Bidirectional Pathways between the Central Nervous and Immune Systems: Implications for Disease

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Bidirectional Pathways between the Central
Nervous and Immune Systems Implications for
Disease

• Anna L. Marsland, Ph.D., RN
• Behavioral Immunology Laboratory
• University of Pittsburgh

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The Biopsychosocial Model of Health (Engel, 1977)
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Psychoneuroimmunology

• Study of interrelations between the central
  nervous and immune systems and their implications
  for health

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Working Model
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Pathways between the CNS and Immune Systems
(Sternberg, 2006 Nature Reviews Immunology, 6,
318-28)
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Evidence for Pathways Between the CNS and Immunity

• Anatomical links between the nervous and immune
  systems
• Autonomic innervation of immune organs (e.g.,
  Felten et al., 1992. Chem. Immunol 52, 25-48)
• Receptors on immune cells for neurochemicals
  released in response to emotions (e.g., Sanders
  Kohm, 2002 Int. rev Neurobiol 53, 17-41)
• Consistent evidence for neuroendocrine-induced
  alteration of specific immune functions (e.g.,
  Elenkov et al., 1996 Proc assoc Am Physicians
  108374-381)

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Outline of Talk
Dispositional Affect
Stress
BRAIN
Systemic cytokines
Parasympathetic Nervous System
Sympathetic Nervous System
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Activated Immune Cells
1
2
IMMUNE SYSTEM
Cellular Immunity
Inflammation
Antigen
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Stress and Cellular Immunity
1
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Human Studies

• LIFE EVENT STRESS
• Job stress Unemployment
• Death of loved one Caring for relative with
  dementia
• Divorce
• Marital conflict
• Natural disasters..

• IMMUNE COVARIATES
• NK cell activity
• lymphocyte proliferation
• Activity latent viruses e.g., herpes

Segerstrom Miller, 2004. Psych Bull 130,601-30
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Acute Stress / Daily Hassles

• Does acute stress also influence
• cellular immune functioning in
• healthy individuals?
• Permit causal interpretations
• Allow control for extraneous factors
• A means to investigate physiological pathways
• Provide model for transient daily life stressors

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• Does acute laboratory stress alter cellular
  immune components?
• What are the mechanisms of stress-induced changes
  in immunity?
• Are individual differences in the magnitude of
  immune reactivity stable across time?
• Are individual differences in stress-induced
  immune reactivity related to ability to resist
  infection?

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Research Methods
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Protocol
Minutes
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Baseline
Task
- HR and BP taken every 90 seconds
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Measures of Cellular Immunity

• Assessment of the numbers
• of various subgroups
• of immune cells.

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Measure of Cellular Immune Function Lymphocyte
Proliferation
Tritiated Thymidine
Mitogen Suspension
lymphocytes
Culture Medium
Filter
Measure radioactivity
centrifuged whole blood
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• Does acute laboratory stress alter cellular
  immune components?
• What are the mechanisms of stress-induced changes
  in immunity?
• Are individual differences in the magnitude of
  immune reactivity stable across time?
• Are individual differences in stress-induced
  immune reactivity related to ability to resist
  infection?

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Stress-Related Increases in Numbers of
Circulating NK and Cytotoxic T Cells
Ps lt .005
Marsland et al., 2002. Physiology and Behavior,
77, 711-16
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Stress-related Decreases in Proliferative
Response to PHA
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Proliferative Responses during the Stroop Test
Herbert et al., 1994 Psychosom Med 56, 337-44
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• Does acute laboratory stress alter cellular
  immune components?
• What are the mechanisms of stress-induced changes
  in immunity?
• Are individual differences in the magnitude of
  immune reactivity stable across time?
• Are individual differences in stress-induced
  immune reactivity related to ability to resist
  infection?

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Hemoconcentration
Small blood vessel
Increased blood pressure
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Changes in Plasma Volume From Before to After
Stress
All significant, p lt .001
Marsland et al., 1997, Health Psychol 16, 1-8.
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Changes in Number of Helper-T Cells Before and
After Adjustment for Hemoconcentration
All significant, p lt .001
Marsland et al., 1997, Health Psychol 16, 1-8.
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Changes in Number of B Cells Before and After
Adjustment for Hemoconcentration
All significant, p lt .001
Marsland et al., 1997, Health Psychol 16, 1-8.
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Possible Active Mechanisms The Sympathetic
Nervous System

• Individuals differ in the magnitude of their
  sympathetic responses to acute laboratory
  challenge, does immunologic reactivity parallel
  this variability?

