Lecture 4 II Flashcards
opsonization and phagocytosis
C3b
C3a
inflammation
inflammation 2nd round
C5a
after C5a
Lysis of microbe
what consists of several plama proteins that work together to opsonize microbes,
to promote the recruitment of phagocytes to the site of infection,
and in some cases to directly kill the microbes
the complement system
What are 3 things that can initiate the complement system?
Classical pathway
Alternative pathway
lectin pathway
What is the second step of complement activation?
C3b and formation of C3 convertase
What does C3b initiate activation of?
C5 and the formation of C5 convertase
What is the last step in the complement activation?
the formation of membrane attack complex, bc it creates holes in the plasma membrane
An inactive precursor enzyme called a zymogen is altered to become an active protease that cleaves the next complement protein in the cascasde…
proteolytic cascade
What does an enzymatic cascade result in?
A temendous amplification of the amount of proteolytic products that are generated
What does the proteolytic products that are generated perform?
vaious effector functions of the complement system
What does the complement system work in cooperation with?
Other medically important proteolytic casesed that include
the blood coagulation pathways
the kinin-kallikrein system that regulates vascular permeability
How does C3 b bind to a microbe?
covalent binding which forms C5 convertase
All three complexes of the complement pathways result in?
sequential recruitment and assembly of additional complement proteins into protease complexes
What cleaves the central protein of the complemetn system, C3?
C3 convertase
What does C3 convertase cleaving C3 produce?
C3a and C3b
What happens to the C3b fragment?
It becomes covalently attached to the microbial surface
What serves as an opsonin to promote phagocytosis of the microbes?
C3b
When the C3b fragment is realeased, it stimulates?
inflammation by acting as a chemoattractant for neutrophils
What do C3b binding to other completment proteins form?
A protease called C5 convertase, that cleaves C5
What does C5 convertase cleaving C5 produce?
a released peptide (C5a) and a larger fragment (C5b) that remains attached to the microbial cell membranes
C5a has a very important chemoattractant role of?
changing the permeabilliy of blood vessels
C5b initiates the formation of what complexes?
the complement proteins C6, C7, C8, and C9, which are assembled into a membrane pore
What is the membrane pore of C6, C7, C8, and C9 called?
the membrane attach complex (MAC)
What causes lysis of the cells where complement is activated/
MAC
What binds to the surface of a microbe, where it functions as an opsonin and as a component of C3 and C5 convertase
C3b
What stimulates inflammation?
C3
What is a serine protease adn the active enzyme of C3 and C5 conertases?
factor B
What is a plasma serine protease that cleaves factor B when it is bound to C3b?
Factor D
What stablizes the C3 convertase (C3bBb) on microbial surfaces?
properdin
What initiates the classical pathway?
C1 (C1qr2s2)
What does C1q bind to?
Fc portion of antibody
What are proteases that lead to C4 and C2 activation?
C1r and C1s
What does C4a stimulate??
inflmmation
What activates C4
C4b covalently binds to surface of microbe or cell where antibody is bound
C4b binds to C2 for cleavage by
C1s
a serine protease functioning as an active enzyme of C3 and C5 convertases
C2
What initiates the lectin pathway?
Mannose beinding lectin (MBL)- it binds to terminal mannose resideus of microbial carbohydrates.
What activates C4 and C2
an MBL associated protease
How does the classical pathway detect Abs bound to the surface of a microbe or other sturucture?
a plama protein called C1q
What happens once C1q binds to the Fc protion of the antibodies?
two associated serine proteases called C1r and C1s become active
What initae a proteiolytic cascade involving other complement proteins C2 and C4?
C1r and C1s
What does MBL recognize?
terminal mannose residues on microbial glycoproteins and glycolipids, similar to the mannose receptor on phagocyte membranes
What family is MBL a member of?
the collectin family
The MBL has what strucutre?
a hexamertric structure similar to the C1q component of the ocmplement system
What are activated after MBL binds to microbes?
two zymogens MASP1(mannose- associated serine protease 1 or mannan binding lectin associated serine protease) and MASP2 are activated
What functions do MAPS1 and 2 have?
Similar to C1r and C1s and initaite downstream proteolytic steps identical to the classical pathway
What three homologous hexameric protines can all initate the complement activation?
C1q, MBL and Ficolin
What binds to the Fc region of IgM and activates the serine protease activity of C1r and C1s? microbial surface antigetn
C1q
MBL binds to?
