Flashcards in L4: Complement Deck (46)
What part of the immune system is complement system part of?
Innate immune system
What are the phases of complement system in elimination of microbes?
Pattern recognition trigger → protease cascade amplification/C3 convertase→inflammation, phagocytosis, membrane attack
What fragments are produced when complement proteins are cleaved?
B factor which is larger and binds to pathogen
A factor which is smaller and released
What are the 3 different complement pathways?
Which are the more prevalent complement pathways?
Classical and lectin
Alternative facilitates the other 2 pathways
What do all 3 complement pathways converge on?
Generation of C3 convertase
What does C3 convertase do?
Cleaves C3, leaving C3b bound to the microbial surface and releasing C3a
What are the effector pathways that occur after generation of C3 convertase?
1. C3a and C5a recruit phagocytic cells to the site of infection and promote inflammation
2. Phagocytes with receptors for C3b engulf and destroy the pathogen
3. Completion of the complement cascade leads to formation of a membrane-attack complex (MAC), which disrupts cell membrane and causes cell lysis
How does C3 convertase activate C3 for covalent binding to microbial surfaces?
C3 protein has a thioester domain (TED)
Before cleavage by C3 convertase, the thioester bond within TED is protected from reacting
Cleavage of C3 releases C3a, and a change in conformation of C3b allows the thioester bond to react w/ a chemical group on the pathogen surface
The reactive thioester group of C3b in TED binds to pathogen surface
How can C3b be inactivated?
What are pathogen associated molecular patterns?
Most microorganisms express repeating patterns of molecular structures on cell surface
Will mostly express carbohydrate side chains w/ different sugars on them
For instance, N-linked glycoproteins of yeasts contain many terminal mannose residues
What are ficolins?
Ficolins are similar in structure to MBL but have a different carbohydrate-binding domain; they bind oligosaccharides containing acetylated sugars
Describe the lectin pathway up to generation of C3 convertase
Mannose-binding lectin (MBL) monomers form trimeric clusters of carbohydrate-recognition domains → MBL binds w/ high avidity to mannose and fucose residues on surface of microbe → associated w/ the MBL molecule are 2 serine proteases, MBL-associated protease 1 (MASP-1) and 2 (MASP-2) → MASP-2 becomes activated when MBL complex binds to the surface of the pathogen → MASP-2 cleaves C4 into C4a and C4b → C4b binds microbial surface → C4b then binds C2, which is also cleaved by MASP-2 → forms the C4b2a complex, which is an active C3 convertase
What is the first protein of the classical pathway of complement activation?
What is the structure of C1?
A complex of different molecules: C1q, C1r and C1s
What are the roles of the components of C1?
C1q is the collagen region; main way to bind to pathogens
C1r and C1s are proteases
Describe classical pathway
The C1q component of C1 can bind by itself to the surface of the microbe or can bind to an antibody that is covering the microbe
What are the 2 forms that the C1 complex can exist in?
Aggregate macromolecular form (able to bind both antibody-covered pathogen and pathogen by itself)
More planar form
How does the alternative pathway amplify the classical and lectin pathways?
By forming an alternative C3 convertase and depositing more C3b molecules on the pathogen
How is the alternative pathway activated?
Can be activated in 2 different ways
The first is by the action of the lectin or classical pathway; C3b is generated by either of these pathways and covalently linked to a microbial surface can bind factor B
The second is by spontaneous hydrolysis of the thioester bond in C3 to form C3(H2O)
Describe the alternative pathway of complement activation by the action of the lectin or classical pathway
C3b deposited by classical or lectin pathway C3 convertase → C3b binds factor B → bound factor B is cleaved by plasma protease factor D into Ba and Bb → C3bBb is a C3 convertase, cleaving many C3 molecules to C3a and C3b
Describe the alternative pathway of complement activation by spontaneous activation of C3
C3 undergoes spontaneous hydrolysis to C3(H20), which binds to factor B allowing it to be cleaved by factor D into Ba and Bb → The C3(H2O)Bb complex is a C3 convertase, cleaving more C3 into C3a and C3b; C3b is rapidly inactivated unless it binds to cell surface → factor B binds noncovalently to C3b on a cell surface and is cleaved to Bb by factor D
What's the C3 convertase for the lectin complement pathway?
What's the C3 convertase for the classical complement pathway?