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PHA Proliferation Response
Baseline
Task
Marsland et al., 2002. Physiology and Behavior,
77, 711-16
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PHA Response to Stress With and Without Labetolol
Bachen et al., 1995, Psychosom Med 57, 673-9.
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• Does acute laboratory stress alter cellular
  immune components?
• What are the mechanisms of stress-induced changes
  in immunity?
• Are individual differences in the magnitude of
  immune reactivity stable across time?
• Are individual differences in stress-induced
  immune reactivity related to ability to resist
  infection?

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Test-Retest Correlations of Residualized Change
Scores across timeplt.05 plt.005
Marsland et al., 1995, Psychosom Med 57, 1163-7
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Test-Retest Correlations of Residualized Change
Scores across taskplt.005, plt.0005
Marsland et al., 2002 Psychophysiology,
39865-868.
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• Does acute laboratory stress alter cellular
  immune components?
• What are the mechanisms of stress-induced changes
  in immunity?
• Are individual differences in the magnitude of
  immune reactivity stable across time?
• Are individual differences in stress-induced
  immune reactivity related to ability to resist
  infection?

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Hepatitis B Vaccination Model

• In vivo antibody response to novel antigen
• Participants
• 84 healthy graduate students
• 51 male
• Aged 21-33 (mean 24)

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Protocol
MONTHS
0
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3
4
6
5
7
8
9
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T2 Ab
T1 Ab

• 10ml blood draw to determine antibody response
  to hepatitis B surface antigen

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Baseline and Weight-Adjusted Change in PHA 10
ug/ml
Low A
High A
p lt .03
Marsland et al., 2001 Health Psychol 20 4-11
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Positive and Negative Affect among High and Low
in Antibody Responders
Low Ab
High Ab
Marsland et al., 2006, Brain, Behav Immun,
20261-269
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Conclusions
1

• Acute stress is associated with a down regulation
  of cellular immune function mediated by
  activation of the sympathetic nervous system
• Individuals vary markedly in the magnitude of
  this immune response and this variability is
  relatively stable across time and task
• Individual differences in the magnitude of this
  immune reactivity may form a physiologic basis
  for differences in susceptibility to infection at
  times of naturalistic stress.

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Outline of Talk
Dispositional Affect
Acute Stress
BRAIN
Parasympathetic Nervous System
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Innate Immunity
Antigen
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Chronic systemic inflammation
Cardiovascular disease Diabetes Arthritis General
functional decline Alzheimers disease
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The Innate Immune System and Inflammation
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Macrophage-Derived Pro-Inflammatory Mediators
Activated macrophages
Cytokines
Chemokines
TNF-alpha IL-6 IL-1beta
IL-8
Recruit and activate leukocytes from
circulation
Attracts neutrophils and naïve T cells
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Proinflammatory Mediators and Disease

• Circulating levels of proinflammatory cytokines
  predict future inflammatory disease
• Cardiovascular disease
• risk in healthy subjects
• (e.g., Ridker et al., 2000, Circulation
  342,836-.)
• Exacerbation of autoimmune
• diseases
• (Papanicoloaou et al., 1998,
• Ann Intern Med 128, 127.)

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Psychosocial Risk Factors for Inflammatory Disease
Psychosocial Risk Factors Depressive
Symptoms Trait Negative Affect Psychological
Stress Hostility
Cardiovascular Disease
Multiple Sclerosis
Rheumatoid Arthritis
Psoriasis
Type 2 diabetes
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• Are psychosocial risk factors for inflammatory
  disease associated with systemic inflammation?

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Common Factor Trait Negative Affect
Trait Negative Affect
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Associations between Antagonistic Dispositions
and Inflammatory Markers (n 855 31-54 years)
Mean (SD) Hostility/Anger Hostility/Anger Hostility/Anger NA
Mean (SD) Cognitive Affect Behavior NA
IL-6 (pg/mL) 1.92 (1.9) .13 .08 .16 .15
CRP (mg/L) 1.67 (1.9) .12 .09 .12 .12
plt.05 plt.005
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Relationships between Hostility Dimensions and
IL-6
Hostile Cognitions
ß .07, p .05
Negative Affect
Hostile Affect
IL-6
ß .06, p .06
ß.10, p .007
Hostile Behavior
ß .12, p .002
ß .09, p .04
Covariates age, sex, race, years of education,
and hypertension
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Relationships between Hostility Dimensions and CRP
Hostile Cognitions
ß .11, p .002
Negative Affect
Hostile Affect
CRP
ß .07, p .03
ß.09, p .009
Hostile Behavior
ß .11, p .003
ß .08, p .04
Covariates age, sex, race, years of education,
and hypertension
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Antagonistic Behavior and Systemic Inflammation
(N 855)
Marsland et al., in press, Brain, Behavior and
Immunity
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Conclusions

• Individuals high in aggressiveness show higher
  levels of systemic inflammation and may be at
  increased risk of inflammatory disease.
• Lifestyle factors (BMI/smoking) provide a pathway
  linking negative/hostile affect and cognitions to
  inflammation.

