Download ImmuneStress2001

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 Stress
Scale
Baseline Finals Week
Obsessive
Compulsive
Symptoms
58.84
63.84
Depression
57.27
59.14
Anxiety
55.89
67.19
Hostility
52.23
58.3
General
52.49
Symptom Index
54.89
Academic Stress
40
35
% Lysis
30
25
Low Lonely
High Lonely
20
15
10
5
0
Baseline
Exam
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)
Immunosuppressive Drugs
Mononucleosis
Increase in
Antibodies to EBV
Why the Increase?
Drug
Suppress Immune System
Increase Virus Activity
Increased
Antibody Production
to EBV
Results
Immune Data
Separated/ Married
Divorced
EBV
520.5
147.2
% of helper T cells 26.43
32.91
% of NK cells
12.79
7.5
Chronic Stress
Caregivers of AD Patients Study: KeicoltGlaser 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
Depression
Inventory
Life
Satisfaction
Self-Rated
Mental Health
Mental Health
vs. 5 yrs.
prior
AD
Caregivers
4.88
Matched
Controls
2.48
1.62
1.91
1.84
2.38
1.57
2.03
Results: Immunological Data
AD
Caregivers
Matched
Controls
Total T
Lymphocytes
Helper T
Lymphocytes
NK Cells
48.7
56.5
33.5
45.9
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
100
90
80
Percent of 70
60
Subjects with
50
Fully Healed 40
Wounds
30
20
10
0
Caregivers
Controls
4
5
6
Time (Weeks)
7
8
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
Former
Controls
Caregivers Caregivers
Perceived
Social
Stress
Social
Support
16.73
10.46
9.61
29.82
37.85
36.57
4.8
4.6
4.4
4.2
4
3.8
3.6
3.4
3.2
3
m
on
th
s
6
m
on
th
s
3
m
on
th
1
ks
we
e
2
in
e
former caregivers
controls
current caregivers
se
l
Ba
Antibody titer
Caregivers of AD Patients Study
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 Island
Measure
TMI
Site
Depression
.58
Anger
.88
Anxiety
.67
Suspiciousness .80
Norepinephrine 2,064
Cortisol
321
Control
Site
.19
.32
.15
.42
1,158
156
Immune Status: Three Mile
Island
Mean
TMI Site Control
Number of Cells
Site
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
Control
Test for NK cell cytotoxicity
Experiment 1 Results
2.5
2
NK
1.5
Cytotoxicity
(lytic units) 1
0.5
0
Control
Stress
Acute Stress and Tumor Growth

Experiment 2 Design:
1 hour
Stress
12 days
inject tumor
cells
1 hour
No Stress
Control
lung
tumor
growth
12 days
inject tumor
cells
lung
tumor
growth
Experiment 2 Results
200
180
160
140
Number of 120
Lung Tumors 100
(% of control) 80
60
40
20
0
Control
Stress
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
Index of psychological stress
Stress and Infectious Disease:
Results
60
50
40
30
20
10
0
low stress (3)
5
7
9
% of subjects with developed colds
high stress
(11)
Stress and Infectious Disease:
Results
70
60
50
Subjects with 40
Colds (%) 30
low stress
high stress
20
10
0
RV (2) RV (9)
RSV
Virus
RV (14)
CV
What causes stress-induced
immunosuppression?
Glucocorticoids
 Halt formation of new lymphocytes in
Thymus
 Kill lymphocytes
 Remove lymphocytes from circulation
 Inhibit communication
Keller, 1985
# of lymphocytes in blood
12

10
8
ADX
Control
6


4
2
0
No Stress
Stress
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
tumor cells
Measure
tumor growth
daily stress
rest
Results
1400
1200
1000
Tumor Weight 800
(mg)
600
400
200
0
Young
Young
Stressed
Old
Old Stressed
Corticosterone
(micrograms/ml)
Is this due to elevated
glucocorticoids?
45
40
35
30
25
20
15
10
5
0
Young
Old
STRESS
0
1
1.5
2
Hours
3
4
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
