agosti sec01 001-018 - lippincott williams &...
TRANSCRIPT
General Maps
Agosti_Sec01_001-018.qxd 2/21/07 7:56 PM Page 1
2 C O M P L E M E N T C A S C A D E N O T E S
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3C O M P L E M E N T C A S C A D E
cascade is composed of serum complementproteins produced mainly by hepatocytes
complement activation occurs in 3 ways
MB-lectin pathway
acute phase protein calledmannan binding lectin (MBL)binds mannose residuesfound on pathogen surface
alternative pathway
complement protein C3 isspontaneously activated(usually by pathogen surface molecules) viahydrolysis
MBL is then bound byMBL associated serine protease (MASP) C3 directly binds pathogen surface
pathogen-MBL-MASPcomplex behaves just like C1s
leading to the formation ofC3 convertase
follows classic pathway fromthis point on
C3 forms
C3a =anaphylatoxin
C3b
C3b binds factor Band forms C3bB complex
C3bB complexis cleaved by factor D
into C3bBb
C3bBb behaves just likeC3 convertase
follows classic pathway fromthis point on
classic pathway
pathogen invades body
complement protein C1qbinds antibody-antigen complexfound on pathogen surface
C1q forms complementprotein C1s
C4b and C2b join to formC3 convertase
C2 intoC2b
C4 intoC4b
C4 into C4a =anaphylatoxin
C1s cleaves complementproteins:
C3 convertase cleavescomplement protein C3 into
C3a =anaphylatoxin
C3b also bindsC4b2a to formC4b2a3b or
C5 convertase
C5 convertase cleavescomplement protein C5 into
C5b binds C6to form C5bC6
C5bC6 binds C7to form C5b67
C5a =anaphylatoxin
cause more inflammationby binding and activatingother inflammatory cells
can lead toanaphylaxis
C5b67 bindsC8 to form
C5b678
C5b678 binds C9forming the
membrane attack complex
a pore forms inmembrane of pathogen
pore allows water and ionsinto organism causing
cell lysis
produces many molecules ofC3b which amplifies thecomplement cascaderesponse
C3b coats pathogenand marks it for phagocytosis =opsonization
complement cascadeis activated as part of theimmune response in order to:• mark pathogens for elimination by other cells of the immune system• lyse pathogens directly
both of these pathways occur without the help of antibodies = innate immune response
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4 C O A G U L AT I O N C A S C A D E N O T E S
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5C O A G U L AT I O N C A S C A D E
intrinsic pathway abnormalitiesmeasured byactivated partialthromboplastin time (aPTT)
intrinsicpathway
in response toinjury "within" bloodvessels:• damaged vessel endothelium• damaged platelets
in responseto tissue injury"outside" blood vessels
extrinsicpathway
begins by the creationof a complex between:
factor VII• calcium• tissue factor (TF)• thromboplastin
this complexactivatesfactor VII to VIIa
factor VIIa activates:
factor X to Xa
extrinsic pathwayabnormalitiesmeasured byprothrombin time (PT)
