Inflammation 2 Flashcards
complement initiated by
soluble PRRs
during complement pathway get release of cleavage products, many components in complement pathway activated by
proteolytic cleavage
split products are
cleavage products that are released following activation of components of complement pathway
most acitivation of compeent component srequire
enzymatic cleavage
complement is important in inducing
but
inflammatory response
it can also cause damage to our own cells
don’t want complement activation on
surface of own cells - they can lead to lysis of own cells
complement consist of
30 plasma proteins
secreted as inactive proenzymes
activation of most inactive proenzymes of compleent requried
activation of proteolytic cleavage
during inflammatory response you get enhance activation of
complement
most importan function of complement in innate response
generate opsinin c3b
when c3b is generated covalently bind to surface ofp athogens - that acts as little flat on surface of that pathogen telling phagocyte to eat it
greaterly increases efficiency of phagocytosis
phagosytosis without opsinization is
very inefficient
opsinization knows what to destroy b/c
it has receptor for opsinin on its surface
when opsinin binds to bacterium the other end
binds to opsinin receptor on phagocyte - really high effincity -greatly enhance efficiency of phagocytosis
generate a lot of opsinin b/c c3 is
very abundant in plasma (c3 is most abundant complement component and is precurser to c3B)
important complement innate function
tell phagocyte to come in
c3a, c4a, c5a are
anaphylatoxin
c3a, c4a, c5a, number of affects, what are they:
vasculature - allows to bring more cells to area
chemoattractants - potent especially for neutrophils
stimulate mast cells
once c3a c4a c5a call neutrophils, what needs to happen in tissue for neutrophils to get from circulation to infected tissue
mast cells need to be activated
at end of complement cascade the complements come together in formation of a
pore
pore is called
mac
mac stands for
membrane attack complex
encapsulated bacteria, will they be sensitive to mac
no
gram + bactiera will they be sensitive to mac
will gram - be sensitive to mac
gram + not sensitive
gram - yes senesitive - this allows the outer part of gram neg to be taken away and the peptidoglycan part revealed
alternative and lectin pathway happend directly where
on surface of microbes or pathogens
classical pathway can only be activated following
antibody binding to antigen
usually requires adaptive response and production of antibody
initaters of complement activation recognize
PAMPs
3 complement pathways come together at the activation of
C3 (into C3a and C3b)
C3 is activated by cleavage
first to act, second to act, third to act of the complement activation pathways
- alternative pathway
- lectin
- classical
does alternative pathway require recongnition
no its always on
complement activation is the same as (another name for it)
complement fixation
what are the three pathways by which complement can become activated
- alternative pathway
- lectin pathway
- classical pathway
C3a and C5a recruit
C3a and C5a activate
phagocytes
mast cells
why is alternative pathway first to act
it is happening all the time
it’s a result of spontaneous hydrolysis of component c3 which is always happening at a low rate
it won’t go further unless there is pathogen surface
do lectin and classical pathway require recognition
yes
why is classical pathway the last to act
requires adaptive immune response
lectin pathway activated by
recognition of structures common to microbes and pathogens but not commonly found on our own cells
end result of the activation events
formation of enzyme that will cleave the most abundant component of complement: c3 - into c3a and c3b
c3b is the most important
opsinin
which are the chemoattractants
c5a
c3a
c4a
what initiates the alternative pathway
c3b binding to surface of pathogen
surface bound c3b now becomes binding site for plasma protein called
factor B
factor B binds to c3b and then what happens
factor B undergoes conformational change that makes it susceptible to cleavage by plasma protease called factor D
C3b is generated and covalently binds to
surface of pathogen
once C3b binds to pathogen and on its surface becomes binding site for
factor B
when factor B binds to C3b what happens
it undergoes conformational change that makes factor B susceptible to cleavage by plasma protease called factor D
some of c3b will bind to
enzyme that generated it and turn it from c3 converates to c5 convertase
properdin
binds to protects c3 convertase
absense of properdin
c3 convertase cleaved by factor I
in alternative pathway C3 convertase is
C3bBb
bacteria opsinized by
c3b
c3a diffuses and recruits
phagocytes
c3a is
chemoattractant
c3a has affects on blood vessels to allow
phagocytes to pull themselves through bood vessel walls and get into tissues
opsinization works
b/c phagocytes haveon surface receptor for other end of c3b, makes inefficient process very efficient
what is most important opsinin generated during complenet activation
c3b
what opsinin beside c3b important
c4b
Igg
Igg during adaptive response binds to
surface of pathogen and the other end (stem of y) binds to receptor
stem of Igg is called
Fc portion of Igg
receptor taht binds to stem of Igg called
Fc receptor
IgM and Igg are
two different types of antibodies
IgM is not
opsinin
IgM and Igg can also activate
complement pathway
in all pathways come c3b generated that some binds to
enzyme that generates it
when c3b binds to c3 convertase that enzyme is now
c5 convertase
c5 convertase
converts c5 into c5a and c5b
c5a does what
goes away and attracts more phagocytes
c5b does what
binds
lectin and classical pathway have to have
recognition
lectin recognition - what does it recognize
sugar residues by lectin
what does lectin pathway specifically recogniae
mannose-binding lectin (MBL)
ficolins
MBL stands for
mannose-binding lectin
MBL and ficolin belong to
same family
associated with heads of ficolin and MBL are
enyzmes
