Inflammation 3 Flashcards
following invasion by pathogens get
immediate response (innate)
innate response starts as soon as
pathogen enters
how long does immediate innate response last
4 hours
activation of what contributes to immediate innate response
adaptive pathway
recognizing pathogen is job of
PRR (on epithelial cell, tissue macrophages, mast cells, etc)
immediate innate response will rarely if ever result in
elimination of pathogen
innate response will lead to what symptom
inflammation
symptos of inflammation
fever
macrophages secrete variety of mediators that promote
inflammatory response
its possible pathogen may be eliminatedat which first stage
PRR and PAMP stage
adaptive response can detect as early as
4-5 days
when is adaptie response optimal
week after infection
once t cells are generated in secondary lymphoid tissue what will have to do to contact the bad cells
go to site of infection
inflammation exists to solve what problem
most infection is in tissue
the cells to fight (immune cells) are in circulation
want to get cells to the infected tissue
describe of inflammation
vasodilation
more permeability
inflammation can be innitated by
immune or non immuen stimulus
first step in Immunological Steps in Inflammation
initiation
describe initiation
trauma, tissue necrosis, infection or immune reaction
what is second step in Immunological Steps in Inflammation
Acute Vascular Phase
crucial for Acute Vascular Phase
activation of mast cells
describe Acute Vascular Phase
release of vasoactive compounds from mast cells and macrophages leads to endothelial cell contraction and vasodilation and transudate release
if non immune stimulas stop at what stage of step in Immunological Steps in Inflammation
stage 3
if immune stimulus continue to what stage after stage 3 for step in Immunological Steps in Inflammation
Acute Cellular Phase
describe Acute Cellular Phase
Chemotaxis, margination and emigration (transmigration/diapedesis) of neutrophils; diapedesis of erythrocytes. Resolution may occur at this stage if stimulus is adequately removed
chemotaxis is largely reuslt of production of
chemokines and other chemoattractants
chemokins promote neutrophils
halting on surface of endothelial cells
when leukocytes pull themselves through gaps b/w endothelial cells that step is called
diapedesis
neutrophils have to actiely do what thorugh gaps
pull themselves through
what is second to last step of Immunological Steps in Inflammation
Chronic Cellular Phase
acute dominated by
neutorphils
chronic inflammation dminated by
mononuclear cells → lymphocytes & monocytes
chronic cellular phase
Emigration of lymphocytes, infiltration by macrophage, emigration of eosinophils in parasitic infections or in allergic responses
what is last step in Immunological Steps in Inflammation
resolution
many mediators are already profiormed inside
mast cells
resolution stage has what two very important cytokines
IL 10
TGF beta
IL-10 and TGF beta are what kind of cytokines
immunosuppressive
downregulate the inflammatory response
downregulate adaptive immune resopnse
some mediator srelease by mast cells stimulate contractino of
endothelial cells - so gap forms b/w endothelial cells
b/w endothelial gaps
leukocytes pull through to get to infected tissue
diaphedes of erythorcytes
why the infected are becomes red - vasodilation and RBC extravacating from cciruation into infected tissue
what are five cardinal signs of inflammation (or main 4 + fifth if severe)
Rubor – Redness Tumor – Swelling Calor – Heat Dolor – Pain Functio laesa – Loss of Function (only if severe)
describe the manifestation of signs of inflammation
immediate line of vasoconsturction then redness and vasodilation fo capillaries and arterioles. then swelling due to increase in vascular permeability due to endothelial cells pulling apart and fluid passing into the tissue
what is crucial to inflammation
mast cells
control of infiltration of inflammatory cells into tissue via
mast cells
how to activate mast cells
c3a and c5a
c3b and c4b are
opsinins
c3b and c4b allow leukocytes to
identify what it is they need to get rid of
c5a and c3a increas vascular
permeability → more complement proteins getinto complement tissue
bradyknin is main mediator that causes
pain
bradyknin induces an increase in
vascular permeability
c5a and c3a bind to receptors on mast cells and stimulate them to
degranulate - release contents fo their granules
mast cells also have PRR on their surface, so infectious agent by PAMPs binding can stimulate
mast cell degranulation
once mast cells stimulated to degranulate they will release
lots of pro-inflammatory mediators
what is released by mast cells
histamine
TNF alpha
IL-1
histamine is stored preformed in
mast cells
histamine induces
vasodilation
increase in vascular permeability
affect of histamine is immediate but
short lived
what induces sustain in vascular permeability
TNF alpha and IL-1
TNF alpha and IL-1 induce iadhesion
on endothelial cells - so endothelial cells are sticky for other neutrophils. now neutrophils can grab on something to halt when they get to site of infection
inreas in vascular permeability allows plamsa proteins to seep from
cirulcaiton into tissue
bradyknin can stimualte degranulation of
mast cells
mast cells secrete what chemoattractant
IL-8 or (CXCL8)
all chemoattracts stimulate through
heterotrimeric G protein coupled receptors
mast cells secrete IL-8 and also release what lipid chemoattractant
LTB4
what is most potent chemoattractant for neutrophils
IL-8
mast cells are not the only cells activatied to initate leukocytes what else can be activated
activated by PAMPs binding to PRRs
activation of macrophages important b/c they are rich source of
pro-inflammatory ctokines
macrophages make