series of enzymatic reactionsthat occur within
secondary hemostasis (see map)in order to form fibrin
occurs on surfaceof activated platelets
and vascular endothelium
divided into 2interconnected pathways
begins by the creationof a complex on vascularsubendothelium between:
• factor XII (aka Hageman factor)• high molecular weight kininogen (HMWK)• Prekallikrein
this complexactivatesfactor XII to XIIa
factor XIIa activates:
Prekallikrein to kallikrein factor XI to XIa
kallikrein converts: factor XIa activatesfactor IX to IXa
plasminogen toplasminHMWK to bradykinin
leads to:• Ò vascular permeability• smooth muscle constriction• vascular vasodilation
activates complementcomponent C3 to C3a(see complement cascade map)
plasmin initiates fibrinolysisas it degrades fibrin intofibrin split products
fibrinolysis can bemeasured in lab as an Ò :• d-dimer level
IXa becomes apart of a new complexincluding:
• IXa• VIIIa• X
this complexactivatesX to Xa
Xa initiates thecommon pathwayby forming a complexbetween:
• Xa• Va• calcium• phospholipid
this complexcleavesprothrombin (factor II)into thrombin
fibrin is cross-linkedby factor XIIIa
amplifiesthe coagulation cascadeby activating factors:• V• VIII• XI• XIII
stimulatesplatelet aggregationand granule secretion(see hemostasis map)
permanent clot isformed as fibrincombines withplateletaggregates
common pathway abnormalitiesmeasured by both PT and aPTT
thrombin
main role ofthrombin is to convert
fibrinogen (factor I) to fibrin
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6 C E L L - M E D I AT E D I M M U N I T Y N O T E S
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7C E L L - M E D I AT E D I M M U N I T Y
first
exp
osur
e to
antig
en:
• int
race
llula
r• t
umor
cel
l
antig
en is
del
iver
ed to
seco
ndar
y ly
mph
oid
tissu
e
antig
en p
rese
ntin
g ce
ll (A
PC)
disp
lays
ant
igen
to n
aive
T c
ell v
iape
ptid
e: c
lass
I M
HC
com
plex
T ce
ll ac
tivat
ion
orpr
imin
g
activ
ated
T c
ell
unde
rgoe
s pr
olife
ratio
n, d
iffer
entia
tion
and
clon
al e
xpan
sion
into
ant
igen
spe
cific
effe
ctor
T c
ells
CD
4 he
lper
T c
ell
activ
ated
T c
ell
secr
etes
IL 2
prom
otes
furth
ercl
onal
exp
ansi
on
cyto
toxi
c C
D8
T ce
ll
activ
ates
end
othe
lium
enab
les
infla
mm
ator
yre
spon
se to
pro
gres
s(s
ee a
cute
infla
mm
atio
n m
ap)
prol
ifera
tion
of e
ffect
or T
cel
lpo
pula
tion
ampl
ifies
infla
mm
ator
yre
spon
se
trave
ls to
site
of in
fect
ion
rele
ases
cyt
okin
es s
uch
as:
• IFN
gam
ma
• TN
F al
pha
rele
ases
cyt
otox
ins
such
as:
• per
forin
• gra
nzym
es
kill
infe
cted
targ
et c
ell b
yin
duci
ngap
opto
sis
in 2
way
s:• c
ytot
oxin
s• F
as li
gand
IFN
gam
ma
enha
nces
act
ivat
ion
ofm
acro
phag
es
activ
ates
mac
roph
ages
via
IFN
gam
ma
and
CD
40 li
gand
mac
roph
ages
pha
gocy
tize
bact
eria
or o
ther
offe
ndin
g ag
ent
byst
ande
rtis
sue
dam
age
gran
ulom
a fo
rms