once ficolin and MBl binds to something it triggers
conformational change which activates the first enzyme
what are enzymes called on ficolin and MBl
MASPS
how many MASPS
1 & 2
MASP 1 activated by
conformational change
MASP 1 does what
cleaves and activates MASP 2
MASP 2 does what
cleaves c4 into c4 a & b
and c2 into c2a and b
pathogens have terminal
mannose residues on glycose proteins
c4a
goes away
c4b
site of generation of c3 convertase of lectin pathway. binds to surface
c2a
binds
c2b
diffuses - don’t know the function
c2a binds to
c4b (convertase, same as in the other pathway)
in lectin pathway c3b functions as
opsinin
classical pathway needs to be activated by
antibody
antibody generated during
adpative resopnse
1st component of classical pathway
c1
c1 complex made of
c1q - c1r & c1s (two molecules of each of them associated with c1q)
c1q binds to
Fc portion of antibody molecule when that antibody has bound to antigen (it will not bind to circulating antibody not bound to antigen)
when c1q binds to Fc what happens
undergoes conformational change and is active
cleaves and activates c1s
active c1r does what
cleaves and activates c1s
c1 molecule has to associate with how many
2 molecules close together - need two fc regions close together in order to activate the classical pathway
antibody molecule that naturally has 2 or more fc domains
IgM
IgM is what kind of antibody
pentomer
one molecule IgM already has
two Fc regions close together
one molecule of IgM binding to C1 is
sufficient to activate classical pathway
draw classical pathway
pg 22
to activate classical pathway with IgG
need two IgG molecules bound close together
what is most efficient antibody at activating complement
IgM
one exception to classical pathway activtion
when molecule called CRP (c-reactive protein) binds to lipids commonly found on surface of pathogens (phosphorycholine) that allows c1q to bind directly to crp
at the stage of C3 convertase in all three pathways will generate a lot of
c3b
when c3b binds to the enzyme that generated it (c3 convertase) what does it do
turns c3 convertase into c5 convertase
alters the specificty of the enzyme
c5 convertase cleaves
c5 - to c5a and c5b
c5a is a potent
it also potently increases
chemoattractant
vascular permeabilty - causes endothelial cells to be able to be pulled apart more
c5b is frist step in formation of what
first step in formation of membrane attack complex
at what point would you begin to form the pore
at c5b
MAC only perferates
membrane - envelope it would perforate, unencapsulated gram neg. bac. are as well
c3a & c5a diffuse away and attract
leukocytes (esp neutrophils)
c3a & c5a cause endothelial vessels lining blood vessel
to pull apart
enhances complement activation where infection is
important step to allow endothelial vessels lining blood vessel to pull apart is
mast cells
c3a and c5a activate what cells to de-granulate
mast cells
c5b generated from c5, once generated what binds to it
c6
c7 binds to
c6
c7 does what
attaches complex to membrane
c8 binds to
c7/complex
multiple molecules of c9
inserts across the memberane forming pore - results in lysis of pathogen
c8 goes
into the membrane
to be lysed by membrane attack compelx MAC need to have
available membrane. so gram neg. more susceptible to lyssi by mac
formation of MAC starts with
c5b
what initiates mac contact with membrane
c7
c8 does what
inserts across membrane
“c8 goes on a date - with the membrane”
c9 does what
forms pores across membrane
for c3b to funtion as opsinin ahs to be recognized by
receptor on phagocyte
cr1
receptor for c3b & c4b
cell that expresses cr1 has to be exposed
to c5a to be an opsinin
main receptor for opsinin
cr1 & cr3 & cr4
receptors on phagocytes for chemoattractats
c5a & c3a
receptors on mast cells for chemoattractsns
c5a & c3a
most complemet control proteins function by
destabilizint of convertases and ultimately degradation of convertases by factor I
c1 inhibitor
removes enzymes from c1 complex and from fycolins and MBL
removes c1q and removes MBL
can block lectin and classical pathway at start using what
C1 inhibitor
just memorize the chart of regulatory proteins in classical and alternative pathways
pg 33
if you destaiblize c3 convertase will never generate
c5 convertase
factor I of plasma protease will
cleave what has been displaced
MCP is active in which pathways
alternative and lectin pathways
decay acceleration factor
slows acceleration of c3 convertases
DAF stands for
what does it do
decay accerlerating factor - accelerates decay of convertases
CD59
prevents insertion of c9 across the membrane
prevents formation of pore membrane attack complex
C1 inhibitor removes enzymes from
initiatiors of classical and lectin pathway
defficient levels or defective C1 inhibitor is what disease
Hereditary Angioedema - HAE
C1 inhibitor prevents production of what part of acute inflammation
bradykinin
bradyknin is
potent inducer of vascular permeability
disregulated production of bradykniin leads to
increase in vascular permeability at the point of trauma - so movement of fluid into the tissue leading to swelling (hereditary angioedema)
iC3b fragments can function as
opsinin - but do not have active convertase. only incative in terms of convertase activity
DAF, MCP, C4BP, CR1
dirsupt c3 convertase formation
c3 convertase necessary to generate
c5 convertase - will nver form the pore
c5 convertase required for genreation of
c5b
CD59 binds to
c5b678
cd59 prevents
echo 11:10
no functional cd59 is what disease?
Paroxysmal Nocturnal Hemoglobinuria - PNH
most sensitive cells to complement mediated lysis
RBC
PNH stands for
Paroxysmal Nocturnal Hemoglobinuria
result in de novo mutations in gene that is required to anquor the complemetnt regulatory proteins to the cell memvrane
PNH
when factor D cleaves factor B it splits off what fragment
what remains bound to C3b
Ba
Bb remains bound to C3b
C3b functions as an
opsinin
What is the CD name for DAF
CD55
What is the CD name for MCP
CD46
write out the diagram (or understand)
pg 42
write out the diagram (or understand)
pg 43
understand the diagram
pg 44
