Lecture 3: Regulation of Complement Flashcards
What is the classical pathway of the complement system activated by?
antibodies -> IgA and IgG
What is the lectin pathway of the complement system activated by?
mannose-binding lectin binding to mannose
What is the alternative pathway of the complement system activated by?
spontaneous hydrolysis of the C3 protein
What is the role of the membrane attack complex?
perforation or lysis of bacterial cells
How does complement form the MAC?
cell-bound C5b binds C6 and C7 (hydrophobic)
C5bC6C7 inserts into cell membrane and binds C8
C5bC6C7C8 cause polymerisation of C9 -> forms MAC and promotes cell death by osmotic rupture and apoptosis
What is common between all pathways of the complement system?
all pathways generate a C3 convertase, which cleaves C3, leaving C3b bound to the microbial surface and releasing C3a
What is a major part of the complement defence system?
opsonisation of the C3b protein
What is opsonisation?
coating of cells to promote phagocytosis e.g. C3b or C4b bound to microbes
What is an opsonin?
material that coats particles to promote opsonisation e.g. C3b or C4b
What are some examples of receptors for complement proteins and what are they expressed by?
CR1 (CD35) and CR3 (Mac-1, CD11bCD18)
expressed predominantly by macrophages and neutrophils
What is the main function of CR1 and CR3?
phagocytosis, clearance of immune complexes and adhesion to endothelium
What is CR1-mediated phagocytosis enhanced by?
C5a and specific IgG binding to microbe
if both are present then CR1-mediated phagocytosis is enhanced even more
How are immune complexes cleared?
small antigen:antibody complexes form in circulation and activate complement -> many molecules of C3b bind covalently to the complex -> bound C3b binds to CR1 on erythrocyte surfaces -> in the spleen and liver, phagocytic cells remove the immune complexes
Where is CR2 expressed and what is its function?
expressed on B lymphocytes and FDCs
co-receptor for B cell activation, traps Ag in germinal centres, receptor for EBV
What plays a major role in the recognition of cleavage products of C3b?
factor I and MCP cofactor
Why is CR2 present on B cells?
allows for activation of a strong antibody response providing that all other important signals have been received
What are C3a and C5a and what do they do?
anaphylatoxins which cause inflammation and they bind to C3a and C5a receptors found on mast cells, endothelial cells and phagocytes
How does C3a and C5a induce inflammation?
induce TNFa and histamine release by mast cells which causes leakage of blood vessels and migration of leukocytes
What does the complement cascade result in?
opsonisation and enhanced phagocytosis, direct lysis, leukocyte chemotaxis and inflammation, B cell activation
What can the complement cascade attack?
extracellular bacteria, free virions, parasites
Why is the complement cascade tightly regulated?
limits complement-mediated damage on host cells and limits C3 “tick-over” activation
What are regulatory elements of the complement cascade?
soluble factors: factor I with assistance from factor H cleaves / inactivates C3b
membrane bound factors: DAF, CR1 and MCP regulate C3 convertase production + CD59 inhibits MAC formation
Why are foreign cells attacked by the complement cascade?
because foreign cells do not have regulatory proteins
RBCs have low levels of complement regulators, thus more susceptible to lysis
What is the role of C1 INH?
prevents C1r2s2 from becoming proteolytically active
also inactivates MASP2
How does factor I inactivate C3b?
acts as a cofactor which proteolytically degrades C3b so that it can’t interact with anything anymore
What is the role of C5 convertases?
cleave C5 to C5a and C5b
these proteins can be inhibited to prevent the complement cascade from continuing
How is formation of the MAC inhibited?
CD59 inhibits poly-C9 assembly and S protein inhibits membrane insertion of C5b-C7
What are other important functions of complement?
solubilisation and clearance of immune complexes
How do pathogenic microbes evade the complement system?
recruit host complement regulatory proteins, produce specific proteins to mimic human complement proteins (e.g. C1q binding protein by E. coli) and inhibition of complement mediated inflammation (S. aureus CHIPS)
How do pathogenic microbes recruit host complement regulatory proteins?
express or scavenge sialic acid, synthesise proteins to recruit factor H to cell surface and viruses can incorporate multiple host regulatory proteins into their envelopes
Which deficiencies lead to issues in the classical pathway?
C1, C2 and C4 deficiencies -> immune complex disease
Which deficiencies lead to issues in the alternative pathway?
B, D and properdin deficiencies -> increased infections with Neisseria bacteria
Which deficiencies lead to issues in the alternative and classical pathway?
C3 deficiencies (or deficiencies in regulatory proteins I and H) -> increased infections with S. pneumoniae, Neisseria spp. and H. influenzae
