Lecture 5: Inflammation and Leukocyte Migration Flashcards
what causes the inflammatory response in general?
local injury or tissue trauma
what 4 physical things characterize the inflammatory response?
- redness (rubor)
- heat (calor)
- swelling (tumor)
- pain (dolor)
t/f the inflammatory response involves various leukocytes, and soluble and membrane-bound molecules
t
in the inflammatory response, CAMs are crucial for _____ interactions during inflammation
leukocyte-tissue
CAMs include _____ (4)
- selectins
- mucins
- integrins
- immunoglobulin-superfamily CAMs
tissue damage and bacteria cause resident sentinel cells to release ___ and ____ to trigger a local increase in ____ and ___
chemotractants and vasoactive factors; blood flow and capillary permeability
when neutrophils and phagocytes migrate to the site of inflammation, this is called _____
chemotaxis
what 2 molecules are involved in neutrophil rolling?
L-selectin and PSGL-1
what 2 molecules are involved in neutrophil rolling?
L-selectin and PSGL-1
what 2 molecules are involved in neutrophil rolling?
L-selectin and PSGL-1
what chemokines are involved in neutrophil activation?
IL-8 and macrophage inflammatory protein 1b (MIP-1b (akaCCL4))
what chemokines are involved in neutrophil activation?
IL-8 and macrophage inflammatory protein 1b (MIP-1b (akaCCL4))
what chemokines are involved in neutrophil activation?
IL-8 and macrophage inflammatory protein 1b (MIP-1b (akaCCL4))
what chemokines are involved in neutrophil activation?
IL-8 and macrophage inflammatory protein 1b (MIP-1b (akaCCL4))
what chemokines are involved in neutrophil activation?
IL-8 and macrophage inflammatory protein 1b (MIP-1b (akaCCL4))
what molcules are involved in neutrophil adhesion?
LFA-1 and MAC-1
what immune cells are typically the first to the site of inflammation?
neutrophils
what do neutrophils respond to?
- C5a
- bacterial peptides containing N-formyl peptides
- leukotrienes in inflammed tissues
what molecule is involved in rolling inflammatory monocytes?
L-selectin
what chemokines are involved with activation of inflammatory monocytes?
monocyte-chemotractant protein-1 (MCP-1, CCL-2)
what is the molecule involved with adhesion of inflammatory monocytes?
VLA-4
what molecules are involved in rolling naive lymphocytes?
L-selectin, LFA-1, VLA-4
what chemokines are involved in activation of naive lymphocytes?
CCL21, CCL19 and CXCL12 (for T cells) and CXCL13 (for B cells)
what molecules are involved in naive lymphocyte adhesion?
LFA-1 and VLA-4
naive lymphocytes travel across ____ to enter the lymph node
high-endothelial venules
give 3 examples of selectins
L, E, and P selectins
what are selectins?
glycoproteins that bind specific carbohydrate groups
give and example of a specific carb group selectins bind to and how they bind
sialyl-Lewis x via a lectin-like domain
what are mucins?
glycosylated proteins that present sialyl-Lewisx and other carb groups to selectins
what are integrins?
cell surface heterodimeric proteins that bind extracellular matric molecules (like fibronectin) and ICAMs
what are ICAMs?
immunoglobulin-superfamily glycoproteins that bind integrins
give an example of a mucin-like CAM
CD34
give 3 examples of Ig-superfamily CAMs
- ICAM-1,-2,-3
- VCAM-1
- MAdCAM-1
MAdCAM-1 has both ___ and ___ like properties
mucin-like and ig-superfamily
give 3 examples of integrins
- a4B1 (VLA-4, LPAM-2)
- aLB2 (LFA-1)
- aMB2 (CR4, p150/95)
chemokines control what 3 leukocyte functions?
- adhesion
- chemotaxis
- actvation
chemokines are ___ expressed and are also produced in response to ___
constitutively; inflammation
most chemokines belong to ____ or ___ subgroups
CC or CXC
what is the structure of chemokine receptors?
7-membrane spanning proteins that signal through hetrodimeric G proteins
t/f individual chemokine receptors are able to bind more than one chemokine
t
chemokine receptor expression is limited to certain cell types to confer ___
specificity to the action of given chemokines
what are the CXC subgroups of the CXCR1 chemokine receptors?
IL-8 (CXCL 8) and GCP-2 (CXCL 6)
what are the CXC subgroups of the CXCR2 chemokine receptor?
IL-8 (CXCL 8), Gro-a (CXCL 1), Gro-B (CXCL 2), gro-y (CXCL 3), NAP-2 (CXCL 7) and ENA-78 (CXCL5)
what are the CXC subgroups of the CXCR4 (CXCL11) chemokine receptor?
