Stress and Disease in Humans Flashcards
Define a stressor
Anything, actual or perceived, that threatens homeostatic balance - physiological/environmental/psychological
Define stress
A state of threatened homeostasis - allostatic load
Define stress response
The body’s attempt to restore homeostasis
What is another term for distress?
Disease
How is stress adaptive? What are sources of stress in wild animals?
Predation (acute)
Disease (acute)
Drought/famine (chronic)
How has causes of death changed over time since the 1900s?
Hicks and Allen 1999 - Infectious and parasitic disease most common, life expectancy 45
Office for National Statistics 2009 - Heart disease and cancer, life expectancy 80
What stressors affect humans?
Traffic jams, work deadlines, dams, relationships, money - anxiety, none are directly life threatening
Give examples of medium-term effects of stress
Tension, headaches, insomnia, dizziness, heart palpitations, muscle pain, depression
Give examples of long-term effects of stress
Angina, atherosclerosis ,cancer, HIV, shingles, stroke
How does stress affect the immune system?
Transiently stimulates the immune system
Immunostimulatory initially, recovery, then immunosupression
IMMUNOMODULATORY
What are the two types of immune disorder linked to stress?
Increased susceptibility to infection
Inflammatory or autoimmune disease
What is the evidence for increased susceptibility to infection?
- Healthy volunteers inoculated with a cold virus - ^ stress -> ^ infection and v WBC (Cohen 1991, 1998, 1999)
- Spousal carers of dementia patients given influenza vaccine - carers v antibody response, ^ rate of infection, v wound healing (Kiecolt-Glaser 1991, 1995, 1996)
How is inflammatory or autoimmune disease affected by stress?
Exacerbate inflammatory diseases like asthma (TH2) and autoimmune disease (eg. rheumatoid arthritis TH1)
Where are the humoral and cell-mediated responses effective?
Humoral - extracellular
Cell-mediated - intracellular
What are the TH1 nd TH2 calls responsible for?
TH1 - Type 1 pathway - cell mediated immunity
TH2 - Type 2 pathway - humoral immunity
What is the cytokine profile of TH1 cells? What is their action?
IFN-y, IL-2, IL-12, TNFa
Pro-inflammatory responses (target intracellular pathogens)
Activate macrophages, cytotoxic T cells and NK cells
Trigger autoimmune responses if unbalanced
What is the cytokine profile of TH2 cells? What is their action?
IL-4, IL-5, IL-13 (eosinophilic responses) IL-10 (anti-inflammatory responses)
Upregulates Ab production (target extracellular organisms)
Trigger allergic inflammatory responses if unbalanced
How do the TH1 and TH2 immune responses interact?
Counter-regulatory by preventing differentiation
eg. IFNy (Th1) suppresses the Th2 response, IL-4 and IL-10 (Th2) suppresses the Th1 response.
How does cytokine directed differentiation from naive T-cells occur?
Cytokines = self-specific growth factors (+ feedback)
Each pathway can down regulate the other.
Optimal scenario: balance
- overaction of either pathway can cause unbalance and trigger disease
How do glucocorticoid levels affect cytokine and Th1/Th2 responses?
Baseline- low level secretion
> ^ Th2 response inhibits Th1 formation by
- v IL-12 production
- Downregulating IL-12 Receptors on T cells and NK cells
> ^IL-4 and IL-10 production (via ^ Th2 cell formation)
How do cortisol levels vary? What are it’s effect?
Diurnal variation
- circadian rhythm
- important for immune system regulation
- v TH1 cytokine production
- ^ TH2 cytokine production
When are type 1 and type 2 immunity most active?
Type 1 - nocturnal sleep (low cortisol)
Type 2 - awakening (high cortisol)
What model describes how acute stress may affect the immune system?
Marshall 1998 - Acute stress eg. exams. [claimed to be too simple]
Cytokine shift model - stress alters the balance of the immune system without changing the overall activation ie. dysregulatino rather than immunosupression.
- describes shifts between Th1 (cellular) and Th2 (humoral) immunity.
What is immunostimulation caused by according to Marshal 1998 cytokine shift model?
