Transcript Chapter 15 – Leukocyte Migration and Inflammation

Inflammation
Normal oesophagus
Normal palatine tonsils
Normal skin
Candida infection
Streptococcal infection
Staphylococcal
infection
Leukocyte Migration and Inflammation
• The IS relies upon the continual circulation
of leukocytes through the body
– For the Innate IR – a variety of lymphocytes,
granulocytes, and monocytes can respond
– For the Adaptive IR – lymphocytes must
contact Ag in either tissue, lymph, or blood
Lymphocyte re-circulation
• Lymphocytes constantly re-circulate from blood to
spleen, lymph nodes, and 3° lymphoid tissues
• Continual circulation provides systemic protection
• A complete circuit can be performed 1-2X per day
• ~1 in 105 lymphocytes can recognize a specific Ag
therefore, constant circulation increases
chance of lympho contacting Ag
How do leukocytes transit the
bloodstream?
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
From Here to There?
• Lymphoid stem cell migrate to central
lymphoid organs
• Mature lymphocyte migrate to peripheral
lymphoid organs
• Recirculation of lymphocytes
• Lymphocyte migrate to the sites of
inflammation
High endothelial venules
Post capillary
venules in 2º
lymphoid tissue
HIGH
ENDOTHELIAL
VENULES.
Specialised to allow
lymphocytes and
nothing else into the
lymph
node
Post capillary
venules in other
tissues are lined by
simple squamous
epithelium
HEV
Recirculation
Non-lymphoid cells
HEV
Pass through the blood vessels in the
lymph node and continue arterio-venous
circulation
Naïve lymphoid cells
HEV
Adhere to and squeeze between High
Endothelial Venules (HEV), then
percolate through the lymph node and exit
via the efferent lymphatic vessel
Role of endothelial cells in trafficking and
recirculation
Endothelial are involved in:
Vasomotor tone, vascular permeability, regulation of coagulation, immune
modulation and lymphocyte extravasation
High endothelial venules
Post-capillary venules
Constitutively present in
secondary lymphoid tissue
Present in non-lymphoid tissues
Need to allow egress of
naïve cells from the circulation
Molecules expressed by endothelial cells regulate trafficking
and recirculation through lymphoid and non-lymphoid tissues
Antigen Collection
• Spleen - collects antigen from the bloodstream;
• Mucosa-associated lymphoid tissues (MALT) - collects
antigen from the respiratory, gastrointestinal and
urogenital tracts and are particularly well organized in the
small intestine, in structures known as Peyer’s patches.
• The lymph nodes are connected to the tissues and the
bloodstream by a system of lymphatic vessels.
• Afferent lymphatics drain extracellular fluid (lymph) from
the tissues, including mucosal tissues, into the lymph nodes.
• Efferent lymphatics carry the lymph out of the secondary
lymphoid tissues and ultimately into a collecting vessel known
as the thoracic duct (or for lymph nodes in the neck, the
cervical duct), and thence through the heart and into the
bloodstream
draining lymph from tissue
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
Selectins & addressins
SELECTINS
Leucocytes inc. Naive T cells: L SELECTIN
Endothelial cells: P SELECTIN & E SELECTIN
P selectin: Weibel-Palade bodies. E selectin: TNF & IL-1 induced
A common core with different extracellular C type lectin domains that bind
carbohydrates in a Ca2+ dependent manner.
