Sapolsky, Chapter 8

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Sapolsky, Chapter 8

• Review of Immunology
• Immunity, Stress, Disease

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Innate immunity

• Skin, mucous membranes, saliva
• Cough, sneeze, vomiting reflexes
• Acidic pH of tissues
• Fever
• Interferon and other substances released by
  leukocytes several plasma proteins
• Natural killer cells, macrophages CNS microglia
• Increase in capillary permeability
• Macrophages, other immune cells enter tissue.

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Acquired immunity

• Late in evolution only in vertebrates
• Born with capacity to respond, but defense is
  triggered only if organism had prior experience
  with the invader.
• Discovered by Edward Jenner (18th century)
• Injected a boy with pus from dairy maid w/ cow
  pox.
• Boy later exposed to small pox he didn't catch
  it.
• "Vaccination" derived from "vacca" (Latin for
  cow).

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Organs of immune system

• Lymphatic system
• Transport lymph interstitial spaces to blood
• Lymph nodes enlarged spaces where foreign
  substances are trapped phagocytized
• Spleen upper left abdomen
• Blood filter, storage for lymphocytes
• Large phagocytic cells devour old red blood
  cells, bacteria, cell particles, toxins
• Antibodies made and released here

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Lymph node
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Organs of immune system

• Thymus behind sternum (breast bone)
• Immature T cells mature here. 90 die because
  they recognize self proteins
• Bone marrow stem cells divide to produce immune
  system cells

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Major histocompatibility complex (MHC) proteins

• How does immune system know what to attack?
• Proteins on cell surface define self
• MHC I On surface of most cells? self
• MHC II On B cells, T cells, macrophages
  police badge of immune sys.

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Cells of immune system

• Macrophages (literally, big eaters)
• Ingest invaders, display epitopes to T cells
• Epitope smallest bit of antigen that can be
  recognized by immune cell
• Also secrete Interleukin-1, which activates T
  helper cells

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Macrophage (gray) approaching a chain of
Streptococcus pyogenes (yellow). On top of the
macrophage is a spherical lymphocyte.
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Natural Killer cell kills cells that do not
have Class I MHC on them
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B cells

• B is for bone, where they mature.
• Activated B cells produce antibodies to invaders
  epitopes.
• Some remain as memory cells, ready for next
  encounter w/ a similar invader.

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Antibodies

• Y-shaped structure
• Forms 2 claws into which epitope fits
• Variable region in claw interacts w/ epitope.
• Constant region confers specific function
• Clumping, making tasty for macrophage, etc.

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Antibodies (cont.)

• Problem Each individual can make 1 M to 1 B
  different antibodies.
• Each requires a complex genetic code. Not enough
  genes!

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Introduce variability by

• Genetic rearrangement Chinese menu 2 from
  column A, 3 from column B
• Genetic mistakes in making Abs (deliberately
  with a vengeance)
• B cell mutations Activation by epitope that
  doesnt fit exactly?proliferation w/ errors,
  some of which fit better than original
• evolution

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T cells

• Mature in thymus (hence their name)
• Cytotoxic T cells kill infected self cells
• Helper T cells activate B CD8 cells
• Suppressor T cells suppress immune response
  after infection is over
• Recognize antigen only if it is presented in
  combination with MHC protein on another cell

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Immune system cells

• Helper T cells
• Recognize MHC II molecules antigen
• MHC II molecules actually hold the antigen
• Activate resting B cells ? to secrete Abs.
• Also produce interleukins
• ? attracts macrophages
• ? proliferation of T cells

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Immune system cells

• Cytotoxic T cells
• Recognize MHC I self molecules portions of
  antigen on cell surface.
• Kills cells by injecting something that forms
  pores in membrane ? innards pour out
• Dont attack bacteria No MHC I molecule
• Dont attack normal self cells no foreign
  antigen
• Function Kill cells taken over by virus

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Brain immunity

• The brain has a vast potential for sticking its
  nose into the immune systems business.
• Actors negative vs. positive scenes ? decreased
  or increased immune response.
• Ader Cohen conditioned immune suppression

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Stress and immunity

• GCs shrink thymus (Selye)
• Inhibit maturation of T-cells
• Inhibit release of interleukins interferons
• ? Lymphocytes less responsive to invaders
• Also, kill lymphocytes (especially T-cells)
• Cause them to commit suicide.

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Stress and immunity

• WHY should stress shut down immune sys?
• First thought save energy.
• BUT Immune system actually spends energy
  disassembling itself!
• Immune sys ? interleukin 1 ? CRH ? ACTH ? GCs ?
  immune suppression

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Stress and immunity

• With short duration stressors, there is actually
  an increase in immune response.
• True for physical, psychological stressors, as
  well as infectious challenge.
• Due mostly to epinephrine
• Downturn after initial 30 rise, due to GCs.
• Baseline levels by 60
• Only continuing stress REALLY suppresses immunity.

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Stress and immunity

• Some of the decreases may not be harmful
• The cells being killed are older, less useful.
• Some cells are sent to front lines of injury.
• Sometimes autoimmune disease is worse with
  lengthy stressors may be due to repeated early
  phase increases.

