Complement System Flashcards
CR1
- What does it bind
- What cells
- Main function?
- C3b ligand
- Macrophages, neutrophils, RBC
- Phagocytosis, clearance of immune complexes.
Speed of compliment pathways?
Alternate, then lectin, then classical
3 complement pathways
- Alternate
- Lectin
- Classical
- What antibody isotypes activate complement the best?
- What cannot activate complement?
- IgM, IgG3> IgG1> IgG2, IgA1/2
- IgD, IgE, IgG4
C4 deficiencies?
- C4a= increased susceptibility to systemic lupus erythematosis
- C4b= increased susceptibility to infections
When looking at picture, look at what’s MISSING.
C3 “tickover”
- which pathway
- final product
- mechanism?
- Alternate pathway- spontaneous hydrolysis of thioester bond of C3
- Final product= C3b binds pathogen surface or C3bBb activates more C3.
- Mechanism- when close to the pathogen surface, C3 hydrolyzes==>active C3, binds factor B, ==> Factor D cleaves factor B==>soluble C3 convertase= C3bBb.
- C3 convertase activates C3 by cleaving it into C3b, C3a
- C3 can also be turned into more convertase= amplification
Mechanism for making classical complement activation with CRP
- C1 (made of C1q, C1r, C1s) is cleaved by C-reactive protein (which binds C1q)
- C1s is serine protease and cleaves C4 and C2
- C4b attaches to pathogen surface
- C2a attaches to C4b= C4bC2a= Classical C3 convertase
Final product= C4b mediated opsonization, C3 convertase formation.
C3–>
C3b= binds pathogen CR1 receptor
C3a= recruites phagocytic cells
C3bBb= C3 convertase, makes C3b/C3a from C3.
Lectin Pathway
- Mannose binding lectin (MBL) circulates in blood until it finds mannose on pathogen membrane
- MBL binds, forms comples with MASP1/MASP2.
- Mannose-bound MBL activates MASP 2= C4 and C2 cleavage==>
- Formation of C4b2a= classical C3 convertase
Complement factors produced in?
made in the liver as zymogens
Factor I defeciency:
- Symptoms
- Complications
- Susceptibility to?
- Labs
- Mechanism
- Genetics?
- repeated cases of pneumonia, sinusitis, ear infections, absecesses,
- glomerulonephritis with C3 deposits, rheumatoid arthritis or systemic lupus erythematosus.
- increased susceptibility to pyogenic bacteria, encapsulated bacteria.
- Normal lymphocyte and immunoglobulin concetrateion, low C3, low-0 factor B, no factor I
- Lack of factor I= constant C3 activation= depletion of C3 and factor B. C3 too low for when pathogens attack.
- Autosomal recessive,
IgG for classical complement activation?
What types of antigens can be bound?
- Can occur when IgG binds antigens on bacterial surface, then C1q bind membrane bound IgG= complement activation
- IgG binds soluble antigen, C1q binds soluble complex and activates complement
CR2
- What does it bind
- What cells
- Main function?
- C3d
- Follicular Dendritic cells, B-cells
- Antigen trapping and B-cell activation
Paroxysmal Nocturnal Hemoglobinuria
- Defect in?
- Gene?
- Symptoms
- Treatment?
- CD55 expression (DAF) and CD59= no MAC prevention on host cells
- PIGA, x-linked recessive
- intravascular and extravascular hemolysis, RBC lysis= anemia, increased free Hb, fatigue, esophageal spasms, thrombosis
- bone marrow transplant, anti C5 antibody= eculizumab. No C5 activation by C5 convertase
Hereditary Angioedema
- Problem/Def
- Clinical presentation
- Labs
- Genetics
- Mechanism?
- C1 inhibitor deficiency
- Recurrent edema of skin, GI tract, UG tract, and larynx. Abdominal pain, pelvic pain, edema==> suffocation
- increased bradykinin, decreased C4, C2, normal C3. NO C1INH.
- Autosomal dominanty
- C1INH usually inhibits activation of plasminogen, kallikrein, bradykinin.
CR3/CR4
- What does it bind
- What cells
- Main function?
- iC3b, LPS,
- Macrophages, neutrophils
- Phagocytosis
2 convertases made by alternative pathway
Alternative C3 convertase= C3bBb==>more C3 convertase, or C3b
Alternative C5 convertase=C3b2Bb==>MAC assembly
Functions of comliment (x4)
- innate immunity- recognition of pathogens
- Opsonization of pathogens
- recruitment of inflammatory cells
- Lysis and phagocytosis of pathogens (and host cells)
Interaction of classical and alternative complement pathways
Formation of classical C4bC2a convertase makes C3b which can bind Bb to make C3bBB (alternative C3 convertase) which makes more C3b= more complement fixation.
AMPLIFICAITON
Membrane attack Complex-
C5 activation= terminal pathway, using Alternative C5 convertase
- 2(C3b)+Bb= C3b2Bb= C5 convertase.
- C5==> C5a +C5b
- C5b binds C6, then C7 and C8.
- C7 and C8 insert into membrane
- Recruit C9= final pore complex
- Pore complex- allows moelecules (like ATP) to leak==> cell death.
Anaphylatoxins
What are they? Main effects?
C5a>C3a>C4a
Effects: Vasodilation, increased vascular permeability, smooth muscle contraction, mast cell degradation, chemotazis of neutrophils
EDEMA
C2 Kinin
vasoactive peptide made when plasmin cleaves C2b fragment
Regulators of alternative complement pathway?
- properdin= factor P- stabilizes C3BbB= extended lifetime
- Factor H- binds C3b and changes its conformation to amke it more susceptible to cleavage by factor I
- DAF, MCP-inactivate C3BbB on human cell surfaces
Regulation of MAC
CD59 on host hcells binds C5b678 complex to prevent C9 formation of pore
CD55=DRF; CD 46=MCP; and HRF (homologous restriction factor), factor H and Factor I according to notes.
CD55 and HRF- according to book.
Classical complement activation with antibodies
- IgM or IgG3 bind C1q part of C1. IgM must be in “staple” form, not planar form.
- Activated C1 cleaves C2 and C4 to form classical C3 convertase=C4bC2a– increased C3b binding
Classical Pathway of Complement activation -
- how is it activated?
- Final product? (x2)
2 ways of activation
- C reactive protein (made by liver when induced by IL-6) OR Antibody binding (1 IgM, or multiple IgGs)
- classical C3 convertase= C4b2a (compared to C3bBb in alternative pathway) OR
- classical** **C5 convertase= C4b2bC3b