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Limitations

• Cross-sectional
• Interpretation difficult
• Immune-to-brain communication
• Evidence for heritability of systemic levels of
  CRP (Wessel et al., 2007, J Hyperten 25, 329-)
• Other third factors premorbid disease

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Inflammatory Competence

• Does stress influence ability to mount an
  inflammatory response?
• In vitro model of ability to initiate
  inflammatory response
• Isolated mononuclear cells
• incubated with endotoxin
• Monitor production of
• inflammatory cytokines
• and chemokines

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Cytokine Responses to Endotoxin
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Trait Negative Affect is Positively associated
with Stimulated Production of IL-8 among 183
Community Mid-Life Adults
Covariates Age/sex/race Education BMI Smoking Slee
p volume Exercise Alcohol Hypertension
Marsland et al., 2007, Brain Behav Immun, 21 218-
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Social Support (ISEL) is Inversely Associated
with Stimulated IL-8 Production among 183
Community Mid-Life Adults
Covariates Age/sex/race Education BMI Smoking Slee
p volume Exercise Alcohol Hypertension
Marsland et al., 2007, Brain Behav Immun, 21 218-
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Trait Positive Affect is Inversely associated
with Higher Stimulated Production of IL-6 among
146 Community Mid-Life Adults
plt.01
N 49
Covariates Age, sex, race BMI WBC
N 43
N 54
Prather et al., 2007. Brain Behav Immun
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Acute Stress and Innate Immune Competence
Marsland et al., in preparation
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• What are the mechanisms of Associations between
  Psychosocial Factors and inflammatory Competence?

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The Cholinergic Inflammatory Reflex (Tracey,2002
Nature 420,853-9)
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Higher Derived Estimates of Vagal Activity
Inversely Associated with production of IL-6 and
TNF-alpha (N 177)
Covariates Sex/Age/Race Education Smoking Hyperten
sion WBC
r -.30, p lt .005)
Marsland et al., 2007, Psychosomatic Medicine
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Conclusions
2

• Psychosocial risk factors for inflammatory
  disease are associated with
• Increased systemic inflammation
• Increased production of proinflammatory mediators
  in response to endotoxin
• Decreased vagal tone is a possible mediator of
  these effects
• May form a physiologic basis for associations
  between psychosocial risk factors and increased
  susceptibility to inflammatory disease

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Outline of Talk
Cognitive function
BRAIN
Systemic cytokines
3
Inflammation
Antigen
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Sickness Syndrome

• Fever
• Increased slow-wave sleep
• Lethargy
• Anorexia
• Depressed mood
• Cognitive changes
• Loss of attention
• Interference with learning/memory
• Activation of HPA and SAM systems

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Inflammation and Neurocognitive Function Animal
Findings

• Peripheral Proinflammatory cytokines
• Associated with increases in central cytokines in
  the hippocampus
• Interfere with long-term potentiation and the
  development of cognitive deficits, including
  impairment of memory (e.g., Gibertini et al,
  1995,Brain Behav Immun,9113-128)

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Peripheral Inflammation and Neurocognitive
Function

• Widely accepted that inflammation plays role in
  the pathogenesis of
• Alzheimers disease
• Vascular dementia
• Age-related cognitive decline

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Cognitive Decline in the Elderly Weaver et al.,
2002. Neurology,59,371-377 Yaffe et al., 2003.
Neurology 61,76-80

• Large scale, prospective studies show that higher
  IL-6 associated with poorer initial cognitive
  function and predicts greater future decline in
  elderly

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Is inflammation associated with preclinical
cognitive function among mid-life adults?
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Auditory and Spatial Memory among Individuals in
IL-6 Tertile Groups (N460)
Marsland et al., 2006, Psychosom Med, 68895-903
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Executive Function among Individuals in IL-6
Tertile Groups (N460)
Marsland et al., 2006, Psychosom Med, 68895-903
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Inverse Association between IL-6 and Total Grey
Matter volume of the Hippocampus (n 76)
Marsland, Gianaros, Hariri et al., in press.
Biological Psychiatry
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Conclusions
Dispositional Affect
Acute Stress
BRAIN
1
2
Systemic cytokines
Decreased Parasympathetic Nervous System activity
Increased Sympathetic Nervous System activity
3
Activated Immune Cells
Down-regulation of Cellular Immune Function
Up-regulation of Innate Inflammatory Responses
Systemic Inflammation
Greater susceptibility to infections
Greater susceptibility to inflammation