if m
acro
phag
esar
e un
able
to e
limin
ate
antig
en(s
ee s
arco
id a
nd T
B m
aps)
Ò e
xpre
ssio
nof
MH
C c
lass
IIm
olec
ules
and
B7
cost
imul
ator
y si
gnal
s
Ò a
ntig
enpr
esen
tatio
n to
T c
ells
ampl
ifies
imm
une
resp
onse
help
s T
cell
deve
lop
effe
ctor
func
tions
CD
4 T
cell
furth
erdi
ffere
ntia
tes
into
1 of
2 T
-hel
per c
ell t
ypes
if se
cret
es a
Th2
cel
l cyt
okin
epr
ofile
if se
cret
es a
Th1
cel
l cyt
okin
e pr
ofile
cell
med
iate
d in
flam
mat
ory
resp
onse
hum
oral
imm
une
resp
onse
( see
map
)
APC
als
o pr
ovid
es T
cel
lw
ith c
ostim
ulat
ory
sign
al (B
7 m
olec
ule)
bind
s C
D28
rece
ptor
on
T ce
ll
lack
of c
ostim
ulat
ory
sign
al c
ause
s an
ergy
=T
cell
unab
le to
resp
ond
to a
ntig
enic
stim
ulat
ion
activ
atio
n ph
ase
thes
e 2
path
way
s ar
e no
t alw
ays
mut
ually
exc
lusi
ve
effe
ctor
pha
se
effector functions include
Agosti_Sec01_001-018.qxd 2/21/07 7:56 PM Page 7
8 H U M O R A L I M M U N I T Y N O T E S
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9H U M O R A L I M M U N I T Y
first
exp
osur
e to
ant
igen
elic
its a
prim
ary
adap
tive
imm
une
resp
onse
2 ty
pes
of a
ntig
ense
en b
y B
cells
durin
g th
is re
spon
se
thym
us in
depe
nden
tan
tigen
s =
B ce
lls d
on't
need
T c
ell h
elp
toac
tivat
e
thym
us d
epen
dent
antig
ens
= B
cells
do
need
T c
ell h
elp
to a
ctiv
ate
antig
en is
del
iver
edto
lym
ph n
ode
whe
reit
is re
cogn
ized
by
both
B a
nd T
cel
ls
antig
en is
bou
nd b
y su
rface
IgM
on
naiv
e B
cel
l
antig
en is
proc
esse
d an
dpr
esen
ted
by A
PC to
naiv
e T
cells
CD
4 he
lper
T c
ells
activ
ated
secr
etes
Th2
cel
lcy
toki
ne p
rofil
e:• e
spec
ially
IL 4
secr
etes
Th1
cel
lcy
toki
ne p
rofil
e
cell-
med
iate
din
flam
mat
ory
resp
onse
(see
map
)
antig
en is
inte
rnal
ized
,pr
oces
sed
and
then
pres
ente
d on
aM
HC
cla
ss II
mol
ecul
eto
Th2
cel
l
linke
d re
cogn
ition
=ac
tivat
ion
of B
cel
l req
uire
s an
tigen
reco
gniti
onby
bot
h B
and
T ce
lls
T he
lper
cel
ls p
rodu
ceC
D40
liga
nd
CD
40 li
gand
on
T ce
llsbi
nds
CD
40 re
cept
or o
nB
cell
and
indu
ces
activ
atio
n of
the
B c
ell
B ce
lls fo
rm a
prim
ary
focu
sw
ithin
the
lym
ph n
ode
for c
lona
l exp
ansi
on(im
med
iate
resp
onse
)
enab
les
isot
ype
switc
hing
and
help
s th
e ge
rmin
al c
ente
rto
sur
vive
B ce
lls tr
avel
to p
rimar
y ly
mph
oid
folli
cle
form
a g
erm
inal
cen
ter w
here
antig
en s
peci
fic B
cel
ls c
alle
d ce
ntro
blas
ts p
rolif
erat
e
B ce
lls w
hich
hav
e a
less
erab
ility
to b
ind
the
antig
endi
e of
f with
in th
e ge
rmin
alce
nter
= n
egat
ive
sele
ctio
n
som
atic
hyp
erm
utat
ion
= cr
eate
s a
set o
f B c
ells
with
var
ying
abi
lity
to b
ind
the
sam
e an
tigen
occu
rs a
t the
sam
etim
e as
isot
ype
switc
hing
diffe
rent
cla
sses
of a
ntib
odie
ssp
ecifi
c fo
r the
sam
e an
tigen
are
prod
uced
resu
lts in
a s
mal
l num
ber o
f the
seB
cells
that
hav
e a
grea
ter a
bilit
y to
bind
the