IL-1 TNF alpha IL-6 IL-8 IL-12
IL-1
TNF alpha
IL-6 control what
acute phase response
IL-8 is a chemoattratant for
neutrophils
IL-12 activtes
natural killer cells
natural killer cells are important for killing spread of
viral infections
IL-6 is main factor responsible for
heat associated with acute inflammation
induces fat and muscle metabolism which riases temp
IL-8 is
chemoattractant
IL-12 activates
NK cells
features of acute phase response
production of proteins importat for inflammation - so it repleneshes what we are using up
bone marrow endothelium - neutrophil mobilization “pus” mobilize the neutrophils from bone marrow and then attracted to site of infection by chemoattractants
hypothalamus - increase in body temp
IL-6 acts on fat and muscle for localized heat
mannose-bindin lectin
initator of ____ pathway
IL-1
TNF alpha
IL-6 are not
acute phase proteins, they just stimulate production of acute phase proteins
acute phase proteins also called
acute phase reactant
main function of acute phase response
replenishes what we are using up - like complement and neutrophils
acute phase response is regulated by
IL-1 IL-6 TNF alpha
IL-1 IL-6 TNF alpha act where
locally and distally - from bone marrow to hypothalamus to liver
acute phase proteins can limit
damage
name a very important representative of acute phase proteins
CRP (C reactive protein)
why are acute phase proteins important
cell surface or soluble PRRs
can measure them to get indication of repsonse to treatment
they will change their plasma concentration if there is inflammation or trauma going on
list the important acute-phase proteins
pg 66
suspect infection what test would you request
plasma or serum c-reactive protein
with activation of mast cells and release of chemoattractants calling out for
leukocytes - particarlly neutrophils
for neutrophils to get to infection
have to leave circulation and get to tissue
to get leukocytes migration need
chemoattractants
formylated peptides are characteristic of
bacteria
n-formlyated baterial peptides do what
chemoattractant
example chemoattractants to get leukocytes to site of infection
Examples: N-Formylated bacterial peptides – FMLP Complement derived – C5a, C3a Lipid derived – Leukotriene B4 (LTB4) Chemoattractant cytokines Chemokines e.g. - IL-8 (CXCL8), CCL5, CCL21
following exposure to chemoattract the leukocyte will migrate
to where the chemoattract is in highest concentration
chemotaxas
moving up the chemoattractant gradient
chemoattractans will stimluate what in neutrophil
to destory the pathogen once it takes it up
all chemoattracts ibnd to
7 pass membrane g protein coupled receptors
exposure of the neutrophil to chemoattractants results in increase in what
affinity of integrin for contrareceptor
four main families of chemokines
CXC chemokines
CC chemokines
(X)C chemokine
CX3C chemokine
chemokines classified on arrangement of
conservedn terminal cystein
CC chemokines have no intervening what the cysteins
no intervening aa
what is the clinical significance of chemokines in regards to HIV
CCR5 (M strain) CXCR4 (T strain)
chemokine receptors can bind more than one
chemokine
there is no numerical correlation b/w chemokine and
chemokine receptor - there is no correlation b/w what they bind to
single chemokine can bind to multiple
receptors
all chemokine receptors are
7 pass transmembrane g protein coupled receptors
for neutorphils to get from ciruclation into tissue have to do w=somethign to blood vessel endothelial cells, they have to adhere, the initial adherence is a very
low infinity interaction
the first reaction to endothelial cells is not sufficient
to stop neturophils b/c its so weak
normally endothelial cells are non inflamed and its not
sticky for neutrophils
during inflammation it induces expression of adhesion molecules onto
neutrophils - the endothelial cells slow down neutrophils
first cell into site of infection is
neutrophil
dominant leukocyte we have
neutrophil
four types of adhesion molecules to regulate immune cell intearaction to get to site of infection
addressins CD34
selectins - L-selectin
integrins - LFA-1
immunoglobulin like - ICAM-1
inital low affinity interactions of neutrophil and endothelial wall are b/w
addressins & selectins
when leukocytes arrive they will roll along surface of endothelial cells this is called
margination
rolling of leukocyte cell in cirulation is due to interaction b/w
adressin and selectins
adressin and selection interaction is not sufficient affinity to
bring neutrophil to a halt
what interaction brings neutrophil to a halt
integrin (LFA-1) and ICAM-1
when neutorphil arrives to ICAM-1 and binds the interaction isn’t strong enough to get it through the endothelial cells - it then binds to CXCL8 and enduces
conformational change in LFA-1 to neutrophil and beocmes high affinity. the high affinity state is responsible for bringing neutrophil to halt on surface of endothelial cells
PECAM1 is located where
at junctions of individual endothelial cells
binding of neutrophils to PECAM-1 pulls it through the gaps of endothelial cells. ligand for PECAM-1 is
PECAM-1
once neutrophil comes to a haltthey will use what to pull them across the endothelial cell layer
PECAM-1
describe the 4 step model of extravastion of elukocyte into tissue
pg 81
diapedesis is what
crossing of blood vessel wall
by who and when are IL10 and TGF beta produced?
by macrophages
produced towards end of inflammatory response
what are prostaglandins
lipid mediator that induces vasodilation
CXC chemokines strucrure
an aa b/w two cycsteins
(X)C chemokine structures
a single cys
CX3C chemokine structure
Cys-X-X-X-Cys
LFA-1 binds to
ICAM-1
what interaction brings the neutrophil to a halt
LFA-1 binding to ICAM-1
where is L selectin located
on neutrophil
