Complement System Flashcards
What is a COMPLEMENT
-Group of serum proteins that play a key role in association with antibody in eliminating pathogens
->30 different proteins
-produced by macrophages & hepatocytes
-triggered enzyme system - inactive in the circulation until triggered - highly regulated
-activation generated split products that perform biological functions
Complement functions
-defence against microorganisms: promotes phagocytosis, lysis of cells - bacteria and some viruses
-contributes to inflammatory response facilitating leukocyte recruitment activation
-elimination of waste (immune complexes, apoptotic cells)
-interface between innate and adaptive immune system
Opsonisation
Promote phagocytosis
Cell Lysis
Kill pathogen
Chemotaxis
Cell activation & migration
Products of enzyme reactions
C3b, C3a = generated from C3
a = small soluble product
b = big and bound product
Complement activation
-triggered enzyme system
-three activation pathways
-each activation pathway has a separate trigger
-activation pathways generates enzymes
-enzymes generate biologically active products
-generation of C3 convertases is the key event in complement activation
Complement trigger
Molecular binding - pathogens, immune complexes
Complement activation
Formation of active enzymes, cleavage of components - release of biologically active products
Complement consequence
Products perform various immune functions
Classical pathway
-C1 complex binds to antibody (IgG/IgM) as part of Ag:Ab complex - C1 crosslinks C1 binding sites on the antibody
-Binding activates C1 which can then bind and activate C4 (C4 –> C4b (large, active) + C4a (small soluble))
-C4b binds to microbe surface - opsonisation
-C2 attaches to bound C4b
-C1s splits bound C2 giving C4b2a
-C4b2a is a C3 convertase
C3 tickover
-spontaneous hydrolysis of thioester to C3(H2O) which is rapidly inactivated [C3(OH)]
-C3(H2O) binds to FB forming C3(H2O)B
-FD splits bound FB giving C3(H2O)Bb
-C3(H2O)Bb is a C3 convertase
starts alternative pathway -> generates C3b
-if microbe present, C3b binds to surface
Alternative Pathway
Microbe present:
-C3b binds to microbial surface - opsonisation
-FB binds to membrane-bound C3b -> C3bB
-FD splits bound FB forming C3bBb
Alternative pathway C3 convertase
-C3bBb forms more C3a and C3b
-C3b binds to microbe and cycle repeats (((amplification loop)))
Lectin pathway
-Pathway activated by mannose-binding lectin (MBL) binding to pathogens surface via carbs
-MBL is made in the liver in response to cytokines released by macrophages activated by pathogen binding
-MBL and two serum proteases, mannan associated protease (MASP-1,MASP-2) form a complex similar to C1
C5 convertases
C3b combines with C3 convertases to form C5 convertases
Lytic pathway
-C5b-6 - soluble complex
-C5b-7 - inserts into membrane via hydrophobic complex
-C5b-8 small transmembrane channels formed
-(C5b-8)^9n - pore formed
Opsonisation
-C3b molecules bind to the microbial surface (react with proteins & carbs)
-Phagocytes have receptors for C3b so recognise the C3b (opsonin)
-Initiates phagocytic cell function
-Increases rate of phagocytosis -> increased rate of microbe clearance
MAC-mediated cytolysis
-C5b6789(n) assemble to create the membrane attack complex (MAC)
-ring structure (pore) of MAC disrupts the membrane of a microbe (hydrophobic external face, hydrophilic internal face)
-Uncontrolled influx of ions & water -> cytolysis
Inflammation 1 - action on mast cells
-complement components involved include (C3a,C4a,C5a)
-Activate mast cells & basophils (C5a>C3a>C4a (anaphylatoxins))
-Trigger release of inflammatory mediators (histamine –> vascular changes in infected tissue to facilitate movement)
-Increase adhesion of cells to endothelium
Inflammation 2 - chemotaxis
- C5a & C3a are released at the site of infection
- These diffuse through the tissues forming a concentration gradient
-Neutrophils enter the tissues from the blood - Migrate along gradient of C5a/C3a
-Encounter opsonised bacteria
-Phagocytose bacteria -> clear infection
Receptors overview
-Mediate opsonic & inflammatory activity
-Range of receptors - CR1, CR2, CR3, CR4, C1qR, C3aR, C5aR
-Range of ligands - C3a, C3b, C4a, C4b, C5a, C5b, C1q, degraded C3b (iC3b/C3bi)
Range of effects - Phagocytosis, cell adhesion, immune complex clearance, antigen persistence, smooth muscle contraction
CR1 (CD35)
Activity:
-Receptor for C3b (primary opsonin) & C4b bound to immune complexes (Ag:Ab complex)
Function:
-leukocytes & tissues: adherence of C3b/C4b particles in preparation for phagocytosis
-Erythrocytes: C3b/C4b immune complexes transported to clearance systems (liver/spleen)
C5a effects via C5aR
Mast cells - chemotaxis & degranulation (histamine, serotonin)
Monocytes/macrophages - cytokine production (IL-1, IL-6, IL-8)
Neutrophils:
-chemotaxis, adhesive properties (via P-selectin expression on vascular endothelium)
-activates cells (secretory granule release)
-NADPH-oxidase pathway activator (respiratory burst)
