Glucocorticoids and the stress response Flashcards
What is a Stressor?
Stressor is a stimulus that disrupts homeostasis and causes the stress response
- Examples: A predator is running towards you, a difficult and important exam, imagined events
What is a Stress response?
Stress response is a suite of physiological and behavioural responses to a stressor that help to restore homeostasis
Explain what is happening in the Stress response?
Stress Response / Fight or Flight response;
- 2 step physiological stress response
1). Sympathetic nervous system (fast/short-term response)
- Quick response system within seconds
- Release of Epinephrine (adrenaline)
2). HPA Axis (Hypothalamic-pituitary-adrenal axis);
- Slower response system, minutes to hours (long-term)
- Release of cortisol
What does the Adrenal Cortex and Adrenal Medulla release?
Adrenal Cortex;
- Glucocorticoids (e.g cortisol)
- Mineralocorticoids (e.g aldosterone)
- Sex hormones (e.g testosterone)
Adrenal Medulla;
- Adrenaline/epinephrine
- Noradrenaline/Norepinephrine
What makes up the HPA Axis?
Hypothalamus (brain) release CRH (corticotrophin-releasing hormone) which stimulates the Pituitary Gland (brain) to release ACTH (adrenocorticotrophic hormone) which stimulates the Adrenal cortex (on top of kidney) to release Cortisol.
Cortisol has a negative feedback system to turn off CRH production by hypothalamus
What are the consequences of the Stress Response on the body ?
Immediate effects;
- Increased heart rate
- Increased oxygen intake
- Increased blood glucose levels
- Increased blood flow to muscles
- Increased alertness
- Inhibition of digestion, immune system
- Release of endorphins
- Dilation of pupils
Is the Stress response a good or bad thing?
Short term vs Long term consequences
- In general stress is a beneficial in the short-term or at mild levels but can cause major long-term problems if stress is chronic
What problems can Chronic Stress be linked to ?
Chronic Stress be linked to;
- Heart disease
- Diabetes
- Ulcers
- Growth problems
- Compromised immune system
What is the link between cortisol levels and depressed people, and cortisol release routine?
Cortisol is elevated in around 50% of depressed patients
But rhythm in cortisol production is high in the morning (7-9am) and low (11pm-4am)
- Relation to sleep disturbance in depression ?
The Dexamethasone Suppression Test shows;
- People usually have high cortisol in morning
- If given Dexamethasone, HPA negative feedback turns off, so no cortisol surge
- Not true of depressed patients
So the test just tells us if you have abnormal production of cortisol throughout day
So what is the link between Cortisol and Mood then ?
Cortisol and Mood;
- Depression is a symptom of Cushing’s disease (increased ACTH & high cortisol)
- But also typical of Addison’s disease (low cortisol, adrenal insufficiency)
- Cortisol is Biphasic as both these patients susceptible to depression - low and high cortisol, so whether cortisol is low or high will get depression, want cortisol levels in middle.
How does the Stress response system affect the immune system ?
Stress response system affect the immune system;
- 1st few minutes - immune system is enhanced
- After about an hour of stress - immune system returns to normal
- Chronic stress surpasses immune system functioning
(Can use clinically if someone has an overactive immune system can mimic stress with synthetic glucocorticoid and bring immune back to normal!)
How does Cortisol affect stress?
Cortisol is a key anti-stress hormone;
- Cortisol helps reduce inflammation during stress, but also acts as an immunosuppressant.
- Various components of the immune system may be influenced due to cortisol
A study was carried out at a University in Korea where they measured students bloods on the day of an exam and four weeks later, what were the significant changes?
They found the students had Lowered levels of Interferon gamma (IFN-y) due to stress, which is normally released by T-lymphocytes and natural killer (NK) cells
They also has lowered T-helper 1 (TH1) cellular immunity
Conclusions;
- Cytokine profiles were take which served as an indirect link to the immune system
- There was a significant decrease in the number of macrophages, interferons, lymphocytes and natural killer (NK) cells.
What did the Space flight study show?
Astronauts bloods were taken before, during and after take off as they would experience the following stresses;
Physical;
- G-force acceleration
- Cosmic radiation
- Pressure variations
Emotional stresses;
- Flight tasks
- Public events
- Being strapped to a rocket
The study looked at the amounts of stress hormones and reactivation of Epstein-Barr Virus (EBV). 80 - 90% population are positive for EBV antibodies but quiescent, unless very immunocompromised as stress reactivates the virus.
The study showed that;
- Reactivation of EBV occurred in 11/28 of the astronauts
- Urinary cortisol and catecholamines were elevated after flight
- Stressed due to space flight lead to decreased vis specific T-cell immunity and reactivation of EBV.
How do Glucocoticoids work in a cell?
Glucocorticoid crosses into the cytosol which crosses and interacts with glucocorticoid receptor which then interacts with a response element (GRE = glucocorticoid response element) which then drives upwards the production of an anti-inflammatory gene, making a anti-inflammatory protein therefore dampening down the immune responses
Why with the Stress response is the immune system initially enhanced then returns to normal and then gets worse?
