Complement and Disease Flashcards
What is complement?
A collection of proteins (zymogens) that circulate the blood until they are activated. Domino effect of activation -> cascade
- 9 main complement proteins
- when cleaved, the products are given a or b; the a fragment is the smaller anaphylatoxin, the b fragment is the larger binding portion (except for in C2)
What is the role of the complement system
Defends the host from infections. Complement system is a cascade of proteins that is part of the innate immune response
- surveillance: discriminate host cell from debris, apoptotic cells, foreign cells, and microbes
- rapid, localized
- finely balanced,
- dynamic and versatile
What activates the classical, lectin, and alterative pathways?
classical: immune complexes, apoptotic cells, RNA, DNA
lectin: bacterial CHOs
alternative: always slightly on; foreign surfaces, bacteria, viruses, damaged tissue
Describe the Lectin Pathway
lectins recognize bacterial CHOs,
Mannose binding lectin (MBL) complexes with MASP1 and MASP2 (proteases)
- when MBL MASP complex binds to pathogen CHOs, conformational change activates MASP to cleave circulating C4 and C2 proteins to form C4b2a (C3 convertase enzyme)
- C3 convertase cleaves circulating C3 into C3b
Describe the alternative pathway
Is always active “tick-over”; activated by foreign surfaces, bacteria, viruses, damaged tissue
- when C3b is bound to a pathogen, circulating factor B can bind, Factor D then cleaves factor b, leaving behind the distinct C3 convertase: C3bBb (vs C4b2a)
- C3b can be generated by the classical or lectin pathways, as well as spontaneous hydrolysis of C3
- C3 convertase cleaves circulating C3
Describe the classical pathway
C1 complex: made of C1q, C1r (protease), and C1s (protease)
- in circulation, C1q can bind to bacterial surface, Ab bound to pathogen, or C reactive protein -> binding of C1q activates C1r which then cleaves C1s
- C1s cleaves circulating C4 and C2
- C4b then covalently binds to pathogen surface, and C2a binds to it, forming the C4b2a complex, or C3 convertase.
- C3 convertase cleaves circulating C3 into C3b
What happens after C3 convertase is formed?
C3 convertase cleaves C3 into:
- C3a which acts as anaphylatoxin: chemotaxis for neutrophils and monocytes, neutrophil degranulation, histamine release, etc.
- C3b which opsonizes pathogens for phagocytosis
- C3b can also bind to C3 convertase to form C5 convertase (C4b2aC3b/ C3bBbC3b) which cleaves C5 into C5a and C5b
- C5a has same function as C3a (anaphylatoxin)
- C5b starts the Membrane attack complex
How is the membrane attack complex formed?
C5b binds to C6 then C7. C5b67 undergoes conformational change and inserts itself into plasma membrane. C8 then binds. finally, 10-16 molecules of C9 polymerize in membrane to form a pore allowing things to flow out (water, ions).
What is the function of C3a, C4a, and C5a? Which is most potent?
These act as the anaphylatoxins which recruits inflammatory and immune cells
Potency: C5a > C3a > C4a
- results in increased vessel permeability, recruitment of immune cells, and degranulation
what is the function of C3b, iC3b, C3d/g, and C4b (acting on their own)
Opsonization: tag pathogens for phagocytosis
How is complement regulated and why is this important
- Almost all enzymes in complement are zymogens (inactive form) (besides factor D)
- all enzymatic activity occurs at pathogen surface
- decay accelerating factor: competes with factor B, and can displace for C3b binding, prevents compliment activation. includes factor H (soluble)and CD55 (membrane associated)
- MAC inhibiting factors: Vitronectin which binds to C7, C8, prevents MAC assembly and membrane insertion. Membrane bound inhibitor CD59 prevents C9 insertion into membrane
Describe clinical disorders with excess complement activation
- atypical hemolytic uremic syndrome
- thrombotic microangiopathic hemolytic anemia, multi-organ damage due to capillary thrombi: brain, kidney, lung, heart, liver, pancreas, GI
- normal HUS is caused by shiga toxin, but in atypical HUS, its familial or sporadic, causing mutations in complement proteins like loss of function in factor H, Clusterin and gain of function in factor B and C3 - paroxysmal nocturnal hemoglobinuria
- acquired disorder of HPC, leads to loss of CD55 (decay accelerator) and CD59 (MAC inhibitor) -> increased C3/C5 convertase activity
- associated with thrombosis - Covid induces activation of all 3 pathways
- Age related macular degeneration
- over 5 % associated with factor H mutations leading to excess complement activation on retinal cells
-> treat aHUS and PNH by drugs that inhibit C5 convertase
What is complement?
A collection of proteins (zymogens) that circulate the blood until they are activated. Domino effect of activation -> cascade
- 9 main complement proteins
- when cleaved, the products are given a or b; the a fragment is the smaller anaphylatoxin, the b fragment is the larger binding portion (except for in C2)
What is the function of C3a, C4a, and C5a? Which is most potent?
These act as the anaphylatoxins which recruits inflammatory and immune cells
Potency: C5a > C3a > C4a
