Stress, Immunity and Health:
An Integrative Approach to Therapy and Prophylaxis
Gailen D. Marshall, Jr. MD PhD FACP
Laboratory of Behavioral Immunology Research
The University of Mississippi Medical Center
Jackson, MS
Health

The physical, emotional and spiritual well being of the individual

Much more than just “absence of disease”

Cannot be attained or maintained solely by “pills or procedures”

Involves the initiation and maintenance of homeostasis

Includes psychological components
– outlook
– physician-patient relationship
– recognition of relationships between spirituality and health
Major Heath Challenges in Western Society

Chronic Diseases prevalent
– Hypertension/cardiovascular disease
– Diabetes mellitus
– Asthma
– Cancer

Increasingly obese and sedentary society

Increasing levels of societal stress

Western Medicine is increasingly technology driven which can
minimize the whole person concept (body, mind, spirit)
The Immune System
Normal Physiological Functions

Preserve homeostasis by host defense

Discerns




Self vs. non self
Pathogenicity
Intracellular vs. extracellular pathogens
Goal is sufficient



Specificity
Intensity
Duration
Immune Deviation
The Th1/Th2 Paradigm
Th1
Balance
Intracellular Pathogens
Th2
Extracellular Pathogens
5
Determination of Th1 Versus Th2
(vs other) Responses
• Depends on the pathogen (intra vs extracellular):
• e.g. parasite vs. virus
• Depends on dose and route of antigen exposure:
• e.g. large vs small, mucosal vs intravenous vs cutaneous
• Depends on host genetic factors:
• e.g. family history of disease susceptibility, specific genes, SNPs
• Depends on the local “cytokine environment” that
comes from natural inflammatory cells
• e.g. IFN (NK) vs. IL-4 (MC) vs IL-10 (DC)
Immunoregulation

Involves the activity of an additional set of T cells collectively called
regulatory T cells
– CD4+CD25+FoxP3 – Treg
– CD4+IL-10+ - Tr1
– CD4+TGF+ - TH3
– CD8+ - suppressor T cell
– CD3+CD56+ - NKT cell

Operate primarily by regulating intensity and duration of the
response including degree of immune deviation
Immunoregulation
Immunoregulation
The Th1/Th2 Paradigm Revisited
Abnormal Immune Deviation
IL-4
Th2
Th1
IL-12
IFN-
IFN-
Imbalance
 Intracellular
IL-4
IL-5
Pathogens
+ Extracellular
Pathogens
 Delayed Hypersensitivity
Allergic Inflammation
Treg
IMMUNE DISEASES
DEFICIENCY
VS
DYSREGULATION
Immune Diseases

Deficiency = Infection
– increased incidence
– opportunists
– latent virus reactivation (?)

Dysregulation
– overregulation - functional deficiency
(infection, malignancy)
– underregulation - hypersensitivity
Inflammatory Diseases
Immunoregulatory and TH1/TH2 Dysfunction

Allergic diseases

Asthma

Autoimmune diseases

Diabetes mellitus

Inflammatory bowel disease

Cardiovascular disease

Malignancy

Neurodegenerative diseases
13
Neuroendocrine Immune Interactions
Neuroendocrine Immune Interactions
Webster, Tonnelli and Sternberg 2002
Psychoneuroimmunology

Behavior, neuroendocrinology and immunity

Evidence for multisystem interactions
– neuroendocrine - HPA, HPT, HPG
– autonomic nervous system (norepi, epi)

Impact on immune system
– effector functions
– regulatory mechanisms

Health implications
Defining Stress

Assessing stressor (situation)
– Intellectual Process
– May be conscious or subconscious
– Asks two questions in response to environmental change
 Is there a danger?
 Can I (or do I need to) do anything about it? (fight or flight)

Eustress (benign assessment)
– No danger exists and/or
– Coping will be adequate to defend/preserve host

Distress
– Situation will involve harm, loss, and/or threat
– Coping is nonexistent or inadequate for host
Clinical Definition of Stress Response

Not necessarily just the event (stressor)

The psychophysiological response to the event (“I’m under a lot of stress”)
– Acute
 fight or flight
 Combination of HPA and ANS with rapid resolution
– Chronic
 anxiety, depression, worry
 Endocrine/immune “exhaustion”

Major factors that impact the nature, magnitude and duration of the response
– Optimism vs pessimism
– Social support upport system
– Belief system
Effects of Stress (Distress) on Immunity
• FUNCTIONAL
•
•
•
•
decreased NK activity
decreased antiviral CTL activity
decreased T cell proliferation
increase in selected antibody levels
• CYTOKINES
• decreased IL-2, IFN
• increased IL-4
• In vivo Responses
• decreased DTH (e.g. PPD)
• increased susceptibility to viral illness
Modifiers of Stress Effects on Immunity

