Psychoneuroimmunology

Question 1

The connection of the central nervous system (CNS) to the immune system involves two pathways; describe both.

Answer 1

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.
CRH, ACTH- cortisol and catecholamines

Question 2

Physical and/or psychological stressors cause the release of neuropeptides and neurotransmitters in the brain:

Which? What effect do they have

Answer 2

Catecholamines, epinephrine (EPI) and norepinephrine (NE)
Gamma amino benzoic acid (GABA)
Acetylcholine (ACH)
Serotonin

These stimulate cells in the paraventricular nucleus (PVN) of the hypothalamus to synthesize and release corticotrophin releasing hormone (CRH) into the portal blood system of the pituitary.

In the anterior lobe of the pituitary gland, CRH stimulates the synthesis and release of adrenocorticotropic hormone (ACTH) into the peripheral circulation.

ACTH ultimately causes the release of the glucocorticoid (cortisol) from the adrenal gland (adrenal cortex) into the circulation.

Question 3

What kind of fibers stimulate the bone marrow? What is secreted?

Answer 3

Bone marrow is primarily stimulated by noradrenergic fibers (secreting norepinephrine)

Question 4

What kind of fibers stimulate the thymus? What is secreted?

Answer 4

Thymus is stimulated by noradrenergic, cholinergic (secreting ACH) and peptidergic fibers (secreting neuropeptides)

Question 5

What kind of fibers stimulate the spleen?

Answer 5

The spleen is strongly noradrenergic

Question 6

What kind of fibers stimulate lymph nodes?

Answer 6

Lymph nodes received noradrenergic and peptidergic stimulation.

Question 7

What innervates the adrenal medulla?

Answer 7

Moreover, the adrenal medulla is innervated directly by sympathetic nerve fibers (with ganglia in the hypothalamus).

When stimulated, the hypothalamus activates the splanchnic nerves, which in turn trigger chromaffin cells of the adrenal medulla to secrete catecholamines (epinephrine and norepinephrine) into the bloodstream.

Question 8

What types of cells have receptors for catecholamines, Ach, and neuropeptides?

Answer 8

T- and B- lymphocytes, neutrophils, mononuclear cells, and NK-cells possess receptors for catecholamines, ACh, and neuropeptides. Their effect on lymphoid tissue is dependent on the type of cell receiving the signal.

Question 9

How do cortisol and epinephrine affect NK cell activity?

Answer 9

Cortisol is best known for its metabolic effects (increasing gluconeogenesis), anti-inflammatory effects (reducing cytokine production, T and B cell reactivity and NK cell activity) and its’ ability to modulate the processing of information from the sense organs.
(anti-inflammatory
reduces cytokine production, reduces T and B cell reactivity, reduces NK cell activity)

Epinephrine and norepinephrine act as neurotransmitters in the CNS and are released into the circulation by the adrenal medulla, increasing leukocyte mobilization, resulting in an increase in NK cell activity.

Epinephrine and norepinephrine:
increase leukocyte mobilization
Increase NK cell activity

Question 10

Where do endorphins originate? From what gene? What are the implications?

Where are enkephalins produced?

Answer 10

Beta endorphins and Enkephalins: increase T cell reactivity and NK cell activity

Endorphins originate from a precursor molecule called pro-opiomelanocortin
(POMC), which is synthesized in the pituitary after CRH stimulation, but can also
be synthesized 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, and endorphin.)

Enkephalins are produced in the brain, pituitary, and adrenal gland (simultaneously with epinephrine and norepinephrine) when stimulated, and play
a role in analgesia. They can bind to the same opioid receptors as endorphins.

Question 11

Between endorphins and enkephalins, which acts more like a neurotransmitter and which acts more like a hormone?

Answer 11

Endorphins act more like hormones, while enkephalins act more like
neurotransmitters.

Question 12

An individual goes parachute jumping. Immediately what cellular changes would occur?

What short lasting stress-related immune modulation would occur?

If monitored 10 minutes before and after jumping, what changes would occur? (Give CD identification)

Answer 12

Experiments with parachute jumping have shown an immediate increase in the number of circulating leukocytes, in particular NK cells. The short lasting stress-related immune modulation in these situations is associated with increased catecholamine levels.

• Heart Rate
• Cortisol (slower rise)
• Epinephrine
• Norepinephrine.
  Slide 20
• T cells (CD3)
• Helper T cells (CD4)
• Cytotoxic T cells (CD8)
• Monocytes (CD16)
• NK cells (CD56).
• NK cell activity.

The increase in NK cell activity is due to the increase in the number of circulating NK cells. The effect on circulating NK cells is reproduced by the administration of
epinephrine or norepinephrine.

Question 13

What stimulates immediate leukocyte mobilization in the circulation?

