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Chapter 15
Leukocyte Activation
and Migration
Lymphocytes bind to the surface
of a high endothelial venule (HEV)
Dec 26, 2006
When an infection is detected, the cells of the
immune system cross the blood barrier and
travel to the site of infection.
How do leukocytes migrate to the tissue?
本章內容:
1. 參與白血球移動的分子及過程
2. 參與發炎反應的分子及生理變化
- For circulating leukocytes to enter inflamed tissue or
peripheral lymphoid organs, the cells must adhere to
and pass between the endothelial cells lining the walls
of blood vessels, a process called extravasation.
- Endothelial cells express leukocyte-specific celladhesion molecules (CAM)
- CAMs on leukocytes serve to adhere to vascular
endothelial cells and to increase the strength of the
interactions between cells of the immune system,
e.g., TH – APC, TH – B, CTL – target cells.
General Structures of the 4 Families
of Cell-Adhesion Molecules (CAM)
(ab heterodimers)
sialylated CHO moiety
L-selectin (CD62L)
P-selectin (CD62P)
E-selectin (CD62E)
Cell Adhesion Molecules (CAM)
(on endothelium)
(on endothelium)
(on neutrophil)
(on leukocyte)
(on inflamed
endothelium)
(CD54, CD102, CD50)
(CD106)
(on mucosal endothelium,
has both mucin-like and
Ig-like domains)
(lymphocyte Peyer's
patch adhesion
molecule-1)
Chemokines
1. Small polypeptides, most of which contain 90 – 130 a. a. residues
2. Control the adhesion, chemotaxis, and activation of leukocytes
– major regulators of leukocyte traffic.
3. Some are primarily involved in inflammatory processes, others are
constitutively expressed and play important homeostatic or
developmental roles.
4. Chemokine-mediated effects are not limited to the immune system.
5. The inflammatory chemokines are induced in response to infection
and recruit phagocytes and lymphocytes to inflammatory sites.
6. Four classes: CXC, CC, C, CXXXC (or CX3C)
7. Ligands: e.g., CXCL8,
Receptors: e.g., CXCR1
Chemokines Signal through Receptors
Coupled with Large G Proteins
(polypeptide chains traverse the
membrane 7 times)
Effects of Chemokines
1. Cell movement
2. Changes in cell shape
3. Promotion of adhesiveness to endothelial wall
4. Generation of microbicidal ·O - (superoxide anion)
2
in phagocytes
5. Release of proteases from neutrophils & macrophages
6. Release of histamine from basophils
7. Release of cytotoxic proteins from eosinophils
Differences in the Expression of Chemokine
Receptors by Leukocytes
CCR1, 2, 3
CCR1, 3
CCR1, 2, 4, CXCR4
CXCR1, 2, 4
CCR2, 3, 4, CXCR3, 4
CXCR4
CXCR1
CXCR2
CXCR3
CXCR4
Table 13-2 Human chemokines
& their receptors
Most receptors bind more than 1
chemokine.
Four Sequential But Overlapping Steps
in Neutrophil Extravasation
(by chemoattractant
stimulus*)
* *
** **
* *
activated (inflamed) endothelium
* Chemoattractant stimuli: chemokines
platelet-activating factor (PAF)
C5a, C3a, C5b67
N-formyl peptides (from microbes)
*
*
Transmigration of Neutrophils and Monocytes
IL-8 (CXCL8),
MIP-1b (CCL4)
integrins
mucin
CD31,
CD321
Neutrophils transmigrate first, later, followed by monocytes.
Lymphocyte Recirculation Routes
Lymphocyte Extravasation Occurs in
High-endothelial Venules (HEVs)
- cuboidal (“high”) shape,
- present in lymph nodes, Peyer’s patches, or tonsils,
- express CAMs of the selectin, the mucin-like, and
the Ig superfamilies.
Extravasation of Naïve T lymphocytes
The general process of lymphocyte extravasation is similar to neutrophil
extravasation. Naïve T-cells circulate indiscriminately to secondary
lymphoid tissue throughout the body.
Selective Trafficking of Effector T cells
CLA :cutaneous
lymphocyte Ag
The trafficking patterns of effector and memory lymphocytes differ
from those of naïve lymphocytes. Different subsets of lymphocytes
exhibit tissue-selective homing behavior. This process is called
trafficking, or homing.
Mediators of Inflammation
1. Chemokines – key mediators of inflammation
2. Plasma Enzyme Mediators
a. kinin system
b. clotting system
c. fibrinolytic system
d. complement system
3. Lipid Inflammatory Mediators
4. Cytokine Inflammatory mediators
– IL-1, IL-6, TNF-, IL-12, IFN-
Tissue Damage Induces
Plasma Enzyme Mediators
plasma clotting factor
clotting
system
kinin
system
fibrinolytic
system
complement
system
The Breakdown of Membrane Phospholipids
Generates Mediators of Inflammation
platelet
activating
factor
(PGE2, F2, D2…)
SRS-A: slowreacting
substances of
anaphylaxis
Inflammatory Response
Acute inflammatory responses:
1. Local responses – swelling, redness, heat, pain,
and loss of function
2. Systemic responses – due to combined effects of IL-1,
IL-6, and TNF-a
induction of fever,
increased synthesis of hormones, e.g., ACTH and
hydrocortisone,
increased production of WBC,
and production of acute-phase proteins in the liver
Chronic Inflammation – accumulation and activation of
macrophages, IFN-, TNF-a
Systemic Acute-phase Response
(adrenocorticotropic hormone)
(potent anti-inflammatory)
The hypothalamus-pituitary-adrenal axis (HPA axis) is a major part of the
neuroendocrine system that controls reactions to stress and regulates various
body processes including digestion, the immune system, mood and sexuality,
and energy usage.
Anti-inflammatory Effects of Corticosteroids
1. Decrease in the number of circulating lymphocytes
2. Alterations in lymphocyte circulation patterns
3. Induction of NF-kB inhibitor, IkB
4. Reduction in the phagocytic and the killing ability of
macrophages and neutrophils
5. Reduction in chemotaxis
6. Decrease in the expression of class II MHC molecules and
IL-1 production by macrophages
7. Reduction in TH-cell activation
8. Decrease in the released lysosomal enzymes at the site of
inflammation
IFN- and TNF-a Play a Central Role in
the Development of Chronic Inflammation
↑ cytokine production
↑ Ag presentation
↑ hydrolytic enzymes
↑ ROS, RNS → tissue damage
Activated macrophages → TNF-a
IFN- & TNF-a act synergistically to induce
ICAM-1, E-selectin, class I MHC molecules, and
recruit large numbers of cells.