Emotional state
– Anxiety
– Depression
– Worry

Physical State
– Conditioning
– Pain
– Nutritional status
– Comorbidity

Environmental exposures
– Allergens
– Chemical/biological toxins and/or radiation
Immune Effects of Acute Stress
Effect of Acute Stress on
NK Cell Cytotoxicity
450
400
350
LU 20
300
250
200
150
100
50
0
Pre Stress
During
Post Stress
p = 0.0055
Marshall and Agarwal 1999
23
Effect of Acute Laboratory Stress on Tregs
in Normal Human Participants
n=12
4
**
*
Post 2
Post 6
3
2
% CD4
+
CD25
HIGH
FoxP3
+
5
1
0
Pre
Post 0
Post 1
Post 24
Time after TSST
del Ben and Marshall 2008el
Effects of Percieved Stress on Regulatory T cells in
Normal Marathon Runners
Treg versus PSS with fitted lines over visit
Pre
Post
4
3
2
1
Treg
5
6
7
Baseline
0
10
20
0
10
20
0
10
20
PSS
Rehm and Marshall 2012
Effects of Anxiety Level on Regulatory Tcells in
Normal Marathon Runners
Treg versus STAIS with fitted lines over visit
Pre
Post
4
3
2
1
Treg
5
6
7
Baseline
20
30
40
50
60
70 20
30
40
50
60
70 20
30
40
50
60
70
STAIS
Rehm and Marshall 2012
Effect of Stress Perception on Immune Balance
in Normal Marathon Runners
Log(Th1/Th2) vs PSS with fitted lines over visit
with outlier
Post
Baseline
Post
3
2
-1
0
1
Log(Th1/Th2)
3
2
1
0
-1
Log(Th1/Th2)
Pre
4
Pre
4
Baseline
w/o outlier
0
10 20 0
10 20 0
PSS
10 20
0
10 20 0
10 20 0
10 20
PSS
Rehm and Marshall 2012
Effect of Anxiety on Immune Balance in
Normal Marathon Runners
Log(Th1/Th2) vs Stais with fitted lines over visit
with outlier
Post
Baseline
Post
3
2
-1
0
1
Log(Th1/Th2)
3
2
1
0
-1
Log(Th1/Th2)
Pre
4
Pre
4
Baseline
w/o outlier
20 40 60 20 40 60 20 40 60
20 40 60 20 40 60 20 40 60
Stais
Stais
Rehm and Marshall 2012
Immune Effects of Chronic Stress
Effect of exam stress on the type-1/type-2 cytokine balance
in normal medical students
IL-10 (pg/ml)
2000
40000
20000
1500
1000
p = 0.003
500
0
0
Pre Exam
Pre Exam
Post Exam
IFN-g : IL-10 Ratio
IFN-g (pg/ml)
60000
100
80
60
40
20
0
Post Exam
p = 0.007
Pre Exam
Post Exam
Marshall et al. 1998
Pre Exam Daily Hassles Scale Predicts
Degree of Stress-induced Cytokine Change
120
IFN-g : IL-10 Ratio
100
80
60
**
*
40
20
0
Pre Exam
Low Hassles
Post Exam
High Hassels
* pre vs. post exam : p = 0.03
** low vs. high Hassles : p = 0.02
Marshall et al. 1998
Treg Cells in PBMC of Normal Volunteers Reporting
High vs. Low Chronic Stress Perception
1.40
Treg
1.20

*
1.00
0.80

0.60
Error Bars show 95.0% Cl of Mean
* p<.01
Low Stress
High Stress
PSS Groups
Marshall et al. 2008
TGF in PBMC of Normal Volunteers Reporting
High vs. Low Stress Levels
Error Bars show 95.0% Cl of Mean
2.00
TGF
1.50
* p<.05

*
1.00

0.50
Low Stress
High Stress
PSS Groups
Marshall et al. 2008
Adrenal Response to Stressor
Plasma Cortisol
Hyperresponse immunosuppressant
Normal response
Hyporesponse hypersensitivity
Time
Stressor
Adapted from Sternberg 2002
Possible Mechanisms for
Variable Stress Susceptibility

Genetic
– SNPs that increase or decrease hormone effects (binding affinities)
– Differential production of stress hormones
– Differential expression of stress hormone receptors on different cells

Endocrine
– Different receptor-ligand interactions
 Hormonal
 Immune

Available cell populations
– Regulatory vs effector
– Previous sensitization
– Other environmental modifiers
Stress and Disease
Possible Mechanisms

Altered perception of severity of illness

Promote bad behaviors
– Overeating
– Substance abuse
– Sedentary existence
– Poor relaxation/sleep habits

