Lec4 Complement Flashcards
Where are complement proteins produced primarily?
Liver
3 major functions of complement
- innate immunity [pattern recognition receptors, facilitate killing and disposal of pathogens]
- waste disposal [clearance immune complexes and apoptotic cells]
- bridge innate and adaptive immunity
Mannose binding lectin activation
- lectin is a pattern recognition receptor for mannose
- binds mannose on pathogens and initiates complement activation
Classical activation
- cross-linkeed antibody is attached to antigen
- initiates complement activation
Alternative pathway activation
- spontaneous breakdown of C3 in serum causes low level activation of complement on pathogen surface
- dominant pathway after initiation
What does C3 convertase do?
cleaves C3 –> C3a and C3b
What is the central amplification step of complement?
C3 –> C3b repeatedly by C3 convertase
get lots of C3b molecules deposited on surface
What 2 factors involved in complement amplification?
factor B and D bind C3b on cell surface [regardless of how it got there] and amplify downstream complement
What are 2 anaphylatoxins?
C3a
C5a
What are 4 inhibitors of complement
- C1q inhibitor
- Factor H
- Decary accelerating factor [CD55]
- CD59 [protectin]
What 3 regulators inhibit C3 convertase
- Factor H/I
- Decay Accelerating Factor
- Membrane cofactor protein
MAC protein deficiency [which component most commonly deficient, effect]
- most commonly C9 deficient
- predisposes to fulminant meningitis [neisserial infection]
Effect of C3 deficiency [in humans, mice]
- uncommon in humans
- associated with pyogenic infections
- in mice leads to T and B cell dysfunction
What set of 3 cofactors degrades C3b? What is function of resulting product?
- Factor I, membrane cofactor protein, factor H
- degrades C3b so don’t get amplification of signal
- instead get iC3b that is an opsinin
C1q inhibitor deficiency [cause, effect]
cause: genetic deficiecny [multiple mutations] or autoantibodies [acquired]
effect: hereditary angioedema
- - get swelling without uticaria in skin, mucosal tissue of GI and upper respiratory
What deficiency associated with hereditary angioedema?
C1q inhibitor deficiency
C1q inhibitor [C1qINH] [function/mech]
regulate complement by:
- blocking classical pathway initiation
What is C1q?
protein involved in early stage of classical pathway initiation
C1q deficiency [disease associated, mech]
- systemic lupus erythematosis
- normal immune complexes cannot be cleared in absence of C1q
- immune complexes then deposited in tissue
Factor H deficiency [effect, 2 diseases]
- local complement activation at exposed basement membranes [because factor H normally protects against this]
- hemolytic uremic syndrome [kidney disease + intravascular hemolysis]
- macular degeneration [eye]
Factor H [Function/mech]
regulate complement by:
- inactivating C3 and C4 convertases
- works with factor I and membrane cofactor protein
- protects from complement activation in exposed basement membrane [kidney, eye]
DAF or CD59 Deficiency [cause, disease]
cause: mutations that prevents attachment GPI anchor [that is mech of how DAF and CD59 insert into cell surface] in some cells [including RBCs]
- get no DAF or CD59 expression
Disease: paroxysmal nocturnal hemoglobinuria – blood in urine, hemolysis
How does HIV subvert complement?
- allows activation and depostion of C3b on surface
- have regulators to prevent amplification
- C3b acts as opsinin so allows virus to enter cell
How does Epstein Barr subvert complement? What cells does it usually infect?
- uses CR2 [CD21] for envelope glycoprotein
- preferentially infects B cells
How does group A streptococci subvert complement?
- have M protein that binds factor H and augments it
- prevent local complement activation
- expresses peptidase that inhibits C5a
How to measure amount of complement proteins? What does this test tell you?
- CH50 blood test
- tells you total amount complement proteins but may still have abnormality in just C3 or C4 etc
