Chapter 13 Leukocyte Activation and Migration Dr. Capers.
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Transcript of Chapter 13 Leukocyte Activation and Migration Dr. Capers.
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Chapter 13
Leukocyte Activation and Migration
Dr. Capers
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Kuby IMMUNOLOGYSixth Edition
Chapter 13Leukocyte Activation and
Migration
Copyright © 2007 by W. H. Freeman and Company
Kindt • Goldsby • Osborne
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Invaders infect our bodiesCells of innate immune system arrive firstAdaptive immune response provides longer
protectionLeukocytes are constantly monitoring for
infectionWhen detected, cells cross the blood barrier and
travel to site of infection
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Inflammatory response○ Redness○ Heat○ Swelling○ Pain
Needs controlled migration of leukocyte populations
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Our tissues are held together by molecular interactions
○ Cell adhesion molecules (CAMs)- Selectins, mucins, integrins, Ig-Superfamily CAMs
(ICAMs)Can be used by leukocytes to interact with tissues
For leukocytes to enter inflamed tissues, cells must adhere and pass between endothelial cells lining blood vessel - EXTRAVASATION
Endothelial cells can express certain leukocyte specific CAMs
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CAMs
SelectinsMembrane glycoproteinsBind to specific carbohydrate groupsInteract with mucin-like moleculesExample:
○ P-selectin is stored in granule in endothelial cell
○ Upon activation, granule fuses with membrane so that p-selectin is expressed
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CAMs
MucinsSerine and threonine-rich proteinsBinding sites for selectins
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CAMs Integrins
Consist of α and β chainsBind cell surface molecules involved with
cell to cell interactions
Leukocyte adhesion deficiency○ Autosomal recessive disease○ Characterized by recurrent bacterial infections
and slow healing
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CAMs
Ig-Superfamily CAMs (ICAMs)Immunoglobulin-like domainsBind to various integrin molecules
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Chemokines
Major regulators of leukocyte traffic Small polypeptides Some involved in inflammation, some
involved in homeostatic roles (“house keeping”)
Induce adherence of leukocytes to endothelial lining
CC subgroup and CXC subgroup
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Chemokines
Chemokine receptors on leukocytes mediate leukocyte activity
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Leukocyte extravasation Various cytokines and inflammatory mediators act on local
blood vessels 4 steps of extravasation:
○ Rolling, mediated by selectins○ Activation by chemoattractant stimulus○ Arrest and adhesion, mediated by integrins binding to
Ig-family○ Transendothelial migration
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Extravasation
Neutrophils are generally firstBind to endothelium when E-selectin and P-
selectin are expressed by endothelium
MonocytesCome in much later This is because it takes time for inflamed
endothelial cells to express CAMs (such as ICAM-1 and VCAM-1)
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Lymphocyte Recirculation○ Unlike other leukocytes, lymphocytes
recirculate continuously from blood to tissues to lymph (1 to 2 times a day)
○ Lymphocytes are antigenically committed○ This recirculation increases chances of
lymphocyte coming into contact with particular antigen
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Lymphocyte Extravasation○ Involves interaction of CAMs○ Ensures proper populations of B and T cell
make it into certain tissues○ Capillaries
Flattened endothelial cellsHEVs – high endothelial venules
- Areas of capillaries that have cells that are more cubodial in shape
- Express variety of CAMs
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Lymphocyte Extravasation
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Lymphocyte Extravasation
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Although lymphocyte extravasation is similar to neutrophils, different subsets of lymphocytes must make it into different tissues
○ Naïve lymphocytesMigrate to secondary lymphoid tissue to encounter
antigen
○ Effector and memory lymphocytesHome to regions of infectionMemory cells will tend to home to tissues in which
they first encountered antigen
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Other mediators of inflammation
Kinin System To the left of figure
Clotting system Fibrinolytic system
To the right of figure Complement system
○ Anaphylatoxins (C3a and C5a)
○ Release of histamines by mast cells
Some lipids Released by tissues from
damage
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Some cytokines are inflammatory mediators
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Inflammation response may be localized or systemic Localized Inflammatory Response
○ Duration and intensity must be carefully regulated to control tissue damage
Systemic Acute Phase Response○ Localized accompanied by acute phase response
Induction of feverIncreased production of WBCs
IFN-γ and TNF-α involved in chronic inflammationContributes to tissue wasting
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IFN-γ role in chronic inflammation
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Anti-Inflammatory Agents Antibody therapies can reduce leukocyte
extravasation○ Monoclonal Abs to CAMs
Corticosteroids○ Cholesterol derivatives○ Decreases number of circulating lymphocytes○ Reduces phagocytosis
NSAIDs○ Found in plants, aspirin○ Pain and inflammation○ Reduces prostaglandins, lowers vascular
permeability