Direct physiological effects
Can Stress Worsen Existing Disease?
Effect of Pain Severity on Immune Biomarkers
in Patients with Sickle Cell Anemia (n=72)
0
.1
.2
.3
.4
.5
40
0
10
20
30
40
30
0
10
20
30
20
10
0
Pain Severity
40
Pain Severity by Biomarkers at V1
0
10
1
2
3
TH2
4
10
5
6
20
30
40
40
0
10
20
30
40
30
10
0
0
0
TH1
20
30
20
10
0
Pain Severity
30
IL6
40
IL1beta
20
0
10
20
30
40
TH1/TH2
50
60
0
5
10
15
TREG
Marshall and Philips 2012
20
25
Influence of Stress Perception on Relationships between
Pain Severity and TH1/TH2 ratio in SCD Patients
-10
Linear Prediction
0
10
20
30
Predictive Margins
0
10
20
30
40
50
60
Th1/Th2
Marshall and
PSS
4
8
16
25
35
Philips 2012
Influence of Anxiety Tendency on Relationships between Pain
Severity and TH1/TH2 ratio in SCD Patients
0
Linear Prediction
20
40
60
80
Predictive Margins
0
10
20
30
Th1/Th2
40
50
60
Marshall and
STAIT
5
10
15
20
Philips 2012
Can Stress Cause Disease?
Human Disease
Genes
Environment
Vs.
Hypothetical Relationships between
Stress and Inflammatory Diseases

Genes controlling anxiety and depression also control inflammation
associated with onset of disease

Individuals with altered inflammatory episodes [i.e. infections,
hypersensitivity] release cytokines/inflammatory factors that
promote/cause anxiety and/depression in susceptible individuals

Recurrent/chronic anxiety/depression alters the immune milieu
such that subsequent exposure to antigens [self or foreign] /other
substances sets up the inflammatory network necessary to develop
the inflammatory disease

High stress periods increase likelihood of infectious/inflammatory
exacerbations
DNA Repair Capacity in Healthy Medical Students Before and
After Exam Stress Cohen L, Marshall GD, et al. J Beh Med 23:531, 2000
44
Spirituality and Health
Spirituality

The way people find meaning and purpose and how they
experience their connectedness to self, others, the significant or
sacred

A universal human characteristic

One’s relationship with the transcendent expressed through
attitudes, habits and practices

Manifestations include religion, arts and humanism, cultural beilefs
and practices

The inner life of a person
Puchanski 2012
Spiritual Diagnoses from the Medical History
Pulchalski CM . Ann Oncol
Spirituality and Health
Is There Evidence?


Spirituality provides psychological comfort but does it provide health benefits?
Ironson-Woods Spirituality/Religiousness Index
– Captures public and private expression of spirituality and religion
– Measures sense of peace, faith in God, religious behavior, compassion for others

Mortality risk  25% in worship service attendees (Powell 2003)

Worship service attendees compared to nonattendees protected again CVD over
8 yrs (n=21204)(Hummer 1999)

Older adults who regularly attend worship services have lower mortality and Il-6
independent of age, sex, BMI, physical illness including hx of CVD, depression
(Lugendorf 2004)
Stress, Immunity and Health
Potential Applications in Caring for the Astronaut Corps

Spaceflight is stressful
– Physical stresses of micro vs zero gravity
– Isolation/social challenges of long term flight
– Nutritionl/radation/toxin exposure issues

Mission dynamics make adequate rest/relaxation challenging
– Potentially subjugates the mental/spiritual components of the individual

Astronauts become less “healthy” as flight duration increases
– Physical deconditioning over time
– Adequate nutrition can decrease /metabolic issues tend to increase over time

All these factors can increase adverse stress effects on health
Stress, Immunity and Health
Future Studies for Integrative Based Interventions

Identifying cause/effect for specific types of stress and disease risk

Identifying stress “susceptible” individuals





genetic markers (starting with family history)
Genomic patterns, SNPs
Immunoregulatory profiles
psychological profiles
Identifying psychological intervention “responders”



underlying psychological dysfunction
suggestibility
role for routine psychological screening

Influence of environmental factors – internal and external

Interventional studies – Integrative approach


psychological, physiological, pharmacological, alone or in combination
specific parameters
 defined clinical outcomes
 identified subpopulations
 confounders and comorbidities/exposures
Acknowledgements

Lianbin Xiang, MD

Kristina Rehm PhD

Denise Montgomery MT(ASCP)

Sheila Belk , CCRC

Okan Ulci PhD

Michael Griswold PhD

Kathryn Hahn PhD
“A glad heart heals like a medicine
but a broken spirit dries the bones…”
Prov 17.22
gmarshall@umc.edu
52