L28: Psychoimmunology Flashcards
The connection of the central nervous system (CNS) to the immune system involves two pathways:
Direct (neuronal)
Indirect (neuroendocrine).
The most direct (neuronal) is the innervation of
primary (thymus, bone marrow) and secondary (e.g. spleen) lymphoid organs as well as the adrenal medulla.
In an indirect (neuroendocrine) manner…
the CNS communicates hormonally with the immune system.
These connections are activated by physical and/or psychological stressors that cause the release of neuropeptides and neurotransmitters in the brain such as:
Catecholamines
GABA
ACh
5-HT
These stimulate cells in the ___________ of the hypothalamus to synthesize and release _________ into the portal blood system of the pituitary.
- paraventricular nucleus (PVN)
2. corticotrophin releasing hormone (CRH)
In the anterior lobe of the pituitary gland, CRH stimulates the synthesis and release of ________ into the peripheral circulation.
adrenocorticotropic hormone (ACTH)
ACTH ultimately causes the release of _________ into the circulation.
the glucocorticoid (cortisol) from the adrenal gland (adrenal cortex)
Most cells of the immune system are sensitive to cortisol and are_______ in their function by cortisol.
inhibited
Bone marrow, spleen, thymus, lymph nodes are innervated primarily by ________ secreting peripheral nerves
NE
Moreover, the adrenal medulla is innervated directly by
sympathetic nerve fibers (with ganglia in the hypothalamus).
When stimulated, the hypothalamus activates the _______, which in turn trigger ________ cells of the adrenal medulla to secrete
__________
splanchnic nerves, chromaffin, catecholamines
T- and B- lymphocytes, neutrophils, mononuclear cells, and NK-cells possess receptors for ____________. Their effect on lymphoid tissue is dependent on the type of cell receiving the signal.
catecholamines, ACh, and neuropeptides.
Cortisol is best known for
(1) metabolic effects (increasing gluconeogenesis)
(2) anti-inflammatory effects (reducing cytokine production, T and B cell reactivity and NK cell activity)
(3) modulate the processing of information from the sense organs.
Epinephrine and norepinephrine act as neurotransmitters in the CNS and are released into the circulation by the adrenal medulla, which has what effect on immune cells?
Increases leukocyte MOBILIZATION, resulting in an increase in NK cell activity.
Endorphins originate from a precursor molecule called
pro-opiomelanocortin (POMC)
POMC is synthesized in the pituitary after stimulation by ____
CRH
POMC can also be synthesized outside of a. pituitary by
immune competent cells.
Endorphins play an important role in ___________.
analgesia and feelings of happiness (euphoria)
In the pituitary the POMC molecule is enzymatically split into the secretory products
ACTH, endorphin (and don’t forget a-MSH from endocrinology)
Enkephalins are produced in
The brain, pituitary, and adrenal gland (simultaneously with epinephrine and norepinephrine) when stimulated, and play a role in analgesia.
Enkephalins can bind the same receptors as
endorphins
Endorphins and enkephalins increase reactivity of what two immune cells?
Endorphins promote T cell reactivity and NK cell activity.
Endorphins act more like hormones, while enkephalins act more like
neurotransmitters.
_____ is one of the most frequently mentioned psychological factors that may modulate the immune system.
Stress
Stress is conceptualized as either a ______ or a ______.
Stimulus, response
An individual _______ a situation as either a challenge or a threat (stressor), dependent upon the individual’s ________ (resources, social support, coping abilities, etc.).
appraises, adaptive capabilities
Any demand-capability imbalance leads to
the perception of stress and the stress response (i.e., activation of the nervous system and the neuroendocrine pathways described above).
Stressors can differ in
type (physical or psychological), intensity, and duration (acute versus chronic).
2 Types of stress
Acute controllable emotional or mental stress.
Chronic uncontrollable negative stress.
The effect on circulating NK cells is reproduced by the administration of
epinephrine or norepinephrine.
Catecholamine (Epi) and cortisol (Cort) induces localization of mononuclear cells to
the lymph nodes
Immediate leukocyte mobilization in the circulation is due to
catecholamines (epinephrine and norepinephrine).
Under the influence of catecholamines and cortisol, leukocytes redistribute to the
lymph nodes where they can respond quickly to antigenic (infectious) challenge.
Redistribution to the lymph nodes is a consequence of hormonal modification of adhesion molecules on the surface of the leukocytes such as _____________, and activation of cognate adhesion molecule _________ on the surface of endothelial cells
CD11a, ICAM-1
Low cortisol concentrations (as a consequence of acute stress) has an what effect on DTH (TMMI) response?
enhances DTH response
High cortisol concentrations (as a consequence of acute stress) has an what effect on DTH (TMMI) response?
depresses DTH response
Effect of chronic stress (extending for several days or weeks) on DTH?
Depresses it
Chronic uncontrollable negative stress like caregiving to the chronically ill (e.g.
Alzheimer’s patients) can cause
immune suppression.
sickness behavior symptoms
Symptoms like fever, headache, muscle and joint pain, diminished appetite, lethargy..
what cytokines are associated with sickness behavior
IL-1, IL-6, and TNF
Cytokines like _____________ change the firing frequencies of nerve cells in the CNS and influence the secretion of neuroendocrine factors of the hypothalamus-pituitary-adrenal gland axis, especially _____ production.
- IL1, IL6, TNF
2. ACTH
Receptors for cytokines (eg. IL1, IL6, TNF) have been found in the
CNS and pituitary gland.