WBC count stays same, maybe increase at start, how come if these are immunosuppressive?
Short term will increase polymorphic leucocytes, does affect lymphocytes but cells like neutrophils, so will see short spike in these.
The innate arm of immune response (one ready to go) is relatively untouched, steroid treatment really affect adaptive response and the B cells and T cells. Primarily effect of these drugs is to stop new gene synthesis, e.g not ones already there in innate, ones that need made in adaptive response.
Steroids stop new gene synthesis !
How do cytokines affect the function of Glucocoticoids in a cell?
Proinflammatory cytokines drives forward the production of something which causes inflammation.
Cytokine binds onto its response element and drives and inflammatory gene and produces and inflammatory protein
Addition of glucocorticoid is blocking the production of the inflammatory protein, so it will not be made at the same levels
What are the features of Synthetic Glucocorticoids ?
We can use Synthetic Glucocorticoids to dampen down patients who’s bodies are making inappropriate autoimmune responses like rheumatoid arthritis, IBS, etc
Treat with synthetic steroids
Can tailor immunosuppression to condition you are treating
Examples;
- Hydrocortisone - Potency 1 (same as cortisol), t1/2 8 hours
- Prednisolone (most prescribed) - Potency 4, t1/2 16-36 hours (mild steroid)
- Dexamethasone - Potency 25-80 (Super potent!), t1/2 36-54 hours (very strong steroid)
What exactly do Glucocorticoids immunosupress?
- Glucocorticoids suppress cell-mediated immunity
- Inhibit production new genes in T cells
- Inhibits production of Interleukins 1-6 + 8 and TNF-a (Proinflammatory cytokines)
- Suppress humoral immunity - B cells express less IL-2R and secrete less IL-2 (interleukins)
- Downregulation of Fc receptors on macrophages - reduced phagocytosis of opsonised cells and bacteria
What are the Side Effects of Glucocorticoids ?
Side Effects of Glucocorticoids;
- Immunosuppression (globally, all of body)
- Hyperglycemia due to gluconeogenesis, insulin resistance, impaired glucose tolerance
- Skin fragility, bruising
- Osteoporosis
- Weight gain
- Adrenal insufficiency (Addisons?)
- Muscle breakdown
- Irregular menstruation
- CNS
- Cushing’s syndrome
If infections happen must withdraw and retreat
What are the guidelines around Withdrawal of glucocorticoids?
Overall take-home - longer treat with synthetic glucocorticoid more careful you have to be withdrawing the treatment as prolonged use induces Adrenal Atrophy and recovery is quite prolonged
withdrawal;
- Excess use of high dose steroids suppress CRH and
ACTH. - Prolonged use leads to adrenal atrophy - recovery can take
months - Careful use of treatment withdrawl - less than one week
treatment, usually ok to withdraw abruptly, 1 week
recovery - 6-10 days - reduce to replacement and taper over 4 more
days. Recovery in 4 weeks. - 11-30 days, reduce to twice replacement, then by 25%
every 4 days. 3 months to recover - > 30 days - reduce to twice replacement, then by 25% per
week, then 0800h check with cortisone. Recovery may
take 1 year. - Monitor for flare-up of underlying condition
What changes to immunity are seen in Diabetes ?
Autoimmunity of diabetes;
- Destruction of insulin producing ß cells in
pancreas - 1st stage: insulitis - lymphocyte invasion of
pancreatic islets (partially destruction of cells, need to loose a lot to see diabetes tho) - 2nd stage: overt diabetes, massive death of
islet B cells - loss of glucose homeostasis
What drives Autoimmunity in diabetes?
What we think drives it, not 100%, multiple pathways to getting it because we don’t know indicates this;
- Immune assault on ß cells mostly T lymphocytes.
- Naive, ß-reactive T cells meet antigen in pancreatic lymph nodes (PLN)
- Antigens delivered to PLN by dendritic cells
- Thus PLN is site where tolerance to pancreas is
first broken down.
- Link of alimentary problems to type 1 diabetes?
- Enteroviruses (coxsackie virus), gluten, coeliac
disease (30% in some patient groups)?
Multifactorial and multicentral points
Explain the Gut theory behind Autoimmunity in Diabetes?
Theory about relationship about gut and type 1 diabetes, as we meet most pathogens eating contaminated foods and that’s where we have encountered most immune responses to pathogens over our lives and ancestors before
If you inject florescent lymphocytes into the intestine they mostly go to pancreas supporting this theory
Lymphocyte access to PLN occurs during infancy - time course is very similar to when dendritic cells capable of presenting pancreatin autoantigens appear.
A research group found if you disturbed gut (by DSS drug - cause permeability in gut wall) function it created a significant insulitis in PLN
Damage to gut changes what’s going on in gut and lymph nodes ! - hence thoughts behind gut theory leading to type 1 diabetes
