Transcript Chapter 13
Chapter 13
Leukocyte Activation and Migration
Dr. Capers
Kindt • Goldsby • Osborne
Kuby IMMUNOLOGY
Sixth Edition
Chapter 13
Leukocyte Activation and
Migration
Copyright © 2007 by W. H. Freeman and Company
Invaders infect our bodies
Cells of innate immune system arrive first
Adaptive immune response provides longer
protection
Leukocytes are constantly monitoring for
infection
When 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
Selectins
Membrane glycoproteins
Bind to specific carbohydrate groups
Interact with mucin-like molecules
Example:
○ P-selectin is stored in granule in endothelial
cell
○ Upon activation, granule fuses with membrane
so that p-selectin is expressed
CAMs
Mucins
Serine and threonine-rich proteins
Binding sites for selectins
CAMs
Integrins
Consist of α and β chains
Bind 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 domains
Bind 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 first
Bind to endothelium when E-selectin and P-
selectin are expressed by endothelium
Monocytes
Come 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 cells
HEVs – 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 lymphocytes
Migrate to secondary lymphoid tissue to encounter
antigen
○ Effector and memory lymphocytes
Home to regions of infection
Memory 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 fever
Increased production of WBCs
IFN-γ and TNF-α involved in chronic
inflammation
Contributes 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