Psychoneuroimmunology: the interaction between brain, behaviour and immunity

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Psychoneuroimmunology the interaction between
brain, behaviour and immunity

• Module Health Psychology
• Dr Rebecca Knibb

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Aims of the session

• Critically review empirical evidence linking
  psychological factors to changes in the immune
  system with reference to
• Conditioning of the immune system
• Stress and the immune system
• Measuring immune changes, in particular how
  psychological factors can affect wound healing

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Psychoneuroimmunology (PNI)

• PNI is the study of the interaction between
  behaviour, neural and endocrine function and the
  immune system
• Research over the last 25years has shown that the
  immune system is influenced by the brain and that
  behaviour, the nervous system and the endocrine
  system are influenced by the immune system

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• The immune system has the capacity to learn
  through classical conditioning and can be
  affected by acute and chronic stressors
• State of mood such as depression or positive
  thinking and ways in which stress is coped with
  are also thought to have an effect on the immune
  system

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The immune system

• Bodies chief defence against disease
• The immune system is a body-wide network of cells
  and organs that has evolved to defend the body
  against attacks by "foreign" invaders.
• Foreign substances such as viruses and bacteria
  (pathogens) are destroyed
• Infected or malignant bodily cells are eliminated
• Internal checks on cell division is carried out
  (immunosurveillance)
• Tissue damaged through injury is repaired

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• The immune system can recognize many millions of
  distinctive non-self molecules, and it responds
  by producing molecules such as antibodies that
  can match and counteract each one of the non-self
  molecules
• Antibodies are immune system-related proteins
  called immunoglobulins (Igs) Igs are divided
  into five classes based on antigenic structural
  differences. In PNI research IgA is measured in
  saliva, known as salivary immunoglobulin A or
  sIgA.
• Any substance capable of triggering an immune
  response is known as an antigen. Antigens are
  normally proteins and can form part of a pathogen
  such as a virus, but can also be found in food
  such as peanuts.

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Organs of the immune system
The organs of the immune system are stationed
throughout the body. They are known as lymphoid
organs because they are concerned with the
growth, development, and deployment of
lymphocyteswhite blood cells that are key
operatives of the immune system.
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Lymphatic System The organs of the immune system
are connected with one another and with other
organs of the body by a network of lymphatic
vessels similar to blood vessels. Immune cells
and foreign particles are conveyed through the
lymphatics in lymph, a clear fluid that bathes
the body's tissues.
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Lymph Node Lymph nodes are small, bean-shaped
structures that are laced throughout the body
along the lymphatic routes. Lymph nodes contain
specialized compartments where immune cells
congregate, and where they can encounter
antigens.
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• Cells of the Immune System
• The most important cells that are used as markers
  for immune system changes in PNI research are
  lymphocytes
• T helper and T cytotoxic (killer) cells
• Natural Killer Cells (NK cells)
• B cells

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T Cells T cells contribute to the immune defences
in two major ways. Some help regulate the complex
workings of the immune system, while others are
cytotoxic and directly contact infected cells and
destroy them.
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T helper cells are needed to activate many immune
cells, including B cells and other T cells.
Another subset of regulatory T cells acts to turn
off or suppress immune cells. Cytotoxic or
killer T cells help rid the body of cells that
have been infected by viruses as well as cells
that have been transformed by cancer. They are
also responsible for the rejection of tissue and
organ grafts.
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Natural Killer Cells Another type of lymphocyte
killer cell are the natural killer cells (NK
cells). To attack, cytotoxic T cells need to
recognize a specific antigen, whereas NK cells do
not. Both types contain granules filled with
potent chemicals, and both types kill on contact.
The killer binds to its target, aims its weapons,
and delivers a burst of lethal chemicals.
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B Cells B cells work chiefly by secreting
antibodies. Each B cell is programmed to make one
specific antibody. When a B cell encounters its
triggering antigen (along with various accessory
cells), it gives rise to many large plasma cells.
Each plasma cell is essentially a factory for
producing that one specific antibody.
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Another important marker in measuring affects on
the immune system are Cytokines. These are
immune mediators secreted by various types of
activated TH (helper T) and other cells which
turn on selective portions of the immune
response.  Categories of cytokine
include interferons (which interfere with
viruses) interleukins (which communicate
between different populations of white cells)
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Measuring immune changes

