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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