chapter 13 leukocyte activation and migration dr. capers

Chapter 13

Leukocyte Activation and Migration

Dr. Capers

Kuby IMMUNOLOGYSixth Edition

Chapter 13Leukocyte Activation and

Migration

Copyright © 2007 by W. H. Freeman and Company

Kindt • Goldsby • Osborne

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

Inflammatory response○ Redness○ Heat○ Swelling○ Pain

Needs controlled migration of leukocyte populations

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

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

CAMs

MucinsSerine and threonine-rich proteinsBinding sites for selectins

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

CAMs

Ig-Superfamily CAMs (ICAMs)Immunoglobulin-like domainsBind to various integrin molecules

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

Chemokines

Chemokine receptors on leukocytes mediate leukocyte activity

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

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)

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

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

Lymphocyte Extravasation

Lymphocyte Extravasation

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

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

Some cytokines are inflammatory mediators

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

IFN-γ role in chronic inflammation

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