Lecture 4-2, complement system Flashcards
What functions will the complement system work to achieve?
- opsonize microbes
- recruit phagocytes
- possibly directly kill microbe
What are the different pathways that can be activated in the complement system?
- alternative pathway
- classical pathway
- lectin pathway
What does the complement system work in cooperation with what other proteolytic cascades?
- blood coagulation pathways
2. kinin-kallikrein system that regulates vascular permeability
Early step 1 of complement activation forms what?
- C3 convertase complexes form C3a and C3b, which produce inflammation and opsonize microbes respectively
Early step 2 of the complement activation forms what?
C5 convertase, which forms C5a and C5b. Start inflammation and start the late steps
What is the late step of complement activation pathway?
form MAC to punch holes into the microbial membranes
What is a strong chemoattractant that can induce changes to blood vessel permeability?
soluble C5a
What is required to activate the classical complement pathway?
- IgM, IgG and C1q,r,s complex
What forms the C3 convertase in the classical pathway?
C4b and C2a
What forms C5 convertase in the classical pathway?
C4b, C2a, C3b
Is the classical system considered innate or adaptive in nature?
not innate, as an Ab is required in order to activate
Of the three pathways which one is the most sensitive? The least?
- Classical
2. Alternative
How is the Lectin pathway activated?
- MBP binds with bacteria and activates MASPs which then contribute to the formation of C4b and C2a
How is the alternative pathway activated?
C3 undergoes spontaneous hydrolysis and combines with factor B and D to form C3b and Bb
What forms C3convertase in the alternative pathway?
C3b and Bb
What forms C5 convertase in the alternative pathway?
C3b, Bb, C3b
What is unique about the alternative pathway?
It can activate C5 convertase, by contacting an organism and also form an amplification loop.
What is required in order to produce the C3b and Bb complex?
Factor D
If properdin is present, what happens when C3b, Bb is formed?
- complex C3b, Bb, P is formed which forms an amplification loop to activate more C3b
If no properdin is present, what is formed in the alternative pathway?
The C3b, Bb complex will combine with another C3b, complex to form C5 convertase and induce the MAC
How is the lectin pathway activated?
1.mannose binding lectin, recognizes and binds with terminal mannose residues on microbial glycoproteins or glycolipids
What is the major role of MBL?
these mediate and active that pathway of when an Ag is present. What happens with too many/too few?
How do Sp-A and SP-D operate or act as?
similar to opsonins, that are located in the alveoli
-inhibit bacterial growth, can activate macrophages
What is ficolin and what does it bind with?
- similar to mannose binding lectin
2. binds N-acetylglucosamine to activate MASP1-2
What type of molecule is ficolin?
humoral molecule of innate immune system
When ficolin bind to bacteria what is the result?
- limit infection and direct adaptive immunity response via opsonization
- initiate lectin pathway by activating MASP1-2
Which complex forms the pore of the MAC?
- C9
- C5b, 6, and 7 bind to PM via C7
- C8 also binds and anchors into the PM
How is the complement system useful in attacking microbes but not our own mammalian cells?
mammals express regulatory proteins that inhibit, destroy the convertases, and therefore can’t signal them for the formation of MAC
What does the decay accelerating factor do? (DAF)
blocks the C2:C4 interaction
can also cause dissociation of C4b:C2a complex
What does complement receptor 1 (CR1) do on mammalian cels?
cause dissociation of C4b:C2a complex
also cleaves the C4b and C3b
What does factor I (FI) do on the surface of mammalian cells?
cleaves the C4b and C3b
What do products C5a, and C3a help to initiate?
produce inflammation at the site, and will therefore attract leukocytes
In what ways are tissue macrophages activated?
- CD40 ligan and IFN-gamma (t lymphocyte stimui)
2. chemotaxis of tissue repair/fibrosis
If tissue macrophages are activated what will this activate?
synthesis of proteins
What cytokines act on local leukoctyes and endothleium to produce inflammation?
TNF and IL-1
- both will cause expression of IL-6
What cytokines are responsible for fever, acute phase protein synthesis and increased lymphocyte production?
TNF, IL-1, IL-6
What pathologic abnormalities can systemic TNF release cause?
- decreased cardiac function
- thrombosis/capillary leakage
- metabolic abnormalities from insulin resistance
What are Acute Phase Proteins (APP) from the pentraxin family?
- C-reactive protein
2. serum amyloid
The increased level of CRP and SAP comes from where, which is under the influence of IL-1 and IL-6?
the liver
CRP recognizes what PM structure?
phosphorylcholine
SAP recognizes what PM structure?
phosphatidylethanolamine
Where are Type I interferons produced (IFN-alpha/beta)
virus-infected cells
What happens when IFN-alpha/beta bind uninfected cell?
a JAK-STAT signaling pathway is activated which produces proteins to interfere with viral replication
What happens when IFN-alpha/beta bind infected cells?
cause the expression of genes the enhance the susceptibility to CTL-mediated killing
TNF is a cytokine mediator for what?
acute inflammation of bacteria and other infectious microbes
What two components are able to cause TNF production?
PAMPs and DAMPs
pathogen and damage/danger associated molecular patterns
Which receptors activate the NF-kB transcription factor, and produce what with that activation?
- TLR, NLR, RLR
2. ultimately produce TNF expression
Production of IL-1 generally requires two signals, that are what?
- activation of new gene transcription
2. activation of inflammasomes
What structures generate the IL-6 in response to PAMPs?
- mononuclear phagocytes
- vascular endothelial cells
- fibroblasts
- cells responding to IL-1
What cells secrete IL-12?
- DC
2. macrophages
What does IL-12 do when released?
- generate IFN-gamma production from NK and T cell
2. promotes differentiation of Th1 cells which defend against intracellular infection
What is IL-18 used for?
- enhances function of NK cells
2. production is based on activation of inflammasome
What is IL-15 used for?
- growth stimulating and survival for NK and CD8+ T cells
When TLR receptors are activated by a microbe, what do macrophages release, and what does this cause in the body?
- TNF, IL-1, IL-6, IL-2
2. produces inflammation and activates the adaptive immune resposne
If cytokine receptors are activated by IFN-gamma, what type of response does the activated macrophage produce?
- kill microbes via use of ROS and NO
2. still also able to generate a inflammatory response with IL-6, IL-2, IL-1, TNF
Which cytokines are responsible for inducing fever in people?
- TNF and IL-1
2. IL-1 has a stronger response, and is most responsible
How do TNF and IL-1 generate the production of a fever?
- increase the production of prostaglandins in hypothalamic cells
What do medications, like aspirin, do to combat fever?
- block the action of cytokines (TNF, IL-1) and prevent prostaglandin synthesis stimuli
What does TNF do to produce hypotension or shock?
- inhibits myocardial contractility and vascular smooth muscle tone
What is the effect of prolonged production of TNF?
- cachexia: necrosis of muscle and fat cells
2. caused by appetite suppression and reduced levels of lipoprotein lipase.