Mannose on the surface of microbes and acitvates MASP1 and MASP2 assocated with mannose binding lectin
What binds to N-acetylglucosamine(bacterial cell wall) on the surface of microbes and activates MASP1 and MASP2
Fibolin
What is the collectin family?
A fmaily of trimeric proteins with lectin head
What are soluble effector molecules in the innate immune system part of the sollectins?
MBL and pulmonary surfactant proteins (2) SP-A and (3)SP-D
what is a soluble PRR that binds carbohydrates with terminal mannose and fucose and enhances phagocytosis of microbes?
MBL
What are low MBL levels associated with?
increased susceptibility to a vairety of infections
What are collectins with lipophilic properties and their major functions are to maintina the ability of lungs to expand and as mediators of innate immune repsonses
SP-A and SP-d
What do SP-A and SP-D bind to?
Various microoganims and act as opsonins, faciciltating phagocytosis by alveolar macrophages
What direclty inhibit bacterial growht?
SP-A and SP-D
What directly activate macrophages?
SP-A and SP-D
What are plama protiens that are strucutally similar to collectins but they have a fibrinogen type carbohydrate recognition domain?
ficolins
What are humoral molecules of the innate immune system?
ficolins
What are the molecular ligands of the ficolins?
N-acetylglucosamine and the lipoteichoic acid component of the cell walls of gram- POSITIVE bacteria
Ficolins have been shown to beind serveral species of….
bacteria, opsonizing them and activating complemetn in a manner simlar to that of MBL
How does involement in a opsonin dependent phagocytosis effect?
limits the infection and concurrently orchestrating the subsequent adaptive clonal immune reponse
How is the lectin pathway of complemetn activated?
that attached serine proteases MASPs
How is the alternative pathway triggered?
when a complement protein called C3 directly recognizes certain microbail surface strucuteres such as bacterial LPS
What is constitutively activated in solution at a low level and binds to bacterail surfaces?
C3
What is the spontaneous activation amplified on?
microbial surfaces
What is the alternative pathway no activated on teh surface of mammalian cells?
the mammals have a regulatory protein that inhibits the activation of alternative pathway
What dissociate the complement C3 convertase (C3bBb) from host mammal cells?
decay- accelerating factor DAF), complement receptor 1 (CR1) adn factor I
What complex binds to membrane vai C7 in the formation of MAC?
C5b binds C6 and C7 and C5b67 complex
What inserts into the cell membrane in MAC?
c8 binds to C5b67 complex
What forms a pore in MAC
up to 19 molecules C9 bind and polymerize
What is MAC?
It is the cytolitic end complex. Membrane attack complex
inflammation
C5a, C3a
phagocytosis
C3b
lysis of microbe
MAC
C3a activation can happen spontaeously, so it has a much lower reaction than
C5a
Contraction of smooth muscles
C3a
C4a
C5a
+
(+)
++++
increased permeability of blood vessels
C3a
C4a
C5a
+
(+)
++++
Degranulation of basophils
C3a
C4a
C5a
+
(+)
+
Chomtaxis, release of O2 racials and lysosomal enzymes
C3a
C4a
C5a
++++
What helps kill microbes in phagolysosomes?
ROS, NO, and lysosomal enzymes
Microbes may be ingested by …. of phagocytes
different membrane receptors
What are microbes internalized into?
phagosomes
What fuse with lysosomes to form phagolysosomes?
phagosomes
How are the microbes killed?
Reactive Oxygen and Nitrogen species and proteolyitic enzymes
What are monocytes actived by?
microbial products such as LPS and by NK cell- derived IFN-gamma
What does monocyte activation lead to?
The activation of transcription factors, the trancription of vaious genes, and the synthesis of proteins
What are monocytes acvited by?
the stimuli from T lymphocytes such as CD40 ligand and IFN-gamma
- they may alternatively be acitvated by other signals to rpomote tissue repair and fibrosis
What lead to inflammation enhanced adaptive immunity?
cytokines TNF, IL-1, IL-6, IL-12
What is the principal cell source of tumor necrosis factor (TNF)
macrophages, T cells
What is the principal celluarl targets for TNF endothelial cells?
activation (inflammation, coagulation)
TNF neutrophils?
