Psychoneuroimmunology

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Psycho-neuro-immunology

• Bi-directional interactions amongst behavior, the
  immune, endocrine and central nervous systems

REMINDER Fire Alarm work and testing on
Saturday 3/3/07 in Psychology
k.doron_at_psych.ucsb.edu
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Overview

• Immune system basics
• The adaptive and acquired immune systems
• The Acquired (specific immune system)
• The Innate (nonspecific)
• The pathogen stress response
• Blood-borne signaling
• Neural signaling
• Cytokines and the acute stress phase
• Behavior and the Sickness response
• Stress, Immunity and Brain

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Acquired Immune System

• This is the antigen response (non-self invaders)
• Slow process (8-12 hours to mount effective
  response)
• T B lymphocytes must be produced for specific
  antigens
• Relatively recent adaptation (450 million years)

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Innate (nonspecific) Immune System
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Innate (Nonspecific) Immune System
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Innate (Nonspecific) Immune System

• First line of defense and important to
  immune-brain communication
• Phagocytes respond to a wide range of pathogens
  (a large receptive field)
• Macrophages release nitric oxide to interfere
  with the ability of cells to proliferate
• Communication with CNS, neural cascade

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Innate (Nonspecific) Immune System

• Activated macrophages release pro-inflammatory
  cytokines interleukin-1 (IL-1) ? and ?, IL-6 and
  TNF- ?.
• These play a key role in organizing and
  coordinating the immune response (highly varied
  communication molecules, showing autocrine,
  paracrine and endocrine functions).

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Innate (Nonspecific) Immune System

• Cytokines initiate the acute phase and
  inflammatory responses.
• Shift liver metabolism to produce acute phase
  proteins (reactants) such as C-reactive protein.
• C-reactive protein is part of inflammatory
  response. Implicated in diabetes, hypertension,
  cardiovascular disease.
• Prolonged inflammatory responsenot so good.

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Immune to Brain Communication

• The CNS responses are initiated by the immune
  system, probably via cytokines.
• Fever is detrimental to microbial growth.
  Temperature sensitive neurons in anterior
  hypothalamus raise core body temperature (CBT).
• Elevated CBT, in turn, helps facilitate immune
  responses (increase white blood cell production).

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Immune to Brain Communication

• The brain is told about infection by the
  periphery (other way around too?).
• IL-1? known to raise CBT.
• Peripheral administration of antibodies to IL-1?
  known to reduce fever by 50-60 (Dinarello, 1991).

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Blood-Borne Signaling

• Administration of IL-1B induced fever when
  administered intracerebroventricularly or
  directly into the ant. hypothalamus
• The brain expresses receptors for IL-1
• Blockade of IL-1 receptors in the brain blocks
  fever and other CNS-mediated responses to
  infection
• SO THEN..
• IL-1 communicates with the CNS first by building
  up at site of infection, then circulating in
  blood and crossing BBB to enter brain parenchyma
  and bind to IL-1 receptors.
• Some question about whether IL-1 too large to
  cross BBB
• Fever and sickness response ensues.

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Neural Signaling Immune-brain communication and
the Vagus Nerve (CN X)
Electrical stimulation of afferent vagus nerve
induces IL-1? expression in the brain
(hypothalamus hippocampus) and activates HPA
axis. Study performed on Adult male
Sprague-Dawley rats Hosoi et al, 2000
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Neural Signalling

• Immune system functions as a diffuse sense organ
  that communicates with the brain via the Vagus
  Nerve.
• IL-1? signals the brain via blood and neural
  routes
• Cytokines --gt Vagus Nerve --gt Nucleus Tractus
  Solitarius --gt Neural Cascade

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Neural Signalling

• Brain-immune system is a bi-directional loop.
• Pathogens bind to immune cells such as
  macrophages. IL-1? is released, Vagus nerve
  stimulation ensues, this activates NTS regions
  that control fever and HPA axis.
• Periphery immune cells affect CNS affects
  periphery immune cells

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Behavior

• The Sickness response

During infection, general activity, social
interaction, aggressive behavior, exploration,
sexual behavior, food/water intake decrease,
while pain sensitivity and sleep increase
Dantzer et al, 1993
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Behavior
Schematic from Maier Watkins, 1999
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Stress and Endocrine System HPA-axis (recall
lecture 6)
IL-1 is a potent activator of the HPA axis and
cortisol release from the adrenal cortex
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Stress, Immunity and Brain

• Sickness can be thought of as a motivational
  state
• Administration of IL-1 to female rats alters
  sexual behavior.
• Male rats show reduced mounting, intromission and
  ejaculation with LPS or IL-1 injected females
• Yirmiya et al, 1995

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Stress, Immunity and Brain

• Stressors do not have sites that bind to
  macrophages (Really? Yes, really)
• Then, the circuit may involve stressors
  increasing brain IL-1?
• Stressor may be able to tap the same immune-brain
  circuitry of the innate immune system response to
  pathogens

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Stress, Immunity Brain

• The ongoing work with finalizing the fire
  alarm/safety system continues and the contractors
  will be working in the Psychology building
  (existing) on Saturday, March 3, during the day
  testing all the components.

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Stress, Immunity Brain

• The cytokine-to-neural communication mechanisms
  might have been co-opted to function in the
  service of fight/flight, distal threat, i.e., to
  operate in an anticipatory fashion.

I have to give a presentation on Wednesday
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Stress, Immunity Brain
Psychological Stressors
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Stress, Immunity and Brain

• Acute stress enhances immune function, chronic
  stress results in reduction of immune responses.
• Chronic stress induces lymphocyte apoptosis
• Shi et al, 2003

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Conclusions and Summary

• I dont know what Im talking about
• The immune, central nervous, and endocrine
  systems have extensive bi-directional
  communication mechanisms.
• This is largely mediated by pro-inflammatory
  cytokines and CN X.
• The machinery of the innate immune system might
  respond to stress and psychological events as an
  anticipatory function designed to conserve energy.