Lecture 3 Flashcards
Define Migration/recruitment (synonymous here)
the general process of leukocytes movement from blood into tissues
Define recirculation (3 parts to it)
The ability of lymphocytes to repeatedly:
1. home to secondary lymphoid organs
- reside there transiently
- return to the blood
Define leukocyte homing
cell migration out of the blood, into the peripheral tissues or to a site of infection
The recruitment of leukocytes and plasma proteins from the blood to sites of infection/tissue injury is a major part of what process?
the process of inflammation
Describe how inflammation is included in both innate and adaptive immune responses AND why it is useful
Innate immune responses recognizing microbes or dead tissues is what triggers inflammation
Adaptive immune responses refine/prolong the inflammation because it delivers the cells/molecules of the host defense to the sites of infection so that they can combat them.
Inflammation causes _____ damage and underlies many ____.
tissue
diseases
When the innate immune system decides to trigger inflammation, what 2 substances are released?
histamine and cytokines are released from granular cells (already have them stored and ready to release)
State the 4 steps of the cascade of adhesive and activation events that helps bring leukocytes out of circulation in the blood and into the tissues
- Tethering (initial contact between the endothelium and the leukocyte)
- Rolling (leukocyte rolling along the endothelium)
- Adhesion and stop
- Transmigration into the tissue
Explain how tethering occurs and how it is different than rolling
tethering occurs through transient interactions of selectins and integrins with their respective ligands
Rolling allows chemokine receptors on leukocytes to bind to chemokines expressed on the endothelium
True or false:
Universal Chemokine receptors throughout the body are what allow leukocytes to migrate wherever they need to be. explain.
False
Chemokine-chemokine receptors are a selective process (has to be the specific receptor interacting with it’s specific kind)
compare the integrins and selectins in terms of the affinity of their interactions with a leukocyte
selectins have a lower affinity, and therefore contribute more to the initial rolling of the leukocyte
Integrins have a higher affinity (adhere more tightly) and therefore help the leukocyte stop completely and begin extravasation
(selectins = fast rolling ; integrins = slow rolling)
Describe the difference in adhesion molecules between the endothelium surface of healthy cells and cells at a site of infection.
Endothelial tissues of healthy cells do NOT express adhesion molecules
Injured/infected endothelial cells are activated by cytokines (secreted by resident tissue macrophages) to express adhesion molecules.
injured/infected endothelial cells that are expressing adhesion molecules attract what cells? (3 of them)
myeloid leukocytes
Ag-activated effector lymphocytes
Ag-activated memory lymphocytes
What are addressins
Addressins: a set of several adhesion molecules on the surface of HEV’s
True or False:
Leukocyte homing includes molecules on the surfaces of both the leukocytes and on the surface of endothelial cells. explain
Leukocyte homing includes molecules on the surfaces of both the leukocytes (homing and chemokine receptors) and on the surface of endothelial cells (chemokines).
Briefly describe what homing is
homing is the process by which leukocytes decide what exact spot in the endothelium they should enter
What expresses P-selectin (CD62P) and E-selectin (CD62E)?
activated endothelial cells at the site of infection
Describe the process by which an endothelial cell will come to express E-selectin (include the type of cells that express E-selecting and which cytokines they produce in order to do so)
Resident tissue macrophages AND Mast cells detect an infection and produce Cytokines IL-1 and TNF
within 1-2 hours of the Cytokines being produced, the endothelial cell will synthesize and express E-selectin
Describe the ligands for E-selectin and P-selectin (include what family they may be related to)
Constitutively expressed complex sialylated carbohydrates related to the Lewis X or Lewis family
What type of cells is L-selectin (CD62L) only expressed on?
Lymphocytes (both T and B cells) and leukocytes (NOT endothelial cells)
Explain what peripheral node addressins (PNAd’s) and why they are important
PNAd’s are L-selectin ligands expressed on HEV’s
They play an important role in naive T and B cells homing into Lymph nodes
For the following molecule, state where they can be found, what activates it, and the ligand that responds to it.
P-selectin (CD62P)
found on the endothelium
activated by histamine or thrombin
corresponds with Sialyl Lewis X
For the following molecule, state where they can be found, what activates it, and the ligand that responds to it.
E-selectin (CD62E)
found on the endothelium
activated by cytokines (TNF or IL-1)
corresponds with Sialyl Lewis X
For the following molecule, state where they can be found, and the ligand that responds to it.