SDF-1 (CXCL12)
give an example of a chemokine that binds to the CCR1 chemokine receptor
RANTES (CCL5)
give an example of a chemokine that binds to the CCR2 chemokine receptor
MCP-1 (CCL2)
give an example of a chemokine that binds to the CCR3 chemokine receptor
RANTES (CCL5)
____ and ____ mediate the migration of leukocytes across the endothelial cell layer of blood vessels
chemotractants and CAM interactions
blood-borne neutrophils and monocytes enter sites of inflammation by a process called ___
extravasation
cytokines and other products of inflammation cause endothelial cells to increase ____ expression
CAM
neutrophil rolling is promoted by _____ interactions
selectin-mucin
chemokines such as ___ activate neutrophils
IL-8
integrins on activated neutrophils assume a ____ conformation that allows neutrophil arrest and adhesion to ____
high affinity; immunoglobulin-superfamily CAMs
selectins are important in what phase of neutrophil rolling and extravasation?
rolling
during neutrophil extravasation, chemokines induce ____ change of neutrophils and clustering of ___
conformational; integrins
during neutrophil extravasation, chemokines induce ____ change of neutrophils and clustering of ___
conformational; integrins
recirculation of lymphocytes from blood to bone marrow, spleen, lymph nodes and tertiary extralymphoid tissues occurs at least once every ____
24 hours
what is the point of lymphocyte recirculation?
ensures that the greatest number of antigen-specific lymphocytes have the opportunity to encounter and interact with antigen in lymphoid tissues
migration of lymphocytes into lymph nodes takes place across ____
high endothelial venules
lymphocyte rolling during lymphocyte extravasation is promoted by ____
weak interactions between lymphocyte L-selectin and endotheial cell mucin
what is the role of chemokines constitutively expressed by endothelial cells in lymphocyte extravasation?
activate lymphocytes, causing integrins to assume a high affinity conformation
what is the role of integrins in lymphocyte extravasation?
mediate lymphocyte arrest and adhesion to immunoglobulin-superfamily CAMs
transendothelial migration of lymphocytes is mediated by ___ molecules
junctional adhesion
what is the function of homing receptors on lymphocytes?
recognoze specific CAMs to mediate the differential migration of lymphocyte subsets into different tissues
give 2 examples of chemokines involved in lymphocyte homing and trafficking and their role
- MIP-1B (attracts naive T cells)
2. RANTES (attracts memory T cells)
naive lymphocytes do not have ____ homing, so they are trafficked to ___
tissue-specific; secondary lymphoid tissues
effector lymphocytes traffic to sites of ___
inflammation
effector lymphocytes traffic to sites of ___
inflammation
where do memory lymphocytes home to ?
the tissue type where a specific antigen was first encountered
what are 3 important lipid mediators of inflammation? What produces them?
- thromboxane
- prostaglandins
- leukotrienes
- tissue mast cell and macrophages
what is the function of thromboxane?
vasoconstriction and platelet aggregation
what are the functions of prostaglandins?
increase vascular permeability, vascular dilation and neutrophil chemotaxis
what are the functions of leukotrienes C4, D4, and E4?
mediate lung inflammation
what is the function of leukotriene B4?
causes neutrophil chemotaxis
what are the functions of platelet activation factor (a lipid mediator of inflammation)
platelet aggregation, neutrophil activation, and eosinophil chemotaxis
chemokines, anaphylatoxins, proinflammatory cytokines and interferon-y are all ___
mediators of inflammation
what are the functions of chemokines as mediators of inflammation?
- attract leukocyte subsets to sites of inflammation
2. regulate the expression and conformation of CAMs
what are the functions of anaphylatoxins (C3a and C5a) as inflammatory mediators?
trigger tissue mast cell release of histamine, leading to contraction of smooth mucle and increased vascular permeability
what are the functions of proinflammatory mediators TNF-a, IL-1 and IL-6?
have multiple redundant effects including fever, acute phase protein synthesis, increased CAM expression and increased vascular permeability during acute inflammation
what are the functions of IFN-y and TNF-a as inflammatory mediators?
important in chronic inflammation and can cause tissue damage
is IL-1 pyrogenic?
yes
is TNF-a pyrogenic?
yes
is IL-6 pyrogenic?
yes
can IL-1 trigger synthesis of acute phase proteins by teh liver?
yes
can TNF-a trigger synthesis of acute phase proteins by the liver
yes
can IL-6 trigger synthesis of acute phase proteins by teh liver?
yes
of IL-1, TNFa and IL-6, which can increase vascular permeability?
all
of IL-1, TNFa, and IL-6, which can cause increased adhesion molecules on vascular endothelium?
all EXCEPT IL-6
of IL-1, TNFa and IL-6, which are capable of chemokine induction?
all EXCEPT IL-6
what are lectins?
sugars that bind to other sugars
are mucins mostly sugar or mostly protein?
mostly sugar
selectins have what 2 domains?
- cysteine-rich and
2. lectin domain
Ig-superfamily CAMs are recognizable by their _____ held together by ____ bonds
loops; disulphide (Ig domains)
CC chemokines have 2 ___ residues with ___ in between
cystine; nothing
CXC chemokines have 2 ___ domains with ___ in between
cysteine; amino acid
CCL is the ___ and CCR is the ___
ligand; receptor
t/f the CXCR1 is found on neutrophils
t
where are CXCR2 found?
many innate immune cells, especially granulocytes
CXCR4 is the ___ co-receptor
HIV
CCR1 is found on most ___
leukocytes
CCR2 is found on most ____, ____ and ___ cells
monocytes, DC, and endothelial
CCR3 is found on ___ and ___ cells
eosinophils and basophils
release of ____ through the endothelium will start the rolling process and the chemotraction of the neutrophil
chemokines
activation of neutrophils allows them to have high affinity form of some ___
CAMs
selectins on inflammed endothelial cells bind to ____ on neutrophils, which starts the rolling process by tethering the neutrophil
mucins
the ___ and ___ ig superfamily CAMs are responsible for grabbing the neutrophils for good (neutrophol arrest)
VCAM and ICAM-1
MIP-1B attracts naive T cells to the ___
lymph node
RANTES attracts memmory T cells to the
site of infection or site where infection had been before
t/f there are different adhesion molecules for different parts of the body
true