activation
TNF hypothalaums
fever
TNF liver
syntehsis of acute phase proteins
TNF mucsle, fat
catabolism (Cachexia)
TNF many cell types
apoptosis
principle cell source for IL-1
mcarophages, endothelial cells, some epithlieal cells
IL-1 endothelia cells
activation (inflammation, coagulation)
IL-1 hypothalmus
Fever
IL-1 liver
synthesis of acute phase protines
IL-1 T cells
Th17 differentiation
principal cell source for chemokines
macrophages, dendritic cells, endothelial cells, T lymphoctes, fibroblasts, platelets
chmokines leukoytes
increased integrin affinity, chemotaxis, activation
Principal cells for IL-12
dendritic cells, macrophages
IL-12 NK cells and T cells
IFN-gamma production, increased cytotoxic activity
IL-12 T cells
Th1 differentiation
IFN-a/b principal cell sources
IFN alpha- Dendritic cells, and macrophages
IFN-beta- fibroblast
IFN gama princiapl cell source
NK cells and T lymphocytes
Target of IFN gamma
activation of macrophages
stimulatioin of some antibody responses
IFN a/b targets
all cells; antiviral state, increased class I MHC expression NK cells activation
IL-10 principal cell source
macrophages, dendirtic cells, T cells
IL10 macrophages, dendritic cells
inhibition of IL12 production, reduced expression of costimulators and class II MHC molecules
IL6 principal cell source
macrophages, endothelial cells, T cells
IL-6 liver
synthesis of acute phase proteins
IL6 B cells
proliferation of antibody producing cells
IL15 principal cell source
macrophages and others
IL15 NK cells
porliferation
IL15 T cells
proliferation
IL18 principal cells source
macrophages
IL18 NK cells and T cells
IFN gamma synthesis
TGF beta principal cell source
many cell types
TGF beta inhibition of inflmmation T cells
differentiation of TH17, regulatory T cells
Local inflammation in endothelia cells
TNF, IL-1 act on adhsion molecule TNF increase permability and give off IL-1 chemokines
Local inflmmation of leukocytes
TNF, IL1 activation… gives IL1 IL6 chemokines
systemic protective effects of the brain
TNF, IL1, IL6 give fever
ststemic protective effects of the liver
IL1, IL6 give actue phase protiens
ststemic protective effect of bone marrow
TNF, IL1, IL6 produce leukocyte production
Systemic pahtologic effects on heart
TNF… low output
systemic pahtologic effects on endothlial cells/ blood vessel
TNF becasue of thrombus gives increased permablity
systemic pathologic effects on multiple tissues
TNF on skeletel muscles insulin resisitance
What have multiple local and systemic inflammatory effects?
TNF, IL1, IL6
what act locally on leukocytes and endothleium to induce acute inflmation/
TNF and IL1
TNF and IL1 induce?
the expression of IL6 from leukocytes and other cell types
What mediate protective systemic effects of inflmmation?
IL1, IL6 and TNF
What induce fever, acute phase protein synthesis by liver, and increased production of leukocytes by bone marrow?
TNF IL1 MAIN, IL6
TNF can cause septic shock, what are 3 pahtologic abnormalities?
decreased cardiac function
thrombosis and capillary leak
metabolic abnormalitites due to insulin resistance
several plama protines that recognize microbial structrue and partcipate in innate immunity belong to the
pentraxin family
What are acute phase protines from the pentraxin
C reactive protein (CRP) and serum amyloidP (SAP)
What can activate complement by binding C1q and intiaitng the classical pathway?
CRP and SAP
What do CRP and SAP recognize?
phosphorylcholine and phosphatidylethanolamine respectively, which are found on bacteria and apoptotic cells
Plasma concentrations of CRP and SAP are very low in helathy individuals but can?
Increase up to 1000-fold during infections and in response to other inflammatory stimuli
What does the increased levels of CRP and SAP result in?
An increased synthesis by the liver induced by cytokines IL6 and IL1, which are produced by phagocytes as part of the innate immune repsone
What are acute phase protines from the pentraxin family
C-reactive protien (CRP) and serum amyloid P (SAP)
opsonize
make more susceptible to phagocytosis
Acute phase reactant Dramatic increase in concentration... C-reactive protine mannose biding lectin alpha 1- acid glycoprotein serum amyloid P component
fixes complement, opsonizes
fixes complement, opsonizes
transport protein
amyloid component precursor
What are produced by virus infected cells?
Type 1 interferons (IFNalpha and IFNbeta)
What is the production of IFNa and IFNb triggered by?
response to intracellular TLR signaling and other sensors of viral RNA
What do IFNalpha and IFN beta bind to?
receptors on neighboring unifected cells and activate JAK STAT signaling pathways
What does the activation of the JAK STAT pathyway induce?
genes whoe products interfer with viral replication
IFNA and IFNb bind to receptors on infected cells and?
induce expression of genes whoe products enhance the cell’s susceptibility to CTL medicated killing