L-selectin (CD62L)
found on Neutrophils, monocytes, naive and central memory T cells, and naive B cells
corresponds with Sialyl Lewis X/PNAd
Describe the strength of the selectin-mediated adhesion that occurs between the leukocyte Sialyl-Lewis X and the endothelial surface.
it is weak and allows the leukocyte to begin rolling along the endothelium
What type of integrin do ALL leukocytes express? what ligand(s) does it bind to?
Lymphocyte function-associated antigen 1 (LFA-1)
LFA-1 binds to ICAM-1 and ICAM-2
for the following integrin, state where it is found and what ligand it binds to
Mac-1
found on neutrophils, monocytes, and DC’s
binds to ICAM-1 and ICAM-2
for the following integrin, state where it is found and what ligand it binds to
VLA-4
found on monocytes and T cells (naive, effector, and memory)
Binds to VCAM-1
for the following integrin, state where it is found and what ligand it binds to
Alpha4 Beta7 integrin
Monocytes, T cells (gut homing, naive, effector and memory), and B cells (gut homing)
binds to VCAM-1 and MadCAM-1*
What happens in all leukocytes in response to a chemokine binding to CCR7 (chemokine receptors on the leukocyte)? explain how this happens.
Integrin activation
this basically rapidly increases their affinity by inducing a conformational change on the extracellular domains of the integrins
What does inside-out signalling describe?
integrin activation
basically the chemokine binding to it’s receptor sends a signal inside of the cell that results in a change on the outside it’s integrin receptor
Describe the conformational change that occurs on the extracellular domains of integrin on a leukocyte AFTER it undergoes integrin activation. describe how this process is selective even after activation occurs.
Bent extracellular domains of the integrin = low affinity
Extended extracellular domains of the integrin = higher affinity
(integrin activation causes the extension of the extracellular domain of the integrin on the leukocyte)
This process is still selective because the extended integrin has to find it’s corresponding ligand before the leukocyte adheres
What is the main function of chemokines?
To stimulate leukocyte movement and regulate the migration of leukocytes from the blood, into the tissues
Describe what differentiates the 4 following families of human chemokines
C chemokines:
CC or Beta chemokines:
CXC or Alpha chemokines:
CX3C chemokines:
C chemokines: have a single cysteine
CC or Beta chemokines: the 2 defining cysteines are Adjacent
CXC or Alpha chemokines: cysteine residues are separated by AA’s
CX3C chemokines: 2 cysteines are separates by 3 AA’s
for the following CC chemokine, state the original name, and it’s major function
CCL2
Original name: MCP-1
Function: Mixed leukocyte recruitment (monocytes)
for the following CC chemokine, state the original name, and it’s major function
CCL5
Original name: RANTES
Function: Mixed leukocyte recruitment
for the following CC chemokine, state the original name, it’s major function, and an important structure it is found on the surface of.
CCL19
Original name:MIP-3Beta
Function: T cell and DC migration into parafollicular zones of lymph nodes
Present on the surface of HEV’s
for the following CC chemokine, state the original name, it’s major function, and an important structure it is found on the surface of.
CCL21
Original name: SLC
Function: T cell and DC migration into parafollicular zones of lymph nodes
Present on the surface of HEV’s
for the following CXC chemokine, state the original name, and it’s major function
CXCL8
Original Name: IL-8
Function: Neutrophil recruitment
for the following CXC chemokine, state the original name, and it’s major function
CXCL10
Original Name: IP-10
Function: Effector T cell recruitment
for the following CXC chemokine, state the original name, and it’s major function
CXCL12
Original Name: SDF-1AlphaBeta
Function: Homing naive B cells to LNs
for the following CXC chemokine, state the original name, and it’s major function
CXCL13
Original Name: BCA-1
Function: B cell migration into follicle ; T follicular helper cell migration into follicles
True or False:
Neutrophils and monocytes are ready to be recruited into tissue sites of infection or injury without any activation. explain
True
not sure about this explaination
Neutrophils and monocytes enter tissues through ____-____ ______. How do they enter parenchyal tissues such as the liver, lungs and kidney?
post-capillary venules
They enter parenchymal tissues via the same route as all other blood cells, through capillaries
State the main molecules involved in the following steps of a transmigrating leukocyte.