antig
en =
affi
nity
mat
urat
ion
B ce
lls w
ith th
e hi
ghes
t affi
nity
for t
he a
ntig
enar
e se
lect
ed a
nd g
ive
rise
to b
oth
mem
ory
B c
ells
prov
ides
bod
y w
ithab
ility
to fi
ght f
utur
e ex
posu
reto
sam
e an
tigen
=se
cond
ary
adap
tive
imm
une
resp
onsepl
asm
a ce
lls
secr
etes
ant
ibod
ies
into
ser
um
allo
w fo
r2
mai
n ef
fect
or fu
nctio
nsof
B c
ells
to b
e ca
rried
out
agai
nst a
ntig
en
neut
raliz
epa
thog
ens
=bi
ndin
g an
d pr
even
ting
path
ogen
s fro
men
terin
g ce
lls
enab
leph
agoc
ytos
is v
ia2
way
s:• o
pson
izat
ion
• com
plem
ent
act
ivat
ion
(see
map
)
maj
ority
of a
ntig
ens
seen
by
B ce
lls
hum
oral
imm
une
resp
onse
cann
ot b
egin
with
out B
and
T c
ell c
oope
ratio
n
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10 A C U T E I N F L A M M AT I O N N O T E S
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11A C U T E I N F L A M M AT I O N
• inf
ectio
n• t
raum
a• e
xpos
ure
to p
hysi
cal o
r che
mic
al a
gent
s• t
issu
e ne
cros
is• f
orei
gn b
odie
s• h
yper
sens
itivi
ty re
actio
ns (s
ee m
aps)
• end
othe
lial i
njur
y
insu
lt el
icits
an
imm
edia
te re
spon
se (i
n se
cond
s to
min
utes
)by
bod
y's
imm
une
syst
em =
acut
e in
flam
mat
ion
3 m
ain
com
pone
nts
begi
ns w
ithac
tivat
ion
of e
ndot
heliu
m
vasc
ular
reac
tion
=de
liver
s pl
asm
a pr
otei
nsan
d im
mun
e ce
lls to
site
of in
flam
mat
ion
cellu
lar r
eact
ion
=le
ukoc
yte
extra
vasa
tion
and
activ
atio
n
leuk
ocyt
e m
argi
natio
n
leuk
ocyt
e ro
lling
and
pave
men
ting
leuk
ocyt
e ad
hesi
on
3. le
ukoc
yte
mig
ratio
n or
dia
pede
sis
thro
ugh
endo
thel
ium
chem
otax
is to
war
dsi
te o
f inj
ury
or in
fect
ion
leuk
ocyt
e ac
tivat
ion
and
phag
ocyt
osis
elim
inat
ion
of o
ffend
ing
agen
t
lead
s to
1 o
f 3 o
utco
mes
:• r
esol
utio
n• h
ealin
g w
ith fi
bros
is• p
rogr
essi
on to
chr
onic
infla
mm
atio
n (s
ee m
ap)
tissu
e in
jury
chem
ical
sig
nals
for c
hem
otax
is p
rovi
ded
by:
• bac
teria
l pro
duct
s• a
naph
ylot
oxin
s (C
5a)
• leu
kotri
enes
• cyt
okin
es
2. Ò
blo
od fl
ow a
nd v
isco
sity
med
iate
d pr
imar
ily b
y:• h
ista
min
e• n
itric
oxi
de
brad
ykin
in fr
omac
tivat
ion
of th
eki
nin
syst
em
1. in
crea
sed
vasc
ular
perm
eabi
lity
via:
• end
othe
lial c
ontra
ctio
n• d
irect
inju
ry• l
euko
cyte
indu
ced
inju
ry• a
ngio
gene
sis-
rela
ted
leak
age
bloo
d vi
scos
ity Ò
as e
xuda
te e
scap
esin
to s
urro
undi
ng ti
ssue
vaso
dila
tion
exud
ate
cont
ains
com
plem
ent p
rote
ins
whi
ch c
an b
ecom
e ac
tivat
ed(s
ee c
ompl
emen
t cas
cade
map
)
elab
orat
es th
e ac
ute
infla
mm
ator
y re
spon
se v
ia:
• Ò v
ascu
lar p
erm
eabi
lity
• leu
kocy
te a
dhes
ion,
che
mot
axis
and
act
ivat
ion
• pha
gocy
tosi
s vi
a op
soni
zatio
n
bloo
d st
asis
allo
ws
leuk
ocyt
es to
colle
ct a
long
vas
cula
ren
doth
eliu
m
Agosti_Sec01_001-018.qxd 2/21/07 7:56 PM Page 11
12 C H R O N I C I N F L A M M AT I O N N O T E S
