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)
-
2. Innate immunity54
-
11. Hypersensitivity reactions49
-
10. Immune response in infections, mucosal immunity46
-
9. Regulation of immune response46
-
13. Transplantation And Pregnancy34
-
3. Complement system35
-
4. Acute phase reaction25
-
5. Antigen, antigen presentation and MHCs33
-
6. Antigen receptors and their formation31
-
7. T cells and cell-mediated immune response33
-
8. B-cells and humoral immune response44
-
Practical lessons68
-
1. Roles, processes, organs and cells of the immune system18
-
12. Autoimmunity and tolerance24
-
14. Antitumor immunity; immunodeficiency42
-
15. Immunopharmacology, neuro- and psychoimmunology37
