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