Chapter 13- leukocyte migration and inflammation

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Chapter 13- leukocyte migration and inflammation

• Ill try VERY hard NOT to be inflammatory!!

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Where were going-lots of details, so well be
hitting the highlights

• Well frame the subject- LOTS of migration
  homing!
• Well learn some CAMs- cell adhesion molecules
• Well learn the neutrophil extravasation story,
  and see a video
• Well learn some inflammation components, and
  more of its value
• Well learn some anti-inflammatory drugs, and
  their targets.

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Lets go see whats inside!
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• Leukocytes(PMN's , Mphages, lymphocytes, mainly
  T) circulate in the blood, but often do their
  work in tissues.
• For T and B cells, circulation increases the
  chances that you'll meet your antigen.
• For both to do their jobs, however, you often
  have to leave the blood to enter either the lymph
  node or the site of damage.
• Once at the site of damage, you want to kill
  microbes, control the damage, and repair it.

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Lymphocyte recirculation- the circulate a LOT!

• Your average lymphocyte will make a complete
  circulation 1-2 times per day
• Increases the likelihood of meeting Ag.

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Key point- mostly activated lymphocytes that are
in the tertiary sites.
Remember, the gamma-delta lymphocytes are out here
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The CAMs- cell adhesion molecules- key players.
Integrins may need to be activated B4 they bind!
Think snot- and lectins- snot-binders!
ICAMs- Ig like VCAMs- ICAM on endothelial cells
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Neutrophil Extravasation
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Lots of cytoskeletal rearrangement to slip
through the endothelial wall.
The endotheliums inflamed!
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Lots of attractants- IL8, C5a, C3a, N-formyl
peptides!!!
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Lymphocyte extravasation homing

• Homing is VERY cool!

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HEVs- cuboidal rather than flat endothelial
cells 1-2 of venule area, 85 of migration!
14,000/sec!
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Key point- skin and intestinal endothelium are
not showing the same CAMs, nor are the effector
cells. Homing to tissue, less entry into lymph
nodes.
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For 3 days after activation, the T cells dont
leave the lymph node (shut-down phase).
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Note the similarities to the neutrophil story
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Inflammation-where were going

• Review-The purpose of inflammation is response to
  injury/infection-usually protective, although not
  always.
• The problem The components of protection-
  mphages, neutrophils, antibodies, complement- are
  mostly in the blood the damage is often NOT in
  the blood, but in tissues bathed in interstitial
  fluid. So inflammation gets the goodies where
  they are needed.
• It also isolates the damage, while bringing
  effectors to the site (mostly cells), from the
  blood.
• Acute inflammation five signs- heat, redness,
  pain, swelling, loss of function.- all related to
  blood vessel changes.

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Mediators of inflammation-injury, clotting,
complement all release them

• Injury-tissue damage usually accompanies
  bleeding- bradykinin, the fibrin clot, and its
  degradation all are inflammatory
• These parts interact w/complement (complement can
  be activated by microbes, of course)- C3a,4a,5a
  are inflammatory- activate mast cells, histamine,
  etc.

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More

• Tissue damage releases prostaglandins,
  leukotrienes- membrane components- damage
  activates enzymes that produce these.
  Inflammatory, and produce PAIN!
• The neutrophils and, particularly, the mphages
  produce cytokines that stimulate inflammation and
  a systemic response.

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Ask your doctor about
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Couldnt cover this w/o showing you a few
prostaglanins
These get whacked off p-lipids from the membrane-
the enzymes that do it are activated by signals,
damage, etc.
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And a few more
From Stryer, Biochemistry
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The mphages that come to the site produce
cytokines!
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Note the target of all these- the endothelial
cells
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Systemic responses

• IL1,IL6, and TNF alpha have systemic effects as
  well.

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These all help the innate response
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Chronic inflammation is BAD!

• Continuous Ag stimulation, or so we think
• Activated mphages and lymphocytes, producing
  granulomas and fused mphages- epithelioid cells.
  Fibroblasts are there, making collagen,
  interfering with function.
• Lymphocytes produce IFN gamma, that stimulates
  the mphages to produce TNFalpha- kills tumors,
  but chronic production produces wasting.

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Be glad YOURE not a transgenic TNF-alpha mouse!
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Anti-inflammatory drugs

• Experimental- Ab's against CAMs- now in clinical
  trials. Stops extravasation, so slows down
  inflammation
• Corticosteroids- from the adrenal cortex. These
  cause apoptosis of lymphocytes, reduction of
  phagocytic ability of mphages/neutrophils
• Non-steroidal anti-inflammatory drugs
• Aspirin, Ibuprofen, etc. ONE mechanism is
  inhibition of prostaglandin synthesis.

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This is the simple view- the other one is that it
also increases stroke risk. BIG lawsuit about
COX-2 inhibitors!
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What to know

• Lymphocyte circulation- they circulate, but the
  activated ones are out in the tertiary tissues.
• Extravasation story
• CAMs- Integrin-ICAM pair, mucin-seLectin pair
• Proinflammatory agents from tissue damage,
  clotting, complement
• Proinflammatory cytokines- IL1,6, TNFalpha
• Systemic response- fever, acute phase proteins,
  hematopoiesis
• Signs of chronic inflammation
• Anti-inflammatory drugs.