What's the C3 convertase for the alternative complement pathway?
What stabilizes the alternative pathway C3 convertase on pathogen surfaces?
Properdin or factor P
What is the initiating serine protease in each pathway?
Alternative - D
Lectin - MASP
Classical - C1s
Which factors between the alternative, lectin, and classical pathways of complement activation are NOT homologous?
Factor D, which is the initating serine protease of the alternative pathway
Factor P, which is unique since only found in alternative pathway
What occurs when C3b binds to C4b2a or C3bBb?
Forms the active C5 convertases C4b2a3b and C3b_2Bb respectively
What cleaves C5?
C5 binds to the C3b component of the C5 convertase enzyme → C5 is cleaved by C2a or Bb to form C5b and C5a
What does C5a do?
It is an anaphylatoxin that can enhance the phagocytosis of microorganisms opsonized in an innate immune response
Bacterium is coated w/ C3b → when only C3b binds to CR1, bacteria are not phagocytosed → C5a can activate macrophages to phagocytose via CR1
Also acts on endothelial cells lining blood vessels to induce synthesis of adhesion molecules
Activate mast cells in submucosal tissues to release inflammatory molecules such as histamine and TNF-alpha
How is iC3b formed?
C3b bound to pathogen surface is cleaved by factor I and MCP cofactor releases the C3f fragment and leaves iC3b on the surface
What is iC3b a ligand for?
CR2, CR3, and CR4
(not for CR1)
How is C3dg formed?
Factor I and CR1 cleave iC3b to release C3c, leaving C3dg bouhnd, which is recognized by CR2
What does C3a do?
Also an anaphylatoxin
How do small complement fragments, such as C5a and C3a, induce local inflammatory response?
Small complement-cleavage products act on blood vessels to increase permeability and cell-adhesion molecules → increased permeability allows increased fluid leakage from blood vessels and extravasation of immunoglobulin and complement molecules;
Migration of macrophages, polymophonuclear lymphocytes (PMNs), and lymphocytes is increased. Microbicidal activity of macrophages and PMNs is also increased
What initiates assembly of the membrane-attack complex?
What does assembly of the membrane-attack complex cause?
Generates a pore in the lipid bilayer membrane
Describe membrane attack complex formation
C5b binds C6 and C7 → C5b67 complexes bind to membrane via C7 → C8 binds to the complex and inserts into the cell membrane → C9 molecules bind to the complex and polymerize → 10 - 16 molecules of C9 bind to form a pore in the membrane
How is complement protein activation on host cells (rather than on pathogen surface) prevented?
Several negative regulatory proteins, present in plasma and in host-cell membranes, protect healthy host cells from injurious effects of inappropriate complement activation on their surfaces
These complement regulatory proteins interact w/ C3b and either prevent the convertase from forming or promote its rapid dissociation
For instance, convertase formation can be prevented by cleaving C3b to inactive iC3b by factor I along w/ membrane cofactor of proteolysis (MCP or CD46)
Stages at which complement activity is regulated
C1q binding to antigen:antibody complexes activates C1r and C1s → C1 inhibitor (C1INH) dissociates C1r and C1s from the active C1 complex
C4b2a is the active C3 convertase → DAF, C4BP, and CR1 displace C2a from the C4b2a complex; C4b bound by C4BP, MCP, or CR1 is cleaved by a soluble protease I to inactive forms C4d and C4c
The C5 convertase cleaves C5 to C5a and C5b → CR1 and H displace C3b; CR1 and H act as cofactors in the cleavage of C3b by I
The terminal components of complement form a membrane pore - the membrane-attack complex → CD59 prevents final assembly of the membrane-attack complex at the C8 to C9 stage
What do deficiencies in complement components of the classical pathway cause?
In C1, C2, C4
Leads to immune-complex disease
What do deficiencies in complement components of the lectin pathway cause?
In MBL, MASP1, MASP2, C2, C4
Deficiency of MBL leads to bacterial infections, mainly in childhood
What do deficiencies in complement components of the alternative pathway cause?
In factor D, factor P
Deficiency leads to infection w/ pyogenic bacteria and Neisseria spp. but no immune-complex disease
What do deficiencies in complement components of C3b deposition cause?
Deficiency leads to infection w/ pyrogenic bacteria and Neisseria spp.
Sometimes immune-complex disease