Introduction to The Concept of Stress

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STRESS and IMMUNITY REVIEWS 10-9-06
Papers Sternberg, 2006 and Elenkov et al., 2005
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GENERAL PRINCIPLES

• Bi-directional communication between CNS and
  Immune System (IS)
• Cytokines signal brain responds
• Brain signals immune system responds
• Receptors on immune cells -- neurotransmitters,
  neuropeptides, neurohormones
• Neural factors immune-cell maturation

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GENERAL PRINCIPLES

• CNS-IS immediate nonspecific host defense
• CNS rapidly responds
• CNS activate same secondary signaling pathway
• G-protein-coupled receptors
• IS mediators interact w/ neurotransmitters
• IS mediators modulate neural pathways
• Neuropeptides (CNS) trigger pro-inflammatory
  mediators

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BI-DIRECTIONAL COMMUNICATION

• Homeostasis of the IS
• Cytokine-dependent
• Chemical messengers
• Cytokines autocrine, paracrine, endocrine
• Proliferation
• Differentiation
• Activity

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CNS REGULATION of IMMUNITY

• Systemic, regional, local sites
• Peripheral NS first line at local sites of
  inflammation
• Neuropeptides increase responses
• SNS PNS inhibit at regional level
• Innervation of immune organs

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CNS REGULATION of IMMUNITY

• Neuroendocrine responses at systemic level
• HPA anti-inflammatory
• HPG sex hormones
• HPT thyroid hormone

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CYTOKINES and IMMUNITY

• Mediate and control immune and inflammatory
  responses
• Common diseases disruption in cytokine balance
  specifically, Th1 and Th2 cytokines
• anti- vs. pro-
• Th2 shift protects overshooting w/ Th1 cytokines

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HPA-MEDIATED IMMUNITY

• Feed-back loop for inflammation
• Blunted HPA
• Autoimmune Diseases
• Inflammatory Diseases
• Excess HPA activity chronic stress
• Increase susceptibility to viruses
• Prolong wound healing
• Reduced vaccine efficacy

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HPA-MEDIATED IMMUNITY - Glucocorticoids major role

• Important physiological mediator
• Inflammation anti-inflammatory
• Inflammation- and glucocorticoid-resistant
  death
• Balance immune homeostasis
• Regulate immune-cell function
• Shift adaptive responses
• Th1 to Th2 via inhibition of IL-12
• Enhance DTH

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HPA-MEDIATED IMMUNITY - Glucocorticoids major role

• Affects innate immune-cell function
• Suppresses maturation, differentiation,
  proliferation
• Inhibit cytokine chemokine secretion
• Inhibit receptor expression (adhesion molecules
  chemokine receptors)
• Regulate innate responses (infection bacterial
  and viral)

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BALANCE of GLUCORTICOIDS REQUIRED for IMMUNE
HOMEOSTASIS
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SNS CONTROL of IMMUNITY

• Regional level -- innervation of immune organs,
  release norepinephrine
• Pathogen activates innate inflammatory response
• Innate cytokine released
• Stimulate SNS to release norepinephrine and
  others
• Inhibits NK macrophage cytokine production
• Negative feedback inhibition dampens
  inflammatory response
• Restores homeostasis

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SNS CONTROL of IMMUNITY

• Increase immune and pro-inflammatory responses
• Norepinephrine inhibitory effects (mostly)
• NPY regional regulation and systemic w/
  epinephrine
• Majority systemic effects are anti-inflammatory,
  some increase inflammation

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PSN CONTROL of IMMUNITY

• Modulate inflammation via vagus nerve, regional
  level
• Signals to brain via IL-1 receptor (afferent)
• Acetylcholine release and negative-feedback
  (efferent)
• Neurotransmitter is acetylcholine
• Mostly dampens inflammatory responses

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Peripheral NS CONTROL of IMMUNITY

• Local regulation via neuropeptides
• CRH, Substance P (SP), calcitonin gene-related
  peptide (CGRP) regulate inflammation
• Expressed at sites
• Pro-inflammatory
• Favor pathogen clearance
• Others Opioids, VIP, a-MSH

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SCHEMATIC of INTERACTIONS BTWN NEUROPEPTIDES and
CYTOKINES Local Responses
Elenkov et at., 2005 Neuroimmunomodulation
12255-269