Psychoneuroimmunology

Report
Psychoneuroimmunology
Margaret E. Kemeny, Ph.D.
Jason Satterfield, Ph.D.
Stress and Coping Assessment:
A Caregiver Case Example
Objectives:
-“Pull forward” stress & disease basics from
MS1
- Illustrate clinically-relevant strategies to
assess stress and coping prior to learning PNI
basics
Mark Simmons is a 62yo man
who was diagnosed with
Alzheimer’s Disease at the age
of 58. Prior to that time he
worked full time as a civil
engineer. He and his wife
Marsha (aged 56) live at home.
Marsha works part-time at
home as an accountant as well
as serving as Mark’s primary
care-giver.
Both Mark and Marsha are your
patients. Marsha has been
having frequent URI’s and
appears worn and fatigued.
How Can Stress Cause
Disease?
What should trigger a stress
and coping assessment?
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Signs of emotional distress,
depression, or anxiety
Multiple somatic complaints –
insomnia, appetite, pain, fatigue
Frequent colds, infections, slow
healing times
Stressor onset or change
Stress Assessment
Step 1: Ask about frequency
“How often have you felt nervous or
stressed out in the past month?”

Step 2: Ask about cause (i.e. stressor)
“What’s been causing you to feel
stressed out?” Be sure to ask, “And is
there anything else?”

Frequency: “I feel stressed
out nearly all the time. It’s
just so hard for us right
now.”
Stressor 1: Caregiving,
grief for husband
Stressor 2: Ms. Simmons
is worried about her own
health.
Stressor 3: Finances are
worrisome but not at crisis
point.
Stress Assessment
Step 3: Ask about duration
“How long has this been going on?”
 Step 4: Ask about impact
“How has this stress been affecting you?”
Be sure to ask about both the social
and occupational domains – “How has
it affected your relationships? Your
performance at work? Any other
effects?”

Stress Assessment
Step 5: Ask about coping strategies
“What have you been doing to cope
with this stressful situation? How well
has that been working for you?”

Be sure to ask, “How can we help you
get through this difficult time? What
would be most helpful for me to do
right now?”
Duration: Mr. Simmons began
having difficulties about 4-5 years
ago. In the past year, the
caregiving demands have been
rapidly escalating. Ms. Simmons
has been ill herself over the past 68 months. Their financial stress is
just now starting.
Impact: Ms. Simmons has trouble
sleeping, fatigue, irritability, and
frequent colds/URI’s. She neglects
her health, avoids some of her
friends, and had to cut way back on
her accounting job.
Coping strategies: She uses an
in-home health aid 20hrs/wk. She
watches TV late at night to relax.
She keeps a journal when she has
time.
Stress Assessment Recap

Be sure to ask about the 5 elements
– Frequency
– Cause
– Duration
– Impact – include social and occupational
– Coping – the good, the bad, and how we
can help
Our Plan for Ms. Simmons?
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Schedule f/u appt for 1-2 wks to discuss adjunctive
tx or stress management programs.
Give her a depression screener to complete before
next visit.
Give referral to social work to arrange respite and
assist with shared care scheduling.
Give URL for local support group and ask her to
consider joining. Will discuss next time.
“Watchful waiting” re insomnia and other somatic sx
possibly related to stress (no meds yet)
How Can Stress Contribute
to Disease?
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2
Psychoneuroimmunology:
Investigations of the bidirectional linkages between the CNS, the
endocrine system and the immune system, and the clinical
implications of these linkages.
3
STRESSOR
NO
MODERATING VARIABLES
Genetic predisposition
Previous life experiences
Coping
Social support
Psychological Stress?
YES
HYPOTHALAMIC
ACTIVATION
CRH
PITUITARY FACTORS
ACTH
SYMPATHETIC ACTIVATION
Norepinephrine
Medulla
GLUCOCORTICOIDS
Cortex
Adrenal Glands
IMMUNE SYSTEM
EPINEPHRINE
4
Noradrenergic fibers innervate
immune organs (lymph node,
thymus, spleen, bone marrow)
• Release NE in close proximity to
immune cells (greater density in T
cell areas)
• Leukocytes express a and b
adrenergic receptors
• NE and E can influence leukocyte
activity e.g., macrophage
production of TNFa
NE and epinephrine can alter lymphocyte
migration:
Immediate exposure (30 min)
Longer exposure (days)

# lymphocytes,
natural killer cells
# natural killer cells
5
6
NE can alter innate and adaptive immune
function in organs and in circulation:
– “Fine tunes” immune responses, allowing
for quick adjustments (within minutes)
– Shift from Th1 to Th2
7
STRESSOR
NO
MODERATING VARIABLES
Genetic predisposition
Previous life experiences
Coping
Social support
Psychological Stress?
YES
HYPOTHALAMIC
ACTIVATION
CRH
PITUITARY FACTORS
ACTH
SYMPATHETIC ACTIVATION
Norepinephrine
Medulla
GLUCOCORTICOIDS
Cortex
Adrenal Glands
IMMUNE SYSTEM
EPINEPHRINE
8
Leukocytes express glucocorticoid receptors;
cortisol acts on glucocorticoid receptors to have the
following effects (as with synthetic GCs):
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inhibit lymphocyte proliferation
inhibit production of pro-inflammatory
cytokines
Shift from Th1 to Th2 cell activity by
stimulating synthesis of IL-10, IL-4
9
Definition of Stressors

