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Inflammation
Normal oesophagus Normal palatine tonsils Normal skin
Candida infection Streptococcal infection Staphylococcalinfection
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
Post capillary venules in 2º lymphoid tissue HIGH ENDOTHELIAL VENULES.Specialised to allow lymphocytes and nothing else into the lymph node
HEV
High endothelial venules
Post capillary venules in other tissues are lined by simple squamous epithelium
Non-lymphoid cells
Pass through the blood vessels in the lymph node and continue arterio-venous circulation
Recirculation
HEV
HEV
Naïve lymphoid cells
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
Constitutively present insecondary lymphoid tissue
Need to allow egress ofnaïve cells from the circulation
Post-capillary venules
Present in non-lymphoid tissues
Molecules expressed by endothelial cells regulate traffickingand 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
SELECTINSLeucocytes inc. Naive T cells: L SELECTINEndothelial cells: P SELECTIN & E SELECTINP 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
Selectins & addressins
VASCULAR ADDRESSINSOn high endothelial venules in lymphoid tissue:
Carbohydrates that “decorate” CD34 and GlyCAM-1Sialyl 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 molecules
Functions 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-1ICAM-2
Participate in many lymphocytes for homing
Adhesion molecules participate in lymphocyte homing
Lymphocyte homing receptor Addressins
Adhesion molecules
Functions Adhesion molecules
Functions
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
Neutrophil extravasation in inflammation
Blood flow
Cell adhesions of neutrophils
RollingActivation 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
Naïve
Activated
+
-
L-s
elec
tin
+ + -+ + -
VL
A-4CD
45R
A
CD
45R
O
CD
2
LFA
-1
CD
44
++ ++ ++ +++-
Associates with TcR and CD4 - phosphatase activity reduces threshold of T cell signalling
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
Gut pathogene.g. rotavirus
Anti-rotavirusT cells activated
Response resolves, lymphocytes non-randomly redistributed
Anti-rotavirusT cells will neverbe needed in the skin
Anti-rotavirusT cells willbe neededin the gut
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 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 migrate to peripheral lymphoid organs
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
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