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13C H R O N I C I N F L A M M AT I O N
continuous activation of T cells
release ofIFN gamma
work in concert toÒ intracellularadhesion
Ò inflammatorycell recruitment andexacerbates inflammatory response
leads to a state of chronic inflammation
accumulation and activation ofmacrophages
cytokines releasedtissue wasting Ò microbicidal
activity Ò cytokine releaseÒ expression ofMHC II molecules
Ò antigenpresenting cellfunctions
release ofTNF α
fibroblast proliferationtissue damage
release ofreactive oxygen speciesand reactive nitrogen species
collagen production
fibrosis
alters structureand function ofinvolved tissues
regardless of etiologyantigen is unable tobe cleared by immunesystem
etiologies include:• ongoing infection• acute inflammation• tissue damage from chronic disease• toxic exposure• autoimmunity• malignancy
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14 R E N I N - A N G I OT E N S I N - A L D O S T E R O N E S YS T E M N O T E S
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15R E N I N - A N G I OT E N S I N - A L D O S T E R O N E S YS T E M
Ú in circulatingblood volume due to:• hypovolemia• Ú total peripheral resistance (TPR)• congestive heart failure (CHF)
kidneys senseÚ blood volume
via 3 mainmechanisms
Ú stretch ofrenal baroreceptorsin afferent arterioles
Ú NaCl deliveryand reabsorption
across macula densa
Ú stretch ofbaroreceptors
in central arterialcirculation
causes Úin calcium concentration
leads to renin releasedby JGA cells into
circulationAT IIsuppresses reninrelease
renin is cleavedby angiotensinogeninto angiotensin I
(inactive form)
stimulation of the AT I receptorcauses multiple
short term physiologicactions which Ò
the circulating volume
Ò sympathetic outflowto beta receptors on
juxtaglomerular cells (JGA)
AT I travels to lungswhere it is cleaved by ACE
into AT II (active form)
ACE cleavesbradykinin
bradykinin
kininogen
kallikrein
inactivepeptides
AT I receptor located in:• vasculature• kidney• adrenals• heart• brain
bradykinin:• vasodilates• decreases platelet aggregation
AT II receptors located in:• vascular endothelium• brain• adrenal glands
opposite affect of AT I
Ò bradykinin
Ò risk of:• atherosclerosis• blood clots
inhibits:• TPA• UPA• protein C
Ò plasminogen activator inhibitor-I(PAI-I )
othereffects
long-term physiologic actionslead to structural changesand disease
• fibrosis• inflammation• hypertrophy
• thrombosis• hypertrophy• vasoconstriction• intimal thickening• hypertrophy of smooth muscle cells
• hypertrophy of myocytes• Ò matrix formation• fibrosis
worsens chronickidney disease(see map)
worsening hypertensionand vascular disease(see maps)
worsensheart failure(see map)
Ò afterloadon heart
Ò peripheralvascular
resistance
smooth muscleconstrictionin systemicvasculature
Ò myocardialcontractility
Ò risk ofarrhythmias