• Enumerative measures
• Counting white blood cell populations
• Counting antibody populations in the blood or
  saliva
• Counting antibodies to specific pathogens or
  antigens
• Functional measures
• Assess how well a specific immune process is
  performed
• Assess a persons immune response to an antigen
  they are sensitive to

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Classical conditioning and the immune system

• Seminal work by Ader Cohen on rats (1975)
• Conditioned group given a saccharin-flavoured
  drink (CS) and an immunosuppressive (UCS)
• Non-conditioned group given plain tap water and
  an immunosuppressive
• Placebo group given plain tap water and injected
  with distilled water

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• All groups immunised with sheep red blood cells 3
  days later
• Conditioned group also given saccharin solution
• Non-conditioned group also given saccharin
  solution
• Placebo group also given plain tap water

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• Haemagglutinating antibody titres were measured 6
  days after immunisation
• High in non-conditioned group
• High in placebo group
• Conditioned group were immunosuppressed
• There was an association between immunosuppresion
  and the saccharin, such that when saccharin was
  given, an immunosuppressive response occurred.

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Conditioning in humans

• TB scratch test response can be conditioned to
  occur on the wrong arm (Smith Daniel, 1983)
• Conditioned alterations in immune functioning
  have been found in HIV-seropositive and at-risk
  gay men after interventions such as cognitive
  behavioural stress management and exercise
  (Esterling et al., 1992)

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Intense, acute stressors

• Immune dysfunction found in bereaved spouses up
  to 6 weeks after bereavement (Bartrop et al.,
  1977 Schleifer et al., 1983)
• Studies only had a few subjects (26 and 15)
• Subjects not very young
• Difficult to generalise results to people who
  suffer sudden bereavement

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• Sleep deprivation is associated with
  immunosuppression (Palmbold et al., 1979).
• Minor surgery temporarily associated with
  immunosuppression (Linn Jensen, 1983)
• Stress of exams can alter immune function, affect
  risk of infectious disease and duration of wound
  healing

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• Sarid et al. (2003)
• Academic stress and antibodies to the
  Epstein-Barr virus
• 54 female students
• Collected questionnaire data and saliva samples
  one month into 1st semester, during exams and one
  month into 2nd semester
• Questionnaires collected information on health,
  coping resources, social support, distress and
  anxiety

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• Results
• Anxiety and distress were significantly related
  to salivary antibody level increase during the
  exam period
• Levels of antibody decreased after the exam
  period and the stressor was over
• Coping resources were not associated with any
  changes in antibodies

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Laboratory studies

• CARDIOVASCULAR REACTIVITY TESTS
• Mental arithmetic
• Stroop test
• Speech stressor
• Acute exercise
• Unsolvable puzzle
• Self-disclosure
• Mood or fear induction
• Cold pressor test

• TRANSIENT IMMUNE CHANGES
• Increased NK cell activity
• Decreased lymphocyte proliferation assays

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Life events

• Individuals who have experienced more recent
  stressful life events may show greater immune
  change in response to minor stressors
• Men who reported more recent stressful life
  events had a greater cardiovascular stress
  response and greater decrease in natural killer
  cell function that lasted longer after a 12
  minute mental arithmetic task, than men with less
  life events (Pike et al., 1997)

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Severe chronic stressors

• Severe stressors may produce more long-term
  immune dysregulation
• Carers of people with Altzheimers show higher
  levels of stress and deficits in T-lymphocyte
  counts (Mills et al., 1999)
• Burn out, job strain and unemployment have all
  been linked to immune dysregulation (Lerman et
  al., 1999)

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Coping styles

• Coping styles have been linked to altered immune
  function (Esterling, 1990 Tutterman et al, 1996)
• Repression or denial
• Lower monocyte counts
• Higher eosinophil counts
• Higher serum glucose
• Reduced memory T-cell response to latent virus
• Escape-avoidance or concealment
• Increased B-cell counts