Each selectin binds to specific carbohydrates and is able to transduces signals
into the cell
VASCULAR ADDRESSINS
On high endothelial venules in lymphoid tissue:
Carbohydrates that “decorate” CD34 and GlyCAM-1
Sialyl LewisX molecules
Peripheral Node addressins (PNAd)
Mucosal endothelium:
MAdCAM-1
Guides lymphocyte entry into lymphoid tissues
Adhesion molecules participate in
lymphocyte homing
Lymphocyte homing receptor
Addressins
Adhesion Functions
molecules
Adhesion
molecules
Functions
L-selectin
Lymphocyte homing to
peripheral immune organs
PNAd
Addressin of peripheral high
venous endothelial cell
CLA
Receptor on memory T cell
surface for directionally
homing to skin
E-selectin
Express on vascular
endothelial cell of
inflammation portion of skin
LFA-1
Participate in many
lymphocytes for homing
ICAM-1
ICAM-2
Participate in many
lymphocytes for homing
Adhesion molecules participate in
lymphocyte homing
Lymphocyte homing receptor
Addressins
Adhesion Functions
molecules
Adhesion
molecules
VLA-4
Receptor of lymphocyte
homing
VCAM－1 Express on vascular
endothelial cell of
inflammation portion
CD44
Participate in many
lymphocytes homing
MAd
Intestinal lymphatic tissue and
lamina propria
integrin
Receptor of lymphocyte for
directionally migrate to
Peyre's Patch
MAd
Addressin of vascular
endothelial cell
α4β7
Functions
Neutrophil extravasation in
inflammation
Blood flow
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
Memory and naïve T cells
L-selectin
LFA-1
CD44
CD2
CD45RA
CD45RO
VLA-4
Naïve
Associates with TcR and CD4 phosphatase activity reduces
threshold of T cell signalling
+
+
+
+
+
-
-
++
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-
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Activated -
Naïve cells need to access lymphoid tissue to become stimulated
Memory cells need to access sites of inflammation
Initial contact of Naïve
lymphocytes
High endothelial venule cell
Steps of extravasation of naïve
T cell
Trafficking, homing and adhesion
Trafficking:
Non-random movement of cells from tissues, blood or lymph.
Includes migration to and from sites of lymphocyte maturation
as well as homing.
Adhesion:
Binding of cells to other cells or extracellular matrix
Homing: Tendency of lymphocytes activated in a particular
region of the body to preferentially return to the same region
Includes localisation of cells in distinct regions of lymphoid
tissue.
Why is lymphocyte homing necessary?
Tendency of lymphocytes activated in a particular region of the body to
preferentially return to the same region.
Gut pathogen
e.g. rotavirus
Gut
Anti-rotavirus
T cells will never
be needed in the skin
Anti-rotavirus
T cells will
be needed
in the gut
Anti-rotavirus
T cells activated
Response resolves,
lymphocytes nonrandomly redistributed
Pro-T cell migrate to thymus
• Homing receptor: CD44 and L-selectin
expressed by pro-T cell
• Adressin: EA1 molecule expressed by
thymus vascular endothelial cell
• And integrin α6β1、α6β4 play an important
role in adhesion of pro-T cell
Lymphocyte migrate to peripheral
lymphoid organs
Lymphocytes migrate to lymph node
• Homing receptor: L-selectin on lymphocyte
• Adressin：peripheral lymphonode vascular
addressin (PNAd)
• LFA-1/ICAM-1、ICAM-2 and CD44/Mad
molecules participate in the adhesion and
penetration
Lymphocyte migrate to peripheral
lymphoid organs
Lymphocyte migrate to Peyer’s Patch
• Homing receptor: integrin α4β7 molecule；
CD44 and LFA-1 molecules
• Adressin: Vascular endothelial cell of peyre’s
patch specifically highly express mucosal vascular
addressin (Mad); ICAM-1、ICAM-2
• Peyre’s patch means the aggregated lymphoid
nodule in small intestine.
Lymphocyte homing
Initial contacts of effector T cells
Quantitative aspects of lymphocyte
migration
Traffic between lymphoid/non-lymphoid tissues involves~ 5 x 1011 cells per
day
Only ~2% (1 x 1010) of these cells are in the blood at any one time
Lymphocytes only stay in the blood for ~30 minutes
Circulating blood pool of lymphocytes is exchanged 48 times a day
However……
Less than 10% of blood lymphocytes migrate into lymph nodes, tonsils &
Peyer’s patches.
~90% of lymphocytes leave the blood to enter organs such as the liver, lung
spleen and bone marrow.
Traffic is 5 times faster than traffic through lymphoid tissue