Complement Flashcards
Functions of Complement (4)
- Lysis (enveloped viruses, RBCs, gram neg bacteria)
- Opsonization (parasites, bacteria)
- Activation of inflammatory response
- Clearance of immune complexes
Complement proteins: most to least abundant
C3 > C4 > C5 > C2
Outline the Classical complement pathway
- antibody (IgM or two IgG) bind target
- C1q binds
- 2x: C1r and C1s bind + Ca2+
- C4 + C2 = C4bC2a (C3 convertase)
- C3 cleaved and C3b binds = C4bC2aC3b (C5 convertase)
- C5 cleaved and C5b binds + C678 + C9 = MAC
What is a challenge with the classical complement cascade ?
- needs an antibody to a foreign antigen to be activated
- foreign antigen must have been seen before (memory)
Outline the Alternative complement pathway
Fluid Phase:
- no antibody involved; spontaneous hydrolysis of C3
- Factor B attaches to hydrolyzed C3 = C3B
- Factor D activates Factor B = C3Bb (C3 convertase)
- C3 cleaved to C3b = rapidly degraded UNLESS microbe is nearby to bind
Cell-bound Phase: (organism)
- C3b binds to microbe (no sialic acid)
- Factor B attaches to bound C3b
- Factor D activates Factor B = C3bBb
- Properdin stabilizes complex
- C3bBb binds another C3b = C3bBbC3b (C5 convertase)
- C5b binds + C678 + C9 = MAC
NOTE: sialic acid on host cell inactivates C3b
Pathogen activators of Alternative pathway
- gram neg bacteria (LPS)
- gram pos bacteria (Teichoic acid)
- fungi and yeast cell wall (zymosan)
- viruses
Non-pathogen activators of Alternative pathway
- IgG, IgA, IgE complexes
- cobra venom
- carbohydrates (insulin, agarose)
Outline the Lectin complement pathway
- Mannose-binding Lectin (MBL) binds CHO residue on microbes
- MASP binds = MBL activated
Same as classical pathway:
- C4 and C2 cleaved = C4bC2a (C3 convertase)
- C3 cleaved = C4bC2aC3b (C5 convertase)
- C5 cleaved = C5b + C678 + C9 = MAC
MASP = MBL-associated serine proteases
Pathogens with D-mannose/ L-fructose for Lectin Pathway
- gram neg bacteria (Salmonella)
- gram pos bacteria (Streptococci)
- yeast
- viruses (HIV, Influenza A)
- parasites (Leishmania)
Describe CR1
- facilitates phagocytosis by monocytes, macrophages,
neutrophils - complement receptor; binds C3b, C4b
- immune complex clearance; delivers RBCs to spleen
- Required for Factor I
NOTE: Plasmodium falciparum uses CR1 to enter RBCs
Describe CR2
- Co-receptor on B cell surface
- Participates in amplification signalling with associated
CD19 and CD81 (TAPA-1)
NOTE: EBV imitates CR2 receptor
Describe CR3 and CR4 Integrins
- facilitates phagocytosis by monocytes, macrophages, neuts
- Help neutrophils and monocytes with extravasation
- complement receptor on NK cells; if bacteria is tagged and has no MHC I = direct killing
How is complement regulated ?
- inhibitors localize complement activation to protect host
- soluble plasma proteins
- membrane bound proteins
Describe C1-Inhibitor
- plasma protein
- affects classical pathway
- removes C1r and C1s from C1q = cannot activate C4 and C2
Describe Factor H
- plasma protein
- affects alternative pathway
- prevents binding of B to fluid phase C3 and bound C3b
- co-factor for Factor I
Describe Factor I
- plasma protein
- requires cofactors (CR1, factor H, CD46)
- affects classical, alternative, and lectin pathway:
- cleaves C3b into C3d + C3c (all pathways)
- cleaves C4b into C4d + C4c (classical and lectin)
Describe DAF
Decay-accelerating Factor (CD55):
- membrane-bound inhibitor
- affects classical, alternative, and lectin pathway
- inactivates C3 convertase (C4b2a and C3bBb)
Describe MIRL
Membrane Inhibitor of Reactive Lysis (protectin/ CD59):
- affects classical, alternative, and lectin pathway
- binds C5b678 = prevents C9 from binding
Early Complement Deficiencies
C1q, C1r, C1s, C4, C2
- susceptible to gram pos infections (Staph and Strep)
Middle Complement Deficiencies
C3
- suffer from wide range of infections
Late Complement Deficiencies
C5, C6, C7, C8, C9
- susceptible to gram neg infections (E. coli, N. meningitidis)
Describe SLE
Systemic Lupus Erythematosus:
- C1, C2, C4-deficient people at higher risk
- immune complexes non-specifically deposit onto tissues = immune system (ie. neutrophil) removes own cells = tissue damage
Describe C1-Inhibitor deficiency
- hereditary angioedema (autosomal dominant) = localized edema in subcutaneous tissue, bowel, respiratory tract
- leads to excess bradykinin formation due to excess kallikrein
- treated with C1-Inh or frozen plasma
Describe Factor I and H deficiency
- increased complement activation = low levels of complement proteins (C3 and C4) = recurrent infections
NOTE: Factor I and H regulators prevent complement activation
Describe DAF and MIRL deficiencies
Paroxysmal Nocturnal Hemoglobinuria:
- no anchoring protein (PIG-A) = absent CD55 and CD59
- anemia, cytopenia, thrombosis, DVT (10-15 year survival)
Gram-positive evasion of complement
- thick peptidoglycan layer prevents insertion of MAC
- capsule provides physical barrier between C3b and CR1
Gram-negative evasion of complement
- long polysaccharide chains prevent MAC insertion
- outer membrane prevents MAC insertion (N. gonorrhoeae)
- elastase inhibits C3a and C5a (P. aeruginosa)
Protein Mimicry used in Microbial Evasion of Complement. Provide examples.
- microbial membrane-bound proteins similar to inhibitor proteins
Ie. Herpes, EBV, T. cruzi, C. albicans
HIV evasion of complement
- gp-41 and gp-120 on lipid envelope binds Factor H (alternative pathway inhibitor)
- HIV incorporates host DAF and MIRL into own membrane = protects HIV from complement
- complement-coated virus gets phagocytosed due to CR1, CR3, and CR4 = RBC transports virus