Imbalance in favour of type 1 immunity (cell mediated) with concurrent suppression of type 2
- v cortisol -> immune systme hyperactivity and ^ phagocytosis
- ^ pro-inflammatory responses -> ^ tissue damage
- ^ risk of inflammatory/autoimmune disease eg. RA, type 1 diabetes
What is immunosuppression caused by according to Marshal 1998 cytokine shift model?
Imbalance in favour of type 2 immunity (humoural) with concurrent suppression of type 1
- ^ cortisol -> v lymphocytes
- ^ susceptability to infection
- delayed wound healing
What model explains the effect of chronic stress on the immune system?
> GC-ressitance model Miller 2002
- Type 1 pro-inflammatory response
- chronic stress alters GC ability to regulate the immune system
- ^GC -> vGC recepetors
- vGC sensitivity -> v suppression of inflammation
- continued stress -> ^^ IL-6 pro-inflammatory cytokine levels
OR extreme prolonged stress -> complete dysregulation
- vTH1 vTH2 -> immunosupression
Give examples of autoimmune disease. Why do they occur?
Immune system over-activation (body tissues mistakenly attacked)
Damage associated with inflammation
- eg. rheumatoid arthritus, type 1 diabetes
What two situations increase the risk of autoimmune diseases?
Phase A without phase B - immune system not down regulated
Multiple transient stressors increasing immune system function until it hits the autoimmune range
Outline the pathophysiology and treatment of rheumatoid arthritis
- Chronic inflammatory (Th1 dominant) disorder
- Risk factor gene
- Stress associated with RA
> major life events eg. death of a spouse and chronic stressors -> ^ disease activity and pain [counterintuitive, GCs should suppress this]
> acute stressors -> transient v disease activity and pain - treatment = anti-inflammatory steroids
How is the inflammatory response normally regulated?
Negative feedback
eg. immune system -> IL-12, TNFa (pro-inflam) -> ^ACTH -> ^GC -> v inflamation
How does regulation of the inflammatory response differ in RA patients?
- hypo functional HPA axis -> vGC production and ^ACTH production to compensate
- Immune cell GC resistance (vGC-R expression/sensitivity)
- Th1 rheumatoid inflammation - excess IL-12 and TNFa, LACK of IL-10
Hypothesis - following exposure to a stressor, blunted GC response and immune cell resistance prevents TH1/TH2 axis being shifted away from TH1 dominant profile -> TH2 dominant
What is the pathophysiology of type 1 diabetes?
Autoimmune disease - pancreatic cells destroyed
v insulin -> v glucose uptake
How has stress been linked with diabetes?
Depression and chornic stress link
^HPA activity and ^ cortisol in diabetic patients
Cortisol promotes insulin resistance -> hyperglyceamia
How does stress promote insulin resistance?
- ^SNS -> v insulin secretion (v PNS)
- ^GCs -> v fat cells sensitivity to insulin, blocking glucose storage
- fat cells secrete hormones to prevent muscle/liver responding to insulin
> Require larger insulin injection
How does Type-2 diabetes occur? What may it lead to?
Failure of cells to respond to insulin
- meals -> insulin release (even when fat cells full)
- full fat cells = less responsive.
- release hormones == cortisol triggering other cells to become insulin resistant
- ^ blood sugar -> ^ insulin from the pancreas
- eventually insulin secreting cells “wear out” and TYPE 1 DIABETES results
What is diabetes a major catalyst/risk factor for?
Heart disease, kidney disease, blindness and stroke (^ fatty acids and cholesterol in circulation)
How does stress increase the risk of myocardial infarction?
^BP, ^HR, ^SV Vasoconstriction (skin, gut, repro) Vasodilation (muscles) Mobilisation of glycogen/FA/lipids -> blood ^ clotting
How does stress affect clotting?