- capture
- Rolling
- Activation
- Arrest
- Firm adhesion
- capture: Selectins
- Rolling: Selectins
- Activation: Chemokines
- Arrest: Adhesion Molecules (VCAM-1, ICAM-1)
- Firm adhesion: Adhesion Molecules (VCAM-1, ICAM-1)
Describe the signalling that signals for P-selectins to be expressed on the surface of endothelial cells and compare it to the signalling/delivery method of E-selectins
(try not to confuse this with E-selectins, they are similar)
Activated Mast cells and resident tissue macrophages produce TNF and IL-1 that induce the expression of P-selectin
P-selectin is expressed RAPIDLY because it is pre-formed and waiting beneath the surface of the endothelial cell to be released
(E-selectin is expressed by a similar signaling mechanism, but it is not pre formed and is therefore a slower process)
State where the following selectins are expressed
L-selectin
P-selectin
E-selectin
L-selectin: on leukocytes
P-selectin: on platelets and activated endothelium
E-selectin: on activated endothelium
Which selectin INITIATES rolling of the leukocyte on the endothelium? then the rolling is further stabilized by which selectin?
P-selectin
L-selectin
Describe how neutrophils migrate to the are of infection after entering the tissue via transmigration.
First, they interact with chemokines and adopt an amoeboid shape
The migrate in a polarized fashion along collagen fibrils in response to a chemotactic gradient that leads to the site of infection
(chemotactic receptors on the neutrophil are how it detects this chemotactic gradient)
Compare the preffered locations of naive T cells and Effector/memory T cells.
Naive T cells preferentially leave the blood and enter LN’s (and return to circulation if they are activated by an Ag)
Effector/memory T cells preferentially enter the peripheral tissues (via venules at the site of inflammation)
What is the main issue if a Lymphocyte is L-selectin-deficient?
it cannot enter peripheral lymph nodes (L-selectin expression is how you enter via HEV’s)
What is the approximate time frame that a naive T cell will spend in the LN, looking for a specific antigen before it transmigrates into the cortical or medullary sinuses and exits via an efferent LV?
6-12 hours
What is S1PR1? why is it important?
S1PR1 is a receptor on T cells that binds to S1P (a blood homing protein), and internalizes it once binding occurs
Naive T cells cannot exit the lymph node for several hours bc that how long it takes to re-express the S1PR1 (which was internalized from contact with the blood)
(while the S1PR1 is internalized, the naive T cell cannot sense the S1P concentration gradient and therefore cannot leave the lymph node)
What happens to S1PR1 if the naive T cell becomes Ag-activated? (include what happens several days after the T cell is Ag-activated)
Ag-activated T cells have low levels of S1PR1 so that they can stay in the lymph node
it takes several days for S1PR1 to be re-expressed in what is now an effector T cell
once S1PR1 is re-expressed in the effector T cell, it senses the S1p gradient in order to exit the lymph node
Describe what type of tissues L-selectin, E-selecting, and P-selectin are used to adhere to/enter.
L-selectin: lymphocytes with this selectin receptor are Naive T cells that use L-selectin to enter lymph nodes
E and P-selectin: lymphocytes with this selectin receptor are Effector T cells that use E and P-selectins to enter peripheral tissues
Explain the role that CD44 plays and how exactly it goes about it’s role (include the other factors that must be present/are affected)
CD44 important for the milization of effector T cells in sites of infection/inflammation
CD44 and Hyaluronic Acid work together to trigger (G protein-coupled receptors) GPCR-dependent “inside out” upregulation of VLA-4-VCAM binding
Explain the significance of the red pulp and the white pulp of the spleen as it pertains to immature/mature naive B cells
immature naive B cells leave the bone marrow and enter the spleen via the Red pulp
Next, the immature naive B cells migrate to the periphery of the white pulp of the spleen where they mature
(they reenter circulation and home to lymph nodes and mucosal associated tissued after that)
State the 3 chemokines (2 of them are specific to HEV’s) that are required for the homing process of B cells
CXCL12
CCL19 (HEV specific)
CCL21 (HEV specific)
CXCR4 and CCR7 are only expressed on what specific cells?
naive B cells
What is the chemokine that drives the migration of B cells into follicles?
CXCL13
Define Diapedesis
the passage of blood cells through the intact walls of the capillaries (typically accompanies inflammation)
What is S1P?
S1P is a blood homing protein that binds to S1PR1 receptors on T cells (then internalizes)