Stressors:
environmental or internal demands
which tax or exceed a person’s
resources
10
Stressor Time Windows
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Immediate acute phase (within minutes of
stressor onset); the “fight/flight” response
Short-term stressors (that last for days or weeks)
– Ex.: exams*, moving, being fired

Chronic stressors (that last for months or years)
– Ex.: caregiving for a family member with Alzheimer’s
Disease, marital discord, poverty
11
Innate Immune System Mobilization in the
Immediate Acute Phase of a Stressor
(fight/flight): min to hrs post stressor onset

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Redistribution of immune cells (increase in
leukocytes in blood)
Increase in innate, non-specific immunity
(increased NK cell activity)
(Decrease in specific immunity)
Alterations in Specific Immunity following
Exposure to Short-term Stressors:
days or weeks post stressor onset

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Decrease in Th1 cellular immune response
(e.g., proliferative response of
lymphocytes)
Increase in Th2 humoral immunity (e.g.,
Th2 cytokine production)
12
13
Alterations in Non-specific and Specific Immunity
following Exposure to Chronic Stressors:
months to years post stressor onset
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Decrease in both Th1 cellular and Th2 humoral
immune response (e.g., lower antibody titers to
hepatitis B vaccines*)
Decrease in innate, non-specific immune
responses (except inflammatory activity)
Persistent inflammatory activity (e.g., increased
pro-inflammatory cytokine production)
*antibody response can be enhanced with stress reduction intervention
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Effects of Stress on the Immune System
Depend not Only on Timing but
Characteristics of the Person

Immune effects are stronger in those
who:
– Are older
– More depressed
– Less supported
Health behaviors (below) are affected by
stress but immune effects of stress exposure
are not due only to these effects.
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Drug use
Alcohol Use
Exercise
Diet
Medication adherence
Sleep loss
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Sympathetic Nervous System (SNS) mediation of
immune effects of immediate acute phase of stressors
(minutes to hours): the fight/flight response
17
SNS mediation of immune effects of immediate
acute phase stressor—parachute jump
18
19
Figure 3
• NK cell # (CD16, CD56)
and activity increased
with jump
•Effect abolished with badrenergic antagonist
•NE levels correlated
with NK cell # and
function
• Similar effects in studies
of acute stressors in the
laboratory
•This and other studies
show that NE is a critical
mediator of the immune
effects of the immediate
fight/flight phase of the
stress response
20
Hypothalamus
CRH
Anterior Pituitary
ACTH
Adrenal Cortex
Cortisol
Certain stressors can activate
the HPA (more selective
activation than ANS)-causing
increased release of cortisol
in blood, saliva an urine
Stressors
 immediate-acute phase
 Short-term-days/weeks
 Chronic-months/years
HPA appears to be an important
mediator of effects of short-term and
chronic stressors on the immune
system
Hypothalamus
CRH
Cortisol suppresses
immune functions such
as pro-inflammatory
cytokine production via
the glucocorticoid
receptor (GCR).
Anterior Pituitary
ACTH
Adrenal Cortex
Cortisol
GCR
Immune Cell
21
22
Hypothalamus
CRH
Anterior Pituitary
But stress-> INCREASES proinflammatory cytokine production
One mechanism: Glucocorticoid
Resistance: stress induced
downregulation of GCR; cortisol
cannot restrain pro-inflammatory
cytokine production so cytokine
production increases (animal/human
studies)
ACTH
Adrenal Cortex
Cortisol
GCR
Immune Cell
23
Glucocorticoid Resistance: Decreased ability for
dexamethasone to suppress IL-6 production in vitro in
chronically stressed individuals (parents of children with
cancer)
Miller et al., 2002
24
Are these stress-induced immunologic
changes clinically significant?
Do they contribute to disease onset or
accelerate disease course?
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Above: A 3.5-mm mucosal wound used to
study delayed closure associated with stress and immune
mechanisms of effect.
26
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Healing time (as measured by response to hydrogen peroxide) is shown for each of the
11 subjects for the two time periods, summer vacation and examinations. Also high
stress increased susceptibility to opportunistic bacterial infections in the wounds.
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Mediators of Stress-related Changes
in Wound Healing
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diminished mononuclear cell trafficking to
the wound site
reduced expression of cytokine, chemokine,
growth factor genes
decreased production of pro-inflammatory
cytokines in wound environment*
How Might Information From the Field of
Psychoneuroimmunology Influence
Your Clinical Practice?
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Ask about life stressors (short term and chronic), impact on
functioning
Ask about how a pt is coping, social supports. “Does it help?”
Recognize that test results during chronically stressful times
could be unreliable (repeat testing?)
Recognize that vaccinations may be less protective during
stressful times (consider other precautions)
Recognize that wound healing may be influenced by stress
Recognize that immune functions may be affected by the use
of drugs that influence the ANS or glucocorticoids (e.g., bblockers).
Ask about therapy and make recommendations and/or
referrals as needed (know what is available in the
community).
recognize the limitations in knowledge when patients ask
about whether a given therapy (visualization, etc) can improve
their immune system.
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