Module 8 Flashcards
complement
opsonins
play an important role in defence and inflammation
- they coat foreign particles to tag or mark them for engulfment by APCs
- opsonized bacteria is easily phagocytosed by the macrophage
discovery of complement
1896, Jules Bordet discovered complement protein through studies of cholera. he discovered complement proteins that exist in the blood by heating serum
- in his findings, the antibody (heat stable) was responsible for immunity against specific microorganisms
- the complement proteins (heat sensitive) was responsible for non-specific antimicrobial activity conferred by all normal serum
complement proteins
enhance the killing of bacteria by binding to bacteria-bound antibodies
- these proteins are heat labile, meaning they lose their effector activity is heated
primary sources of complement
monocytes, macrophages, and hepatocytes are the primary synthetic sources of glycoprotein (complement)
activation pathways
classical pathway
alternative pathway
lectin pathway
regulation pathways
glycoproteins regulate complement activation
complement activation
can be divided into 2 components:
- in the first component, there are 3 distinct pathways that can result in the production of C5b proteins
- the pathways converge to result in inflammation, opsonization, and lysis
classical pathway
Ag:Ab complexes
classical pathway requires antibodies and is activated by immune complexes (Ab:Ag) involving human IgM, IgG1, IgG2, and IgG3
- IgG4 is NOT a complement activator
lectin pathway
pathogen surfaces
an antibody independent process that is activated by mannan, which is expressed only on bacteria and viruses
alternative pathway
pathogen surfaces
activated by non-Ab substances, such as LPS, polymers, or venom factors
- these substances can originate from pathogens or human IgA and IgG aggregates
classical pathway step 1
antibodies bind to a multivalent antigen on the cell membrane of the target cell
- the C1 complex then binds to the Fc portion of the antibody bound to the target cell
C1 complex
C1qr2s2
classical pathway step 2
inactivate circulating C4 binds to the C1q portion of the Ig-associated C1 complex the r2s2 enzymes then cleaves C4 into C4a and C4b
classical pathway step 3
C4b covalently attaches to cell membrane or antibody
- C2 binds to C4b
- C1qr2s2 cleaves C2 into C2a and C2b
classical pathway step 4
C4b and C2a combine to form C3 convertase
C3 convertase
C4bC2a
classical pathway step 5
C3 convertase binds to and cleaves C3 into C3a and C3b
classical pathway step 6
C3b molecule binds to C4bC2a to form C5 convertase
- unbound C3b can either by hydrolyzed (becomes inactive) or form covalent bonds with target cell surface
classical pathway step 7
C5 convertase binds to C5 and cleaves it into C5b
- C5b is the end product that all 3 complement pathways create
lectin pathway step 1
serum mannose-binding lectin (MBL) binds to mannose residues on glycoproteins or carbohydrates on microbe surface
- MBL is an acute phase protein produced during inflammation
lectin pathway step 2
MBL-associated serine protease (MASP) binds to MBL
lectin pathway step 3
the active MASP-MBL complex cleaves inactive C4 into active C4b and C4a
lectin pathway step 4
C4b can covalently attach to the pathogen cell membrane via mannose binding. following this, C2 binds to C4b
lectin pathway step 5
C2 of the C4bC2 complex is cleaved by MASP to form C4bC2a (C3 convertase)
lectin pathway step 6
C3 convertase binds to and cleaves C3 into C3b and C3a
lectin pathway step 7
C3b molecules bind to C4bC2a to form C5 convertase
- unbound C3b can either by hydrolyzed (inactivated) or it can form covalent bonds with target cell surfaces
lectin pathway step 8
C5 convertase binds to C5 and cleaves it into C5b
- C5b is the end protein of the three complement pathways
alternate pathway step 1
in the plasma, a continuously low rate of spontaneous cleavage of C3 occurs
- this cleavage results in C3a and C3b
internal thioester bonds of C3
intact C3 has a concealed thioester group
- during C3 cleavage, the C3 alpha chain is cleaved by C3 convertase, leaving the thioester group exposed in C3b, which can result in two different things
two fates of C3b thioester bond
- in fluid phase, C3b is inactivated by hydrolysis
- covalent attachment of C3b to microbe, cell surface protein, or polysaccharide by thioester linkage
alternative pathway step 2
some C3b binds to the microbial cell surface via active thioester bond
- from here, factor B binds to C3b
alternative pathway step 3
factor D cleaves Factor B (which is still bound to C3b)
alternative pathway step 4
properdin, or Factor P, stabilizes the C3bBb complex
- stabilized C3bBb complex is called C3 convertase
alternative pathway step 5
there is cleavage of an additional C3 molecules by C3 convertase
alternative pathway step 6
binding of the additional C3b to the cell surface forms C3bBbC3b complex called C5 convertase
alternative pathway step 7
C5 convertase cleaves C5 into C5b
- C5b is the end product
activators of each pathway
Classical: Ag-Ab complex
Lectin: MBL:mannose complex
Alternative: spontaneous hydrolysis of C3
C3 convertase in each pathway
C: C4bC2a
L: C4bC2a
A: C3bBb
C5 convertase of each pathway
C: C4bC2aC3b
L: C4bC2aC3b
A: C3bBbC3b
late steps of complement activation
the 3 complement activation pathways converge at C5b. late steps of complement activation forms the membrane attack complex (MAC), which will form a pore in the target cell membrane, leading to its destruction
complement activation outcomes
inflammation
opsonization
lysis
complement cascade formation of MAC
- C5 convertase cleaves C5 into C5a and C5b. C5b remains bound to C5 convertase
- C6 and C7 sequentially bind to C5b. C5bC6C7 complex becomes directly inserted into the lipid bilayer of the target cell membrane 3. after insertion of the C5bC6C7, C8 is bound to C7 to stabilize the complex 4. up to 15 C9 molecules polymerize around the C5bC6C7C8 complex to form the MAC
MAC attack
MAC creates pores in the cell membrane, and each pore is made of the C9 proteins - a pore in the membrane results in the spilling of intracellular contents, initiating cell death (MAC attack)
regulation of complement activation
complement activation is continuously occurring at a low level and can result in normal cell damage if not regulated
- fragmented complement proteins can diffuse to adjacent cells and injure them
complement activation is inhibited by regulatory proteins that are present on normal host cells, but are absent on microbes
- types of regulation: C1 complex inhibition, C3 Convertase inhibition, C3b inactivation, MAC inhibition
C1 inhibitor deficiency
causes HAE
- HAE results in the overproduction of C2b by activating the vasoactive C2 kinin peptide in the presence of plasmin
- HAE results in edema of skin
complement deficiencies
can have detrimental effects on immunity
can be caused by a partial or complete loss of protein synthesis (ex: minimal to absent C3)
deficiencies can also be caused by formation of an incomplete or abnormal protein
complement deficiency diseases
C1, C2, and C4 deficiency: immune complex disease
MAC deficiency: increased risk of infection
C3, Factor D, Factor I deficiency: pyogenic infections
MBL deficiency: susceptible to recurrent infections and decreased lung function