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Social support

• Support by social relationships can be a buffer
  when facing acute or chronic stress and can
  protect against immune dysregulation
• Low levels of social support when under job
  strain, as a caregiver, during surgery can lead
  to poorer immune function
• Disruption in social support through bereavement
  or divorce has consequences for immune functioning

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• Esterling et al. (1994)
• Social support and chronic stress in care-givers
• 14 caregivers of Alzheimers Disease, 17 former
  caregivers and 31 controls
• Measures taken for psychological distress,
  depressive symptomatology, perceived stress, NK
  cell response (in vitro)

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• Results
• Present and former carers did not differ in
  depressive symptomatology and perceived stress,
  but were more depressed and stressed than
  controls
• Present and former carers did not differ in their
  NK cell response, but had poorer response to
  cytokines than controls
• Physiological and psychological consequences of
  chronic stressors may persist beyond cessation of
  the actual stressor

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Health consequences

• Animal studies have demonstrated that stress can
  affect immune response and mortality rates
• Social stress and number of animals in a cage
• Rearranging the dominance hierarchy
• Change of housing in rhesus monkeys
• Social separation from familiar animals

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• Humans who are more stressed take longer to
  demonstrate immunity after vaccination
• Stressed individuals may also show a slower
  antibody response to other pathogens and may
  therefore be at greater risk for severe illness
  (e.g. Kiecolt-Glaser et al. 1996 and flu virus)

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• Greater fear or stress prior to surgery leads to
  poorer outcomes such as longer hospital stay,
  more post-operative complications and increased
  rates of re-hospitilisation (linn, 1988
  Kiecolt-Glaser et al., 1998)
• Stress impedes the immune response to infectious
  onslaught and increases the risk for contagion
  and increased episodes of illness
• Stress slows wound healing (Kiecolt-Glaser et
  al., 1998)

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Wound healing

• John Weinman, DHP conference 2003
• The immune system plays a key role in wound
  healing, regulating the 2nd and 3rd stages of
  tissue repair
• Stress (measured by the PSS and salivary
  cortisol) has been shown to slow wound healing
• Wound healing has been shown in some studies to
  respond to interventions such as emotional
  disclosure (cf studies by Pennebaker et al.)

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• Wounds have been examined in the literature in a
  number of ways
• Experimentally induced punch biopsy wounds, or
  skin blisters induced on the arm or hard palate
• Size assessed by photograph or fibreoptic camera
• Healing assessed by application of hydrogen
  peroxide applied to the wound
• Chronic or acute naturally occurring wounds
• Healing measured through clinical experience and
  acetate tracings

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Two types of injury occur in naturally occurring
wounds
Partial Thickness Injury - limited to the
epidermis and superficial dermis with no damage
to the dermal blood vessels. Healing occurs by
regeneration of epithelial tissue.
Full Thickness Injury - injury involves loss of
the dermis and extends to deeper tissue layers
and disrupts dermal blood vessels. Wound healing
involves the synthesis of several types of tissue
and scar formation.
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Chronic wounds are are a frequently encountered
problem in elderly and bedridden patients and are
produced by trauma or pathologic insult.
Characteristics of chronic wounds include a loss
of skin or underlying tissue and do not heal with
conventional types of treatment.
Example of a pressure sore
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Wound healing

• Wound healing is an extremely complex process
  which can be affected by a number of factors,
  including psychological factors such as stress,
  anxiety and depression
• The immune system plays a large role in the
  different phases of wound healing
• Tissue damage triggers the immune system to begin
  the healing process

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Phases of wound healing

• Inflammatory Stage cytokines are released and
  co-ordinate the release of neutrophils, monocytes
  and macrophages, which appear in large numbers at
  the wound site to clean the wound of debris and
  to stimulate fibroblast cells to produce
  collagen.
• Proliferative Phase - new blood vessels and
  collagen are laid down in the wound bed. The
  result of this process is referred to as
  granulation tissue. Contraction and
  epithelialization of the wound also
  occur.Maturation Phase - turnover and
  remodeling of collagen in the wound. This healing
  process results in the formation of a scar.

