Soluble mediatros of the immune system Flashcards
Complement system
- part of innate immune system
- composed of ~18 different heat- labile proteins; most are enzymes/ proteinases
- major component of beta 1 and beta 2 globulins on SPEP
- most components made in liver
- C1 from epithelium of GI and urogenital tracts
- acitivation of C’ via 3 different pathways
Activities of the CS
Host defense vs. infection - opsonization - chemotaxis and leukocyte activation - lysis of bacteria and mammalian cells Interface between innate and adaptive immunity - Augments Ab response - Enhaces immune memory Disposal of wastes - Clears immune complexes - Clears cell fragments
Complement Activation
C’ components circulate in inactive for
Control proteins: C1 Inh, Factor I, Factor H, C4-biding protein also present to inhibit uncontrolled activaiton
Classical pathway- Ab activated
Alternative pathway - amino or hydroxyl grps on bacterical and mammalian cells surfaces
Lectin pathway- Mannose binding Lectin (MLB) - on surface microbes and serine proteasess (MASP1 and MASP2)
3 stges for all pathways: recognition, activation and membrane attack
All pathways converge at the point of cleavage of C3 to C3b
Proteins of Classical Pathway
- system consists of 9 components (C1-C9)
- for several steps in activation the product is an enzyme that catalyzes the next step generating 2 fragments:
- the larger fragmen “b” becomes associated with the other C’ proteins/Ab and in some cases is a proteolytic enzyme.
- the smaller fragment “a” is released into surrounding environment.
- so… a cascade that amplifies the activation of large amount of C’ by a relatively small initial signal
- there are several sites for regulation
Classical Pathway- activation of C1
C1 is a complex of 3 proteins (C1q, C1r, C1s) held together by Ca2+ ions
- C1q has 6 identical subunits—activation requires biding of C1q subnites to C1q - specific receptors on the Fc regions of at least 2 adj IgG molecules
- Or … 2 Fc regions of one IgM
- C1q receptors become available following conformational changes on at least 2 Abs each binding 2 epitopes on a multivalent Ag
- Activated C1q activates C1r which then activates C1s
- Activated C1s has proteolytic properties and acts on the next component … C4
Classical Pathway - activation of C4
C4 is a glycoprotein made by macrophages
- activated C1s cleaves a fragment C4a from C4 thereby activating it to C4b
- function of C4b to bind to cell membrane adj to the Ab-Ag complex that initiated the process; interacts with C1s to induce cleave of C2
- If C4b doesn’t bind to membrane, it decays and is active.
Classical Pathway - activation of C2
C2- a glycoprotein — cleaved by action of C1s and C4b, C2a remains associated with C4b — the complex is new enzyme - C4b2a = C3 convertase (unstable half-life of 5 minutes as C2b is released and decays
- Constraints on activity of C1s on C4 and C2 and on the stable formation of C4b2a: protease inhibitor C1 esterase - binds to C1s and C1r inhibits in the fluid phase, i.e., stop excessive rx. —- C3b inactivator: destroy acceptor site for C2 by disintegrating C4b on membranes so … no C4b2a convertase
Classical Pathway - activation of C3
- C3 is a beta globulin from macrophages
- activated by C3 convertase: split into smaller C3a and larger C3b, a single C4b2a can activate hundreds of C3 molecules= amplification
- C3b: – attaches to cell membrane in immediate vicinity of site of activation (many C3b’s attach to target cell membrane) —one C3b combines with C4b2a giving C4b2a3b = C5 convertase
- C3a remains in fluid phase - anaphylatoxin
MAC -activation of C5, C6, and C7
- C5, C6 and C7 are globular proteins
- C5 convertase splits C5 into 2 fragments
- C5b binds with C6 and C7 to form C5b67 on the cell membrane — this complex focuses the activity of C8 and c9 onto the target membrane
MAC - activation of C8 and C9
- C8 and C9, directed by C5b67 insert themselves in the membrane and produce transmembrane channels: ions pass through, disturbs osmotic equilibrium … cell lyses.
Alternative pathway
- Doesn’t require Ag-Ab complex for initiation
- 3 proteins unique to the AP: Factor B, D and P (proper in)
- C3- most abundant C’ protein – spontaneous cleavage occurs continuously
Alternative pathway - recognition and activation
- Reactive C3b exists in trace amounts in normal serum – C3b binds to pathogen surface – protein B binds to stabilized C3b –> C3bB – protein D clips part of protein B, resulting in C3bBb
- C3bBb = convertase that cleaves C3 to become C3a and C3b (which combines with more protein B…amplification) – Amplification is balanced by rapid C3bB dissociation – Regulation is by factor P = properdin which stabilizes C3bBb complex
- C3b also activates C3, resulting in C3bBbC3b = C5 convertase, which activates the remaining components of the cascade
- C5 convertase then activate other components to form the MAC, resulting in cell lysis.
MBL pathway
Ca2+ dependent
- MBL - homologous in structure to C1q
- MASP1 and MASP2 are homologous to C1r and C1s
- Result is C3 convertase from bound C2a and C4b
- MLB binds to mannose grp on – yeast, viruses, bacteria, parasites.
MAC
- generation of C5 convertase by classical/MBL and alternative pathways: Classical and MBL pathways - C4b2a3b – Alternative pathway: C3bBb
- C5 converted to C5b and C5a, but only when bound by C3b
- C5b binds C6, then C7, which all binds to cell membrane
- C8 then binds to complex and inserts into lipid bilayer
- 10 -15 molecules of C9 then bind to complex and polymerize to form cell mb pore
Protection of HOST cells vs. C’ attack
- CD55: decay accelerating factor (DAF)
- CD59: protectin
- Factor I: results in inactive C3b (iC3b)
- Factor H -competes with Factor B
- properdin: binds to pathogen surface and stabilizes the convertase