In addition to making IL1, IL6, TNF, leukocytes are capable of neuropeptide and neurotransmitter production.
Activation of T- and B-lymphocytes can stimulate these cells to produce:
ACTH
Beta-endorphin
Enkephalins.
The production of endorphins and enkephalins by activated immune cells may induce an
analgesic effect in infected tissue.
The production of these cytokines, hormones, neurotransmitters, and neuropeptides may modulate on-going immune or inflammatory responses and may also influence/induce behavioral changes, known as
sickness behavior.
Cytokines produce sickness behavior symptoms by two known means:
- Via the circulation
2. Via afferent neurons (i.e., vagal).
Via the circulation, IL1 IL6 and TNF cytokines cross the BBB most likely through the circumventricular organs (CVO) and neurons in this area express receptors for IL- 1, TNF, and IL-6. Interaction of these cytokines with their cognate receptors results in
neural system activation and the production of prostaglandins.
Via the _____ , IL-1 produced by leukocytes stimulates the related regions of the brain.
vagal afferents
Thus these molecules, as part of the immune system, alert the brain to
infection or injury, communicating the body’s distress.
Inflammation, mediated by IL-1, IL-6, and TNF, is necessary for protection from microbial pathogens. However, excessive production of these cytokines can result in
systemic inflammation that can result in organ failure and death.
The CNS interacts with the immune system to regulate excessive inflammation via what 2 nerves?
- the efferent vagus
2. and the splenic nerve.
Action potentials transit the splenic nerve releasing ____ , which stimulates the production of _______ by T lymphocytes (via surface beta 2 adrenergic receptors).
NE, ACh
ACh interacts with macrophages (via ________ receptors) within the spleen and INHIBITS transcription of _________ (for simplicity only TNF is presented in Figure 11). Thus controlling the production of these proinflammatory cytokines.
- surface alpha 7 ACh
2. IL-1, IL-6, and TNF
Splenic n. dumps NE on what kind of receptor, on T-lymphocytes?
B2AR
Effective immune responses require significant mobilization of
energy and resources.
In addition to mobilizing immune response, the immediate stress response is also associated with the mobilization of energy to enable
the body to deal with a threat or danger.
In a ‘fight or flight’ situation, energy is diverted to
the muscles, heart rate increases, and the body is made ready for physical action and increased sensory performance.
The mobilizations of energy for immune function and for fight or fight responses, however, are
roughly opposite! Energy cannot be diverted in both directions simultaneously.
So after the immediate release of _________, which mobilize the leukocytes of the immune system, the immune response is temporarily suppressed by the slower release of _____, in order to maximize energy for the fight or flight response.
catecholamines, cortisol
This is achieved by cortisol production (that is normally used by the body to ________).
slow down immune system activity
This slow release of cortisol is a HIGHLY ADAPTIVE RESPONSE TO SHORT-TERM STRESSORS where the body may soon resume normal immune function. It becomes disadvantageous when _____________
stress responses are maintained over longer periods of time.
Although the word ‘stress’ generally has negative connotations, stress is a familiar aspect of life, being a stimulant for some, but a burden for others. It is often overlooked that, an acute stress response can have______ (health promoting) effects.
salubrious
The ________ of a stressor is thought to be important when considering its impact on individuals.
duration
The timing of the stressor and the nature of the stressor (acute versus chronic) determine the __________
magnitude of the immune response.
Differences exist in the ways that acute (short-term) and chronic (long-term) stressors affect the immune system. For example, chronic stress significantly _______ delayed-type hypersensitivity (DTH) responses (e.g. to skin test) and ______ leukocyte mobilization to the skin
suppresses, decreases
Acute stress ______ the DTH response and increases __________ mobilization
enhances, mobilization.
So although stress is typically thought to be immunosuppressive, acute stress can result in __________, but alternatively could contribute to _________
- immune enhancement that can promote protection from infections
- the exacerbation of immunopathology.
In response to immunological challenge, acutely stressed individuals show …
significantly greater leukocyte infiltration, enhanced production of chemokines (chemoattractant proteins for leukocytes), IL-1, IL-6, TNF and IFN gamma (proinflammatory and Th1 cytokines).
Further, acute stress enhances maturation and trafficking of _______ to sites of antigenic challenge.
dendritic cells (DCs)
DCs are efficient antigen presenting cells (APCs) and these APCs effectively promote the activation and recruitment of T lymphocytes during initial antigen challenge, inducing a ______. The result would be subsequent augmentation of the immune response during secondary antigen exposure.
long-term increase in immunologic memory
Thus, the evolutionarily adaptive fight-or-flight stress response may prepare the immune system for _______.
impending danger (e.g. infection and wounding by a predator). The result would be enhanced immunological protection from the infectious agent and more rapid healing of the wound.
However, stress could also exacerbate a pathological condition that is worsened by an increased immune responsiveness such as
an autoimmune response or an inflammatory insult or disease condition.
Moreover, inopportune stress could contribute to the ______ of a pathological or autoimmune condition if it occurred at an inopportune period of significant insult.
initiation
Cytokines responsible for the fever, headache, muscle and joint pain, diminished appetite, lethargy, and weakness associated with infection are:
A. IL-1, IL-6, TNF. B. IFN alpha, IFN beta, IFN gamma. C. G-CSF, M-CSF, GM-CSF. D. IL-12, IL-15, IL-18. E. IL-4,IL-5,IL-10.
A