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Psychological factors in wound healing

• Cole-King et al., 2001
• Examined relationship between naturally occurring
  wounds, anxiety and depression
• Methods
• 53 participants (31 women 22 men)
• Examined chronic lower leg ulcers
• Wound healing rated on a 5 point likert scale and
  by acetate wound tracings
• Anxiety and Depression measured by HADS

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• Results
• Delayed healing associated with higher mean HADS
  score (plt0.05)
• Participants scoring over the cut-off for
  clinical anxiety and depression had delayed wound
  healing (plt0.05)
• Discussion
• Depression is associated with impairment of
  cellular and humoral immunity
• Stress can influence secretion of cytokines at
  wound site
• Psychological factors could have affected
  behaviour, eg eating, sleep
• Longitudinal research needed

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• Marucha et al., 1998
• Examined relationship between examination stress
  and mucosal wound healing
• Methods
• 2 punch biopsy wounds placed on hard palate of 11
  dental students
• 1st wound in summer holidays, 2nd just 3 days
  before a major exam
• Wound healing examined by daily photographs and
  foaming response to hydrogen peroxide
• Whole blood assays analysed for the cytokine
  IL-1ß
• Health-related behaviours and PSS scores taken

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• Results
• Students took on average 3 days longer to
  completely heal the 3.5mm wound during
  examinations (40 longer to heal)
• IL-1ß declined 68 during examinations
• PSS scores were higher during examinations than
  in the summer (plt0.01)
• Greater caffeine intake reported during exams
  (plt0.05)
• Less sleep reported during exams (plt0.01)
• However, health related behaviours were not
  reliably related to poorer healing

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• Discussion
• A relatively mild, transient stressor had a
  sizeable affect on wound repair
• Data suggest that other everyday stressors that
  elicit comparable emotional responses may produce
  similar deficits in wound repair
• Earliest stages of wound healing were affected,
  ie within 24 hours
• Stress may be affecting wound repair at every
  stage as IL-1 is involved in all stages
• Stress-related defects such as these could have
  important implications for surgical recovery

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Difficulties in PNI research

• Immune system is highly complicated and
  measurement techniques are not sensitive enough
• Difficulties in defining the concept of a
  psychological stressors
• Difficult to generalise from animal studies to
  humans due to our cognitive abilities to process
  stressors in different ways
• Emphasis on acute stressors, little research on
  chronic stressors and everyday hassles
• Lack of prospective studies

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Inadequacies of studies

• Failure to take adequate account of chronic or
  contextual factors
• Individual differences
• Complexity of the factors involved
• Relative lack of real longitudinal studies or
  adequate control groups
• Bias towards study of major acute stressors

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Conclusion

• Literature is generally supportive of a link
  between psychological factors and changes in the
  immune system
• A clear causal chain has yet to be established
  and there are inconsistencies across studies

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References

• Ader, R., Cohen, N. Felten, D. 1995.
  Psychoneuroimmunology interactions between the
  nervous system and the immune system. The
  Lancet, 345, 99-103.
• Kiecolt-Glaser, J.K., Maguire, L. Robles, T.F.
  Glaser, R. 2001. Emotions, morbidity and
  mortality New perspectives from
  psychoneuroimmunology. Annual Review of
  Psychology, 531, 83-107.
• Kiecolt-Glaser, J.K., McGuire, L., Robles, T.F.
  Glaser, R. 2002. Psychoneuroimmunology and
  psychosomatic medicine Back to the future.
  Psychosomatic Medicine, 641, 15-28.
• Miller, G.E. Cohen, S. 2001. Psychological
  interventions and the immune system A
  meta-analytic review and critique. Health
  Psychology, 201, 47-63.
• Sarid, O., Anson, O., Yaari, A. Margalith, M.
  2003. Are coping resources related to humoral
  reaction induced by academic stress? An analysis
  of specific salivary antibodies to Epstein-Barr
  virus and cytomegalovirus. Psychology, Health
  and Medicine, 81, 105-117.