3. Complement system Flashcards
Opsonization
Expression of Fc receptor and/or complement receptor in addition to the normal PRR (“pålegg på brødskiva”)
Complement system pathways
1) Classical pathway (Ag:Ab)
2) Mannose-binding-Lectin pathway (Lectin: pathogen surface)
3) Alternative pathway (C3b:pathogen surface)
Complement activation results in
1) Recruitment of inflammatory cells (inflammation)
2) Opsonization of pathogens (+phagocytosis)
3) Killing of pathogens (lysis)
Characteristics of complement system
- Ancient
- Humoral system (immediate)
- No antigen specificity (innate)
- Effector - mainly against extracellular pathogens
C3b roles
- Opsonization (also C4b)
- Initiation membrane attack complex (MAC)
C3a role
Causes inflammation
- Histamine release
- Increased permeability of vessels
- Chemotactic attraction of phagocytes
- Etc.
C5a role
Causes inflammation (same as C3a and C4a)
Membrane attack complex (MAC)
C5b-C9
- C5b, C6 and C7 clusters together and attaches to lipid bilayer (C7)
- C8 attaches to lipid bilayer as well
- C9 attaches to lipid bilayer and polymerizes -> pore
Activation of C3
C3 convertase -> C3a and C3b
C1q
Binding to Ag:Ab complexes and pathogen surfaces
- Has C1r and C1s parts
- C1s cleaves C4 -> C4a and C4b
- C1s also cleaves C2 -> C2a and C2b
Classical pathway
- Mainly IgM
- Also IgG1, -2 and -3
1) Binding of antibody
2) C1q binds to Ab:Ag complex
3) C1r2s2 (on C1q) cleaves C4 and C2
4) C4bC2b = C3 convertase (cleaves C3)
5) C4bC2bC3 = C5 convertase (cleaves C5)
Classical C3 convertase
C4bC2b
- Cleaves C3-> C3a and C3b
Classical C5 convertase
C4bC2bC3b
- Cleaves C5 -> C5a and C5b (initiate late steps of complement cascade)
Lectin pathway
1) MBL binds to polysaccharide antigen (mannose-containing)
2) MASP-1, -2 or -3 on MBL cleaves C4 and C2
3) Classical C3 convertase
Same as classical pathway
MASP
MBL-associated serine-protease
Sits on MBL
Cleaves C2 and C4
Alternative pathway
1) C3b is produced spontaneously
2) Binding of C3b on surface of pathogen
3) C3b + factor B is converted to Alternative C3 convertase (C3bBb) by factor D
4) C3 -> C3b + C3a (amplification loop)
5) C5 convertase (C3bBbC3b)
In what genetic region can we find all elements of C3 convertases
MHC III gene region (HLA region)
- C4, C2, Bf
Late events complement activation
C5 convertase
- Either C4b2b3b (classical/MB lectin) or C3Bb3b (alternative)
Main factor of complement system
C3, because:
1) Lysis
2) Opsonization
3) Inflammation
4) B cell stimulation (Complement fragment C3d to CR2 receptor on B cell)
Can bind with covalent binding
C3b and C4b
- “The covalent binding of C3 to target molecules on the surfaces of pathogens is crucial in most complement-mediated activities”
- Bind via inner thioesther bonds
Effects of C3a, C5a, C4a
Local inflammatory mediators: anaphylatoxins
- Recruitment of inflammatory cells
- Activation of granulocytes
- Degranulation of mast cells
Exogenic and endogenic tissue damage
Exogenic: infection, burn
Endogenic: intensive local immune reaction
Complement activation in local inflammation
- C3a and C5a activates mast cell degranulation (histamine, prostaglandins, leukotrienes) -> Vasodilation, increased blood permeability, leukocytes bind to vessel wall
- C3a, C5a, C5b67 attracts leukocytes by chemotaxis
Signs of inflammation
- Tumor (swelling/edema)
- Rubor (red)
- Calor (heat)
- Dolor (pain)
- Functio laesia (loss of function)
Role of complement activation
- Lysis
- Opsonization (phagocyte)
- Activation of inflammatory response (Degranulation, extravasation)
- Clearance of immune complexes (phagocyte)
Complement receptor (CR) function
1) Elimination of bacteria
2) Elimination of immune complexes
CR: Elimination of bacteria
Activated phagocytes by opsonization (CR1 on macrophage bind C3b on bacterium -> phagosome -> phagolysosome)
CR: Elimination of immune complexes
By binding of C3b to the Ab:Ag complex, so that it can be transported by RBCs via CR1 to the liver/spleen for elimination (CR1 and FcR+CR3)
- A cluster of Ab:Ag complexes have non-covalent interactions of Fc regions and is insoluble
- C3b can sterically block these Fc-Fc interactions and make the immune complexes soluble -> travel with RBCs
Regulator proteins
1) C1 inhibitor (initiation control)
2) C4bp,DAF, MCP, CR1 Factor H (regulate C3 convertase)
3) Vitronectin, Clusterin, CD59 (regulate MAC)
C1 inhibitor
Dissociates C1r and C1s from the active C1 complex
C4bp,DAF, MCP, CR1 Factor H
Regulate C3 convertase
1) DAF, MCP and CR1 displace C2b from C4b (classical)
2) DAF and CR1 displace Bb from C3b (alternative)
3) MCP (and CR1) act as cofactors for Factor I-mediated proteolytic cleavage of C3b, producing iC3b (+C3f)
Regulation MAC
CD59: inhibits poly-C9 assembly
S protein inhibitsmembrane insertion of C5b-C7
Deficiencies in early components complement system
- No appropriate opsonization
- Not cleared immune complexes
- Immune complex disease
- > Poor phagocytosis (recurrent bacterial infections)
- > No MAC (recurrent Neisseria infections)
- > Poor imflammatory response
Inhibitory viruses
Inhibited
- C1: Astrovirus, Influenza A
- C3 convertase: Dengue
- C5 convertase: KHSV, HSV-1 and 2, Vaccinia, Variola, Cowpox
Complement system effect on adaptive immunity
- Augmentation of antibody response
- Promotion of T cell response
- Elimination of self-reactive B cells
- Enhancement of immunologic memory