^ catecholamines -> pro-thrombotic state
^ clotting factors
^ fibrinogen
^ platelet count and aggregation
Abnormal heamostasis -> ^ risk of thrombus formation or haemorrhage
Black and Garbutt 2002, Thrall 2007
Define hypertension
Consistently high Bp at rest -> damage of arterial walls and organs (esp kidneys)
Triggered by consistently high catecholamines due to SNS hyper-reactivity
Flaa 2008
Outline the stages of formation of plaque formation
(deposition of fatty substances, calcium and cholesterol)
- hypertension damages endothelia
- WBCs congregate - chronic inflammation -> further damage
- LDL cholesterol penetrates arterial wall
- WBCs ingest cholesterol and produce initial plaque deposits
Plaque calcifies -> v arterial diamter and flexibility
What are the consequences of atheroscelorosis?
v blood flow -> myocardial ischeamia
Plaque debris and blood clots may break off
Give a study demonstrating the effects of stress on atheroscleroisis in animals
In stable social groups, subordinate female monkeys develop greater atheroscelrosis than dominants - Kaplan 1996
Social disruption causes heater atheroscelrosis in male monkeys - Manuck 1995
How is stress associated with asthma?
- Common, chronic, inflammatory disease
- Triggers - allergens, irritants, infections, stress
- Stress -> Th2 dominant, enhanes susceptability to bronchiole inflammation (th2 linked to allergic disease swell)
> Liu 2002
How is stress linked to peptic ulcer disease?
Helicobacter pylori and psychological stress two main factors
Stress
- v blood flow to gut altering stomach acid secretion
- v stomach wall thickness
- v mucous/bicarbonate excretion
- v prostaglandins (v cellular repair)
- type 1 immune supression
Basically - ^ cortisol -> TH2 biased response -> TH1 suppression, alongside gastric hyperacidity ->. H pylori ulcer formation
Stress also ^risk of 2dry infection and ^ susceptibility by behaviour (less sleep, NSAIDs)
How can PGs aid healing?
^blood flow
How are stress and depression linked?
major depression ranks 5th among leading causes of global disease burden due to link with ^morbidity/mortality from other medical conditions
complex aetiology/pathology - genetic, neurological, endocrinological, immunological components
- Numer/severity of major stressful life events associated with risk of developing MD, and the course of the disease.
What are the potential hypothesess for the biological cause of depression?
hyperactive HPA axis
NT imbalance
Cytokine hypotheses of depression
- overall dysregulation of the stress response
What is evidence for the hyperactive HPA axis hypothesis?
Lee 2002; Chrousos 2009
MD patients
- ^ plasma cortisol due to CRH hypoersecretion
- a defective feedback system
> constant anxiety, over-reaction to stimulation -> learned helplessness and loss of motivation
- excessive GC down-regulates GC receptors in the hippocampus
- prolonged cortisol hyper secretion may lead to neuronal death and hippocampal atrophy, which is associated with ^no/duration depressive episodes.
What is the evidence for the NT imbalance hypothesis of major depression?
Inhibitory NTs
-Serotonin v with stress, low levels associated with depression
-Many antidepressants ^ serotinergic transmission
-Serotonin receptor abnomalities in MD patients
Excitatory NTs
-DA responsible for motivation and interest. Low levels - v concentration and v energy. High levels = smoke/drug dependance
-NA - high levels linked to anxiety, stress, ^BP, low levels linked to lack of energy, focus (Seen in depression)
What is the evidence towards the cytokine hypothesis of depression?
Symptoms of sickness behaviour in animals == depression
Hypothesis = ^pro-inflamatory cytokines and v anti-inflam act upon the brain
Evidence
- depressed patients have immune abnormalities
- depression common side effect of cytokine therapy
- antidepressant medication v pro-inflammmatory cytokine secretion
- IL-1 -> sickness behaviour in animals and actuates both SAM and HPA
- IL-1, IL-6 and TNFa affect 5-HT transmissino in the brain
BUT
> little evidence for ^IL-1 in depressed patients
> ^IL-6 linked to depression/infection/stress but not sickness behaviour
What are the main factors affecting th stress resonse?
- Mediating processes
- appraisal
- coping strategies (problem-focused or emotion-focused coping) - Vulnerability factors
- personality types (Friedman and Rosenmn 1974 - type A [aggressive, impatient] v type B[alm, laid back] behaviour)
- health habits
- social support
- genetics
- experience
- demongraphic
- pre-existing stressors
