Lecture 5: The Complement System Flashcards
Complement system
Plasma proteins that work together to opsonize microbes, promote the recruitment of phagocytes, and, in some cases, to directly kill the microbe
C3a involved in
Inflammation, by acting as a chemoattractant for neutrophils
C3b involved in
Opsonization and phagocytosis- attaches to microbial surface
C5a involved in
Inflammation- it is a potent chemoattractant that also induces changes in permeability of blood vessels
Early step 1
Formation of C3 convertase complexes that produce C3a and C3b which trigger inflammation and opsonization
Early step 2
Formation of C5 convertase complexes that produce C5a and C5b which perpetuate inflammation and initiate late steps
Late steps
Formation of MACs which form holes in microbial membranes
Complement activation involves
Proteolytic cascades in which a zymogen is altered to become and active protease that cleaves the next complement
C5 convertase formed from
C3b and C3 convertase
C5b
Attaches to bacterial membrane and initiates formation of a complex of C6-C9 proteins, forming MAC
MAC
Membrane attack complex
Multiple MACs cause bacterial leak and lysis
Alternative pathway Auto-activation and Tickover
Alternative pathway is capable of autoactivation because of “tickover” of C3, which spontaneously generates C3a and C3b
C3b and Factor B
C3b is capable of binding factor B which can be cleaved into Ba and Bb by protease factor D
Bb associates with
Bb associates with C3b, forming C3bBb (Alternative pathway C3 convertase), which can then cleave additional C3 molecules creating more C3b
Properdin
Stabilizes protein:protein interactions during the process of auto-activation and “tickover” in the alternative pathway
Alternative pathway amplification loop
Alternative pathway can be initiated as an amplification loop when fixed C3b that was generated by classical or lectin pathway activation binds Factor B
Classical pathway mediated by
Antibodies
Steps in classical pathway up to C3 convertase
C1q binds to Fc portion of Ig, activating C1r which activates C1s
C1s activates C2 and C4 into C2a/b and C4a/b
C4b joins C2a to form C4bC2a (C3) convertase
C3 convertase cleaves C3–> C3a/b
C3b joins C4bC2a complex to form C5 convertase
Lectin pathway
Activated MASP-2 cleaves C4 to C4a/b C4b binds to microbial surface MASP-2 also cleaves C2 to C2a/b C3a binds to surface C4b forming classical C3 convertase C3 convertase cleaves C3 to C3a/b C3b binds microbial surface
Lectin pathway C5 convertase consists of
C4bC2aC3b
What triggers the lectin pathway
Mannose binding lectin (MBL)
MBL function
Recognizes terminal mannose residues on microbes
Activates zymogens MASP1 and MASP2
Alternative pathway differences from classical
C3 undergoes spontaneous hydrolysis
Factors B and D are needed
C3bBb is the C3 convertase
C3bBbC3b is C5 convertase
Lectin pathway differences from classical
Does not use C1
When MBP binds to bacteria, MASPS are activated
Same convertases as classical
T or F: Compliment system may be activated on surface of mammalian cells
False, they express regulatory proteins that inhibit, disassemble or cleave the convertases
DAF function
Blocks C2-C4b interaction
DAF or CR1 enhance what
Dissociation of C4bC2a interaction
CR1 and Factor I (FI) function
Cleave C4b and C3b
FI is also known as (think of its function)
C3b/C4b inactivator
Inflammatory effects of C3a
Some contraction of smooth muscles and increased permeability of blood vessels
Degranulation of basophils
Inflammatory effects of C5a
Strong contraction of smooth muscles and permeability of blood vessels
Degranulation of basophils
Chemotaxis, release of O2 radicals and lysosomal enzymes
TNF and IL-1 act on
Act locally on leukocytes and endothelium to induce acute inflammation, and induce the expression of IL-6 from leukocytes and other cells
TNF, IL-1 and IL-6 work together to mediate
Mediate protective systemic effects of inflammation (fever, APP synthesis, leukocytosis)
Side effect of systemic TNF
Can cause pathologic abnormalities that lead to septic shock
CRP and SAP are
APPs
Plasma concentration of CRP and SAP in healthy individual
Concentrations are low but can increase 1000-fold during infection
What synthesizes SAP and CRP and what stimulates synthesis
Synthesized by liver, stimulated by IL-1 & IL-6
CRP recognizes
Phosphorylcholine on bacteria
SAP recognizes
Phosphatidylethanolamine on apoptotic cells
SAP and CRP can activate
Complement system by binding C1q and activating classical pathway
What stimulates production of IFN-a and IFN-b
TLR mediated signaling which activates IRF transcription factors
IFN-a/b function on infected cells
Bind to receptors on infected cells inducing the expression of genes whose products enhance the cells susceptibility to CTL-mediated killing
Function of IFN-a/b on uninfected cells
INF-a/b produced by infected cells can bind to receptors on uninfected cells, activating JAK-STAT pathway which activates genes whose products interfere with viral replication
Signal one for the activation of lymphocytes is caused by
Ag recognition by B cells
Signal two for the activation of lymphocytes
Molecules induced by innate immune responses to microbes provide signal two
