Sirkulasi dan Migrasi

Leukosit
Lab Fisiologi Jurusan Biologi UNESA
• Sistem imun bergantung pada sirkulasi
berkelanjutan dari Leukosit di dalam tubuh
• Immune respons innate– Beberapa macam
lymphocytes, granulocytes, dan monocytes
dapat merespons
• Imun respons adaptive – Limfosit harus
berikatan dengan Ag di semua jaringan,
limfe , atau darah
 Re-sirkulasi Lymphocyte
• Lymphocytes mengalami resirkulasi secara
constant dari darah ke limpa, nodus limfe, dan
jaringan limfoid
• Sirkulasi berkelanjutan memberikan proteksi
sistemik
• Berlangsung 1-2x sehari (complete sirkulasi)
• ~1 dalam 105 lymphocytes dapat mengenali
specific Ag → meningkatkan kesempatan limfosit
berikatan dg Antigen
 How do leukocytes transit the
bloodstream?
How do Leukocytes migrate to the tissue

They must bind to an endothelial cell first!

• Endothelial cells exhibit ‘cell adhesion

molecules’ – CAM’s

• Lympho’s, granulo’s, and mono’s form

receptors which bind to CAM’s
- 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 cell-
adhesion 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 leukocyte)

(on endothelium) (on inflamed
(on neutrophil) endothelium)

(CD54, CD102, CD50)

(CD106) (lymphocyte Peyer's
patch adhesion
molecule-1)

(on mucosal endothelium,

has both mucin-like and
Ig-like domains)
The four types of CAM’s
• Selectins – resp. for intial
contact between
leukocytes and endothelial
cells
– Bind to specific CHO
groups (i.e., mucins)
• Mucins – glycosylated
proteins
– Bind to selectins on
endothelium
– Bind to other mucins
(CD34 and glyCAM) on
endothelium of lymph
nodes
The four types of CAM’s
• Integrins – heterodimer
proteins formed by all
leukocytes
– Bind to ICAM’s along vasc.
endothelium

• ICAM’s – CAM’s with Ig

domains on vasc. endothelia
– Bind to integrins at Ig domain
– MadCAM’s – have both IG
and mucin-like domains; found
on mucosal endothelia
• Bind to integrins on
lymphocytes
 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, 3 CCR1, 2, 4, CXCR4
CCR1, 2, 3
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.
 Cell trafficking in immunology
• The trafficking of leukocytes into and within
lymphoid and peripheral tissues is central to
immune cell
• development, immunosurveillance and effector
function.
• Interstitial leukocyte trafficking is the result of
amoeboid
• polarization and migration, guided by soluble or
tissuebound chemoattractant signals for
positioning and local
arrest.
 Cell types
• Both innate and adaptive immune functions depend upon
interstitial leukocyte migration.
• After leaving the bone marrow by way of the blood, monocytes and
granulocytes reach lymphoid or peripheral tissues, move toward their
targets and execute effector functions.
• Dendritic cells (DCs) collect and process antigenic material and, in
response to maturation signals, migrate from the periphery to lymphoid
tissues to present antigens and trigger T cell activation.
• T lymphocytes emigrate from the thymus, become activated by a
cascade of cell-cell interactions in secondary lymphoid organs and
circulate to peripheral tissues for effector function.
• Similarly, B lymphocytes move within secondary lymphatic tissues to
capture antigen, receive T cell help and recirculate and become
resident in the bone marrow and other lymphoid organs as
antibodysecreting plasma cells
 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)
Cell adhesions of neutrophils

Rolling
Activation Adhesion
 Lymphocyte extravasation
• Involves same 4 steps as neutrophils

• Small % of endothelial cells w/i lymphoid

organs exhibit “high-endothelial venules”
(HEV’s) which contain many CAM’s

• CAM’s function in “Homing” and

“Trafficking” of lymphocytes
Initial contact of Naïve
lymphocytes

High endothelial venule cell

 Steps of extravasation of naïve
T cell

The general process of lymphocyte extravasation is similar to neutrophil

extravasation. Naïve T-cells circulate indiscriminately to secondary
lymphoid tissue throughout the body.
Initial contacts of effector T cells
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.
Transmigration of Neutrophils and Monocytes

IL-8 (CXCL8),
MIP-1b (CCL4) integrins
mucin

CD31,
CD321

Neutrophils transmigrate first, later, followed by monocytes.

 Pengayaan
• Bacalah Artikel Review terlampir, buatlah
ringkasan untuk lebih memahami
bagaimana migrasi Leukosit/ Limfosit