Ò adrenergictone
enhancesrelease of catecholamines
from adrenal medulla
Ò in:• nitric oxide• cyclic GMP
acts onhypothalamus
to stimulate thirstand ADH release
Ò intotal bodyfree water
acts onzona glomerulosaof adrenal cortex
to releasealdosterone
Ò sodiumreabsorption
at distal tubules
Ò fluidreabsorpbtion
causes constriction ofefferent arterioles
more than afferent arteriolesto Ò perfusion pressure
Ò water andsodium
reabsorption
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16 H E M O S TA S I S N O T E S
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17H E M O S TA S I S
norm
al e
ndot
heliu
mdo
es n
ot a
llow
inac
tivat
ed p
late
lets
to a
dher
e
1. a
nti-p
late
let f
unct
ions
endo
thel
ium
syn
thes
is o
fni
tric
oxi
de a
nd p
rost
acyc
lin (P
GI2
)ca
uses
:• v
asod
ilatio
n• i
nhib
ition
of p
late
let a
ggre
gatio
n
expr
essi
on o
f ade
nosi
nedi
phos
phat
ase
whi
ch d
egra
des
ADP
and
prev
ents
pla
tele
t agg
rega
tion
inhi
bits
coa
gula
tion
casc
ade
fact
ors:
Va VIIIa
activ
atio
n of
pro
tein
C(s
ee c
oagu
latio
nca
scad
e m
ap)
thro
mbo
mod
ulin
bin
dsan
d co
nver
ts th
rom
bin
into
an a
ntic
oagu
lant
2. a
nti-c
oagu
lant
func
tions
3. fi
brin
olyt
icfu
nctio
ns
synt
hesi
zes
tissu
e ty
pepl
asm
inog
en a
ctiv
ator
(t-P
A)w
hich
hel
ps to
cle
ar fi
brin
dep
osits
from
the
endo
thel
ium
by
activ
atin
gpl
asm
inog
en to
pla
smin
allo
ws
for l
iqui
d bl
ood
flow
via
3 m
ajor
mec
hani
sms:
tissu
e fa
ctor
path
way
inhi
bito
r
endo
thel
ium
mem
bran
eas
soci
ated
hep
arin
-like
mol
ecul
es a
ugm
ent
antit
hrom
bin
III
inac
tivat
eco
agul
atio
n fa
ctor
s:• X
a, IX
a, X
Ia, X
IIa• t
hrom
bin
the
pref
erre
d st
ate
unde
rno
rmal
con
ditio
ns
norm
al h
emos
tasi
s =
bala
nce
betw
een
anti-
and
pro
-thro
mbo
ticfu
nctio
ns
anti-
thro
mbo
tic fu
nctio
nspr
o-th
rom
botic
func
tions
occu
r in
resp
onse
toin
jure
d va
scul
aren
doth
eliu
m
loca
l neu
rohu
mor
al fa
ctor
sca
use
trans
ient
arte
rial
vaso
cons
trict
ion
synt
hesi
zes
tissu
e fa
ctor
thro
mbo
geni
c su
bsta
nces
of
the
sube
ndot
helia
l ext
ra c
ellu
lar m
atrix
expo
sed
to b
lood
flow
plat
elet
s ad
here
via
vW
F to
inju
red
endo
thel
ium
and
bec
ome
activ
ated
secr
ete
gran
ules
con
tain
ing
ADP,
thro
mbo
xane
A2
whi
ch le
ad to
:
coag
ulat
ion
casc
ade
(see
map
) casc
ade
ultim
atel
yac
tivat
es th
rom
bin
thro
mbi
n co
nver
tsfib
rinog
en in
to fi
brin
loca
l fib
rin d
epos
ition
occ
urs
at th
e si
te o
f vas
cula
r inj
ury
fibrin
and
pla
tele
t agg
rega
tes
com
bine
to fo
rma
perm
anen
t plu
g
thro
mbi
n al
sore
crui
ts m
ore
plat
elet
s an
dle
ads
to fu
rther
gran
ule
rele
ase
prev
ents
furth
erhe
mor
rhag
e
recr
uitm
ent o
fm
ore
plat
elet
s an
dpl
atel
etag
greg
atio
n
prim
ary
hem
osta
sis
secondary hemostasis
form
atio
n of
ahe
mos
tatic
plug
Ú th
rom
bin
form
atio
n
allo
ws
for
Ò fi
brin
olys
is
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