Download Kuby Immunology 6/e - Dr. Jennifer Capers, PhD

Chapter 14
Immune Response in Space and Time
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
○ Cytokines that are responsible for movement
of immune cells
Small polypeptides
 Some involved in inflammation, some
involved in homeostatic roles (“house
keeping”)
 Induce adherence of leukocytes to
endothelial lining

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