation of psychiatric disorders.

32. References Isabella Heuser, I & Lammers, C. (2003). Stress and the brain. Neurobiology of Aging 24, S69–S76. Daruna, J. H. (2004) Introduction to Psychoneuroimmunology. Burlington, MA: Elsevier Press, Inc.