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Why isnt the link between chronic stress and
illness stronger?

• Variable severity of stressors perception of
  stressfulness
• Retrospective studies
• Moderate increases STIMULATE immune system.
• Inhibition of estrogen testosterone decrease
  hormone-sensitive cancers.

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Why isnt the link between chronic stress and
illness stronger? (cont.)

• Minor fluctuations may not be critical.
• Immune system is complexcant measure all
  aspects of it.
• Laboratory studies usually study induced
  diseases.
• Most of us are only randomly exposed to pathogens
  or carcinogens.

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Social support and longevity

• Social isolation is as important a factor as
  smoking, obesity, inactivity, hypertension.
• 2.5 X rate of mortality
• Lonely people
• Less Ab response to a vaccine
• Faster decline with AIDS
• Less natural killer cell activity in women with
  breast cancer

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Social support and longevity

• Is the effect due to altered risk factors (taking
  worse care of themselves)?
• Is it because sickly people dont have energy to
  maintain relationships?
• NO controlled studies in humans and monkeys
  found an effect of social support.

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Bereavement

• Increased risk of death only in those with
  additional risk factors.
• Parents of killed soldiers who were already
  widowed or divorced.

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The common cold

• Controlled prospective study People rated how
  stressed they felt then exposed to rhinovirus
• More stress ? 3 X more colds
• Same finding with mice monkeys
• Subordinate animals got the colds.

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Cold is most common illness. By age 70, most will
have suffered an average of 200 colds and spent 3
years coughing and sneezing.
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AIDS
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• T helper cells are infected (a.k.a. CD4 cluster
  designation 4).
• 1 or more of viruss gp120 molecules binds
  tightly to CD4 molecule(s) on the cells surface
  ? conformational change in the gp120 molecule
  allowing it to bind to a co-receptor on the cell
  surface. The envelope of the virus and the cell
  membrane then fuse, leading to entry of the virus
  into the cell. The gp41 of the envelope is
  critical to the fusion process. Drugs that block
  either the binding or the fusion process are
  being developed and tested in clinical trials.

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(Dont worry about the details here!!!)
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Stress AIDS

• GCs increase infected lymphocytes grown in a
  dish.
• Norepinephrine (NE) ? easier for virus to invade
  cell, enhances its replication.
• Isolated monkeys infected w/ SIV
• Higher GCs
• Fewer Abs against the virus
• Higher mortality

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Stress AIDS

• Humans higher mortality with
• Denial coping style
• Minimal social support
• Socially inhibited temperament
• More stressors (especially loss of loved ones)
• Partly due to increased SNS activity (not GCs)
• Especially in socially inhibited people
• Therefore, stress seems to be a factor.

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Latent viruses

• Herpes virus causes cold sores, genital herpes
  enters cell may be latent for many years.
• Replicate when immune system is suppressed may
  be numerous bouts.
• The virus has a GC sensor!!!
• Also, if it gets into the brain, it causes
  hypothalamus to ? CRH ? ACTH ? GCs ? suppress
  immune system!!!

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Stress Cancer

• Rats controllable stress ? no effect
• Uncontrollable stress ? more virus-caused cancer.
• GCs had same effect as uncontrollable stress.
• Stress decreases natural killer cells
• GCs also increase new capillaries (angiogenesis),
  which deliver blood to tumor
• GCs increase glucose for tumor growth
• Tumor grabs glucose before muscles.

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Stress Cancer

• Animal studies used induced tumors.
• Humans little link with cancer onset.
• Early studies showing a link were retrospective
  or quasi-retrospective.
• Women working night shift had more breast cancer,
  but also had disruption of melatonin, which
  inhibits some cancers.

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Stress Cancer

• But optimism, assertiveness, social support can
  extend life in those who already have cancer.
• David Spiegel women w/ breast cancer
• He didnt think social support would help.
• But, it extended life 18 months.
• Later studies less or no effect
• Because hard to get controls not to have
  support?
• Less support ? fewer natural killer (NK) cells,
  but that did not predict survival.

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Stress Cancer

• Bernie Siegel all you need to survive to 100 is
  faith and the will to do so!
• His program was studied and found not to improve
  longevity.

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Postscript

• Crib death (SIDS)
• 19th century SIDS babies had larger thymuses
  than did normal babies.
• Therefore doctors shrank thymus by radiation.
• BUT normal babies had died of chronic
  diarrhea, malnutrition, tuberculosis, etc.
  (stress!)
• Therefore, doctors drew wrong conclusion did
  more harm than good.

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Main Ideas

• B-cells ? antibodies, remain as memory cells
• Antibodies bind to epitope of invader and assist
  in removal of invader
• T-cells
• Killer ? Kills infected self cells
• Helper ? activates other immune cells
• Suppressor ? shuts down response after invader is
  gone
• Natural killer cells can kill a variety of
  invaders (w/o MHC I) or infected self cells
  that have antibodies bound to them.

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Main Ideas

• Controllable stress can be good.
• Increases immune response
• Individual differences
• Perception of stress (half empty/half full)
• Social support