Post on 21-Dec-2015
Stress and Infections
Antigens ~ proteins on the surface of cells that identify microorganisms as native or foreign.
Lymphocytes ~ specialized white blood cells that play important roles in immune reaction.
Immune System Barriers
Nonspecific Immune System Barriers:– Mucus Membranes: destroy foreign organisms– Phagocytosis: process where foreign organisms
and debris are consumed and destroyed by phagocytes
– Natural Killer Cells (NK Cells): able to kill foreign organisms
Specific Immune System
Cell Mediated Immunity: T lymphocytes Develop in the bone marrow Mature in the Thymus gland macrophage ingests a foreign micororganism
and displays the antigen which attracts T cells– helper T cells: cytokines– killer T cells
Specific Immune System
Antibody-Mediated Immunity Directed by B lymphocytes Develop and mature in the Bone marrow Once T cells are helping the macrophage,
they secrete a protein to cause B cell proliferation
B cells produce antibodies for the specific antigen– memory B cells
Academic Stress: Kiecolt-Glaser, et al. 1984
First year medical students Baseline immune response
– 1 month before final exams Exam immune response
– first day of final exams Self report measures of distress UCLA loneliness scale
Academic Stress
Results: Self-report data: greater distress during
finals week Immune function:
– significant decrease in NK cell activity during finals week
– students with higher distress scores had lower NK cell activity
Academic StressScale Baseline Finals WeekObsessiveCompulsiveSymptoms
58.84 63.84
Depression 57.27 59.14
Anxiety 55.89 67.19
Hostility 52.23 58.3
GeneralSymptom Index
52.49 54.89
Academic Stress
0
5
10
15
20
25
30
35
40
Baseline Exam
% L
ysis
Low LonelyHigh Lonely
Marital Stress: Kiecolt-Glaser, et al., 1987
38 married women 38 separated/divorced women Immunological data
– helper T cells– NK cell activity – Epstein-Barr Virus: higher in patients on
immunosuppressive drugs indicates increase in amount of infectious virus (reactivation)
Epstein-Barr Virus (EBV)
Epstein-Barr Virus (EBV) Mononucleosis
Immunosuppressive Drugs Increase in Antibodies to EBV
Why the Increase?
Drug Suppress Immune System
Increase Virus Activity Increased Antibody Production
to EBV
Results
Immune Data Separated/Divorced
Married
EBV 520.5 147.2
% of helper T cells 26.43 32.91
% of NK cells 7.5 12.79
Chronic Stress
Caregivers of AD Patients Study: Keicolt-Glaser et al., 1987
34 Caregivers of Alzheimer’s Disease Patients
34 Age Matched Controls– Psychological Data– Blood Samples
Caregivers of AD Patients Study
Psychological Data
1. Self-Report Data
a. Life Satisfaction
b. Degree of Loneliness
c. Physical Health
d. Mental Health
2. Depression Inventory (Beck Depression Inventory)
Caregivers of AD Patients Study
Blood Samples (Immunological Data)
1. Total T Lymphocytes
2. Helper T Lymphocytes
3. Natural Killer (NK) Cells
4. Antibody levels to EBV– Epstein-Barr Virus: Higher in patients on immunosuppressive drugs– Indicates increase in amount of infectious virus
(reactivation)
Results: Psychological Data
ADCaregivers
MatchedControls
DepressionInventory
4.88 2.48
LifeSatisfaction
1.62 1.91
Self-RatedMental Health
1.84 2.38
Mental Healthvs. 5 yrs.prior
1.57 2.03
Results: Immunological Data
AD Caregivers
Matched Controls
Total T Lymphocytes
48.7 56.5
Helper T Lymphocytes
33.5 45.9
NK Cells 12.9 15.4
Epstein-Barr Antibodies
640.7 376.7
Conclusion
Caregivers of Alzheimer’s Disease patients are more distressed
They have poorer immune function Despite all of this, there were no health
differences between the two groups.
More Results
Caregivers of Alzheimer’s Disease patients showed slower healing of wounds as a result of an arm biopsy used to test recuperative function.