Answer 13

Immediate leukocyte mobilization in the circulation is due to catecholamines (epinephrine and norepinephrine).

Question 14

Immediate leukocyte mobilization in the circulation is due to catecholamines (epinephrine and norepinephrine).

What effect will catecholamines and cortisol have?

Answer 14

Under the influence of catecholamines and cortisol, leukocytes redistribute to the lymph nodes where they can respond quickly to antigenic (infectious) challenge.

Question 15

Under the influence of catecholamines and cortisol, leukocytes redistribute to the lymph nodes where they can respond quickly to antigenic (infectious) challenge.

Describe mechanistically why redistribution to lymph nodes results.

Answer 15

Redistribution to the lymph nodes is a consequence of hormonal modification of adhesion molecules on the surface of the leukocytes (increased expression of CD11a) and activation of cognate adhesion molecules on the surface of endothelial cells (ICAM-1).

After the stressful event, hormone levels return to normal and leukocyte numbers return to normal in the circulation.

induce expression of CD11a so they can bind through endothelium through ICAM-1- this allows entrance into lymph nodes

Question 16

How do hormones change during stress and after?
0-10 minutes
1-2 hours
1-4 hours (after stress)

Answer 16

Slide 29
0-10 min- Epi and NE increase
1-2 hours - Epi and CORT increase
1-4 hours E, NE and CORT decrease

Question 17

Describe how cortisol affects delayed type hypersensitivity.

Low cortisol (acute stress) 5mg/kg has what effect on DTH?
Higher cortisol? 40mg/kg

Answer 17

Low cortisol concentrations (as a consequence of acute stress) of 5 mg/kg markedly enhance DTH responses. Interestingly, higher concentrations of 40 mg/kg depress DTH responses. Moreover, chronic stress (extending for several days or weeks) actually decreases immune responsiveness as judged by DTH

acute stressor increases DTH response ( increased response - cell mediated immunity against tuberculin ) better way to fight disease
if chronic stressor, high levels of CORT for long periods of time, decrease immune response.

For example, chronic stress significantly suppresses delayed-type hypersensitivity (DTH) responses (e.g. to skin test) and decreases leukocyte mobilization to the skin. Acute stress enhances the DTH response and increases leukocyte mobilization

Question 18

Individuals who have given care for several years to Alzheimer’s patients were monitored over an extended period for their levels of stress and for their capacity to mount an immune response in comparison to a matched control group of individuals who were not chronically stressed.

1. What cytokine production would decrease?
2. What tests would demonstrate changed antibody production?

Answer 18

1. Decreased cytokine production (IL-1).
2. Decreased antibody production, judged by enzyme linked immunoadsorbent assay (ELISA) and by hemagglutination inhibition (HAI).

Question 19

When divided into high stress and low stress groups, the high stress group exhibited:

What type of cytokine response to influenza vaccine (Fluzone)?

Number of colds?

Answer 19

Decreased cytokine response to influenza vaccine (Fluzone) as judged by cytokine production (IL-2).

An increase in the numbers of colds.

Question 20

Effect of the Immune System on the Nervous System

Cytokines produced as a consequence of an on-going immune or inflammatory process can have direct effects upon the CNS. These cytokines are:

What results?

Answer 20

IL-1
TNF
IL-6.

fever, headache, muscle and joint pain, diminished appetite, lethargy

brain alerted by immune system that something is going on. macrophages, DC, making cytokines trafficking to brain and binding to receptors in brain, inducing sickness behavior…

Question 21

Cytokines 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 ACTH production.

Receptors for cytokines have been found in the CNS and pituitary gland.

Furthermore, leukocytes are capable of neuropeptide and neurotransmitter production. Activation of T- and B-lymphocytes can stimulate these cells to produce:

Answer 21

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.

Question 22

Symptoms like fever, headache, muscle and joint pain, diminished appetite, lethargy, are a consequence of these cytokines and are characteristic of sickness behavior.

Cytokines produce these symptoms by two known means:

Answer 22

Via the circulation
Via afferent neurons (i.e., vagal).
Alerting the brain to infection or injury.

Via the circulation, cytokines cross the brain blood barrier 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 vagal afferents, IL-1 produced by leukocytes stimulates the related regions of the brain.

Question 23

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 the efferent vagus and the splenic nerve.

Answer 23

Action potentials transit the splenic nerve releasing NE, which stimulates the production of ACh by T lymphocytes (via surface beta 2 adrenergic receptors).

ACh interacts with macrophages (via surface alpha 7 ACh receptors) within the spleen and inhibits transcription of IL-1, IL-6, and TNF. Thus controlling the production of these proinflammatory cytokines.

Question 24

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.

Answer 24

A