Psychoneuroimmunology

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Psychoneuroimmunology
Margaret E. Kemeny, Ph.D. Jason Satterfield, Ph.D.
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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

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Mark Simmons is a 62yo man who was diagnosed with
Alzheimers 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 Marks primary
care-giver. Both Mark and Marsha are your
patients. Marsha has been having frequent URIs
and appears worn and fatigued.
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How Can Stress Cause Disease?
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What should trigger a stress and coping
assessment?

• Signs of emotional distress, depression, or
  anxiety
• Multiple somatic complaints insomnia, appetite,
  pain, fatigue
• Frequent colds, infections, slow healing times
• Stressor onset or change

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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)
• Whats been causing you to feel stressed out?
  Be sure to ask, And is there anything else?

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Frequency I feel stressed out nearly all the
time. Its 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.
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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?

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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?

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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
6-8 months. Their financial stress is just now
starting. Impact Ms. Simmons has trouble
sleeping, fatigue, irritability, and frequent
colds/URIs. 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.
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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

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Our Plan for Ms. Simmons?

• 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)

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How Can Stress Contribute to Disease?
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Psychoneuroimmunology Investigations of the
bidirectional linkages between the CNS, the
endocrine system and the immune system, and the
clinical implications of these linkages.
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• MODERATING VARIABLES
• Genetic predisposition
• Previous life experiences
• Coping
• Social support

STRESSOR
Psychological Stress?
YES
NO
HYPOTHALAMIC ACTIVATION
CRH

• PITUITARY FACTORS
• ACTH

• SYMPATHETIC ACTIVATION
• Norepinephrine

EPINEPHRINE
GLUCOCORTICOIDS
IMMUNE SYSTEM
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• 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

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NE and epinephrine can alter lymphocyte
migration
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• Immediate exposure (30 min)? lymphocytes,
• natural killer cells
• Longer exposure (days) ? natural killer
  cells

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NE can alter innate and adaptive immune function
in organs and in circulation
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• Fine tunes immune responses, allowing for quick
  adjustments (within minutes)
• Shift from Th1 to Th2

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• MODERATING VARIABLES
• Genetic predisposition
• Previous life experiences
• Coping
• Social support

STRESSOR
Psychological Stress?
YES
NO
HYPOTHALAMIC ACTIVATION
CRH

• PITUITARY FACTORS
• ACTH

• SYMPATHETIC ACTIVATION
• Norepinephrine

EPINEPHRINE
GLUCOCORTICOIDS
IMMUNE SYSTEM
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Leukocytes express glucocorticoid
receptorscortisol 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

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Definition of Stressors
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• Stressors
• environmental or internal demands which tax or
  exceed a persons resources

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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
  Alzheimers Disease, marital discord, poverty

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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)

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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)

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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
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• Immune effects are stronger in those who
• Are older
• More depressed
• Less supported

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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
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SNS mediation of immune effects of immediate
acute phase stressorparachute jump
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Figure 3

• NK cell (CD16, CD56) and activity increased
  with jump
• Effect abolished with b-adrenergic 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

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Hypothalamus
Certain stressors can activate the HPA (more
selective activation than ANS)-causing increased
release of cortisol in blood, saliva an urine
CRH
Anterior Pituitary

• Stressors
• immediate-acute phase
• Short-term-days/weeks
• Chronic-months/years

ACTH
Adrenal Cortex
HPA appears to be an important mediator of
effects of short-term and chronic stressors on
the immune system
Cortisol
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Cortisol suppresses immune functions such as
pro-inflammatory cytokine production via the
glucocorticoid receptor (GCR).
Hypothalamus
CRH
Anterior Pituitary
ACTH
Adrenal Cortex
Cortisol
Immune Cell
GCR
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Hypothalamus
But stress-gt INCREASES pro-inflammatory 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)
CRH
Anterior Pituitary
ACTH
Adrenal Cortex
Cortisol
Immune Cell
GCR
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Glucocorticoid Resistance Decreased ability for
dexamethasone to suppress IL-6 production in
vitro in chronically stressed individuals
(parents of children with cancer)
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Miller et al., 2002
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• 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 tostudy
delayed closure associated with stress and
immune mechanisms of effect.
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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

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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., b-blockers).
• 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.