Percent Wounds Healed
0102030405060708090
100
Percent of Subjects with Fully Healed
Wounds
4 5 6 7 8
Time (Weeks)
CaregiversControls
Caregivers of AD Patients Study
Glaser, et al., 1999: 3 groups: – 11 current spousal caregivers– 13 former caregivers– 28 non-caregivers– all groups matched on age, health, education,
etc examined immune response to a pneumonia
vaccine
Caregivers of AD Patients Study
Psychological measures:– Perceived Stress Scale– Interpersonal Support Evaluation List
Immune measures:– obtain blood sample prior to pneumonia
vaccine– additional blood samples at 2 weeks, 1 month,
3 months, and 6 months after the vaccine
Caregivers of AD Patients Study
Current Caregivers
Former Caregivers
Controls
Perceived Social Stress
16.73 10.46 9.61
Social Support
29.82 37.85 36.57
Caregivers of AD Patients Study
33.23.43.63.8
44.24.44.64.8
Ant
ibod
y ti
ter
former caregiverscontrolscurrent caregivers
Conclusions
Current caregivers were able to process the pneumonia vaccine initially, but were not able to maintain it over time
Former caregivers did not demonstrate a deficit in immune function
More Chronic Stress: Davidson and Baum, 1986
Three Mile Island: 1979 58 months after the accident Two groups of subjects:
– 5 mile radius– 80 miles away
Measured self-reported symptoms of distress Measured physiological variables Measured immune status
Three Mile IslandMeasure TMI
SiteControlSite
Depression .58 .19
Anger .88 .32
Anxiety .67 .15
Suspiciousness .80 .42
Norepinephrine 2,064 1,158
Cortisol 321 156
Immune Status: Three Mile Island
MeanNumber of Cells
TMI Site ControlSite
B cells 679 1,210
T cells 2,310 2,746
NK cells 687 1,1266
EBV 3.0 1.5
Are we likely to get into trouble because stress suppresses our
immune system?
S. Ben-Eliyahu rt al., 1991
Relationship between: Acute stress NK cell cytotoxic activity Metastatic spread of lung tumor
Acute Stress and Tumor Growth
Tumor: MADB106 cell line NK cell cytotoxicity:
– NK cells from the spleen– incubate with MADB106 tumor cells
Induction of tumor metastasis:– inject tumor cells into tail vein on Day 0– euthanize Day 12– count the number of lung tumors
Acute Stress and Tumor Growth Stress Procedure:
– attach a weight to the tail of a rat– place the rat in a water tank for three minutes– repeat 5 times with a 3 minute rest interval
Experiment 1 design:
1 hour
Stress Test for NK cell cytotoxicity
1 hour
No Stress Test for NK cell cytotoxicity
Control
Experiment 1 Results
0
0.5
1
1.5
2
2.5
NK Cytotoxicity (lytic units)
ControlStress
Acute Stress and Tumor Growth Experiment 2 Design:
1 hour 12 days
Stress inject tumor lung
cells tumorgrowth
1 hour 12 days
No Stress inject tumor lung
Control cells tumorgrowth
Experiment 2 Results
020406080
100120140160180200
Number of Lung Tumors (% of control)
ControlStress
Conclusions
Acute stress reduces NK cell cytotoxicity Acute stress increases lung tumor growth
Does this apply to humans?
Stress and Infectious Disease
Cohen et al., 1991 Common Cold Unit, England 394 healthy adult subjects questionnaires first day at unit
– psychological stress– health habits– personality
Stress and Infectious Disease
Nasal Drops– saline control group– viruses (n=5 different respiratory viruses)– concentration similar to person-to-person
contact (20 to 60% illness rate) measured levels of virus in nasal washings
for 6 days after
Stress and Infectious Disease: Results
0
10
20
30
40
50
60
low stress (3) 5 7 9 high stress(11)
% of subjects with developed colds
Inde
x of
psy
chol
ogic
al st
ress
Stress and Infectious Disease: Results
0
10
20
30
40
50
60
70
Subjects with Colds (%)
RV (2) RV (9) RSV RV (14) CV
Virus
low stresshigh stress
What causes stress-induced immunosuppression?
Glucocorticoids Halt formation of new lymphocytes in
Thymus Kill lymphocytes Remove lymphocytes from circulation Inhibit communication
Keller, 1985
0
2
4
6
8
10
12
No Stress Stress
# of
lym
phoc
ytes
in
blo
od
ADX
Control
Removed adrenal glands from rats (ADX)
stress the rat with inescapable shock
measure number of lymphocytes in the blood
Stress-Induced tumor growth increases with age
Sapolsky and Donnelly, 1985 aged rats during stress secrete higher levels
of glucocorticoids than young rats determine if chronic stress increases tumor
growth in aged rats
Sapolsky and Donnelly, 1985 Tumor: Fujinami sarcoma Stress sessions:
– vibration– cold exposure– immobilzation
4 groups of rats:– young-stressed– young-no stress– old-stressed– old-no stress
Sapolsky and Donnelly, 1985
Design:
1 week 1week
Inject Measure
tumor cells tumor growth
daily stress rest
0
200
400
600
800
1000
1200
1400
Tumor Weight (mg)
Young YoungStressed
Old Old Stressed
Results
Is this due to elevated glucocorticoids?
05
1015202530354045
0 1 1.5 2 3 4
Hours
Cor
tico
ster
one
(mic
rogr
ams/
ml) Young
Old
STRESS
What is the adaptive value of inhibiting the immune system
during stress? Immune system activation leads to sickness
behaviors– lethargy, weakness– increased sleep
This is not conducive to confronting acute/chronic stress
Stress causes a brief increase in immune function, followed by a decrease