Lecture 16-17 - Complement Flashcards
Fixation of complement involves forming ___ and ____ from ____
C3 –> C3a + C3b
cleavage of C3 exposes ______ which undergoes _____ attack by ______
exposes thioester bond
undergoes nucleophilic attack by H20, R-OH or R-NH2
Attack by H20 gives _______
Attack by R-OH or R-NH2 gives _________
- Soluble C3b
- C3b bound to pathogen surface
Features of the complement pathways (3)
- Amplification
- Factors produced by liver (as zymogens)
- Converge onto C3 (the factor with the highest concentration)
What are the three complement pathways?
(and their relative orders, and general schemes)
-
Alternative
- Pathogen surface creates a local environment conduction to complement activation
-
Lectin
- Mannose-binding lectin binds to pathogen surface
-
Classical
- CRP (acute phase protein) or antibody binds to specific antigen on pathogen surface
In the alternative pathway, you need to form…
C3bBb
= Alternative C3 convertase
Alternative pathway steps (6)
- H20 exposes C3’s thioester bond (becomes iC3b)
- Factor B binds to C3b
- Factor D cleaves Factor B —–> Bb + Ba
- forms iC3bBb (unstable)
- binds another plain C3, which is cleaved into C3a + C3b (starts over…Amplification!)
- New C3 leaves, thioester is bound by another ROH/RNH2 = C3bBb = Alt. C3 Convertase
Positive and Negative Regulators of Alt. Pathway
- Stabilizer of C3Bb?
- Inactivator of C3b on both Pathogen and human cell surface?
- Stabilizer = Properdin stabilizes C3 convertase C3bBb (active) on a pathogen surface
- Pathogen = C3bBb is bound by factor H and then bound to factor I. When this all breaks up, it takes a part of the C3bBb, leaving iC3b (which is inactive)
- Human = DAF and MCP inhibit surface bound C3bBb
What are DAF and MCP (function and name)
Inhibitors of Human cell surface bound C3bBb
- DAF = Decay Accelerating Factor
- CD55 = Membrane cofactor protein
Consequences of Factor I deficiency in Alt pathway
- Unchecked C3 activation
- C3 depletion (too low to attack when pathogens infect)
- Chronic *encapsulated *bacterial infection
- Factor I deficiency inheritance?
- Symptoms?
- What will the blood counts look like (lymphocyte, IG)
- Autosomal Recessive
- Recurring infections of URT, ears, skin, UG (PNA, Meningitis, sepsis). Glomerulonephritis with isolated C3 deposits, **RA **or SLE.
- Normal lymphocyte ct, nml immunoglobulin concentration
Human cells are covered in ____, which is negative, and it reduces affinity for _____ and increases affinity for ___
Sialic acid
C3b
Factor H
C3b binding causes _____ by cells
opsonization
C3b on the pathogen binds to ____ on the MQ?
What happens next? (2)
C3b binds CR1 on MQ
- Endocytosis
- vesicle fusion –> phagocytosis
Ligands for CR1, CR2, and CR3/4
CR1 and CR2 = C3b
CR3/4 = iC3b
Associated cells for
CR1, CR2, CR3/4
CR1 = MQ, PMN, RBC
CR2 = FDC, B cell
CR3/4 = MQ, PMN
Function of CR1, CR2, and CR3/4
1 = phagocytosis, clearance of immune complexes
2= Antigen trapping, B cell activation
3/4 = phagocytosis
CR1 reduces the ___________
What happens when RBC’s CR1 recepor binds?
amount of Ag-AB complexes in the blood (some are coated with C3b)
–RBC will take the immune complex to the liver/spleen where it is eaten by a MQ
Terminal pathway of the Alternative path involves activation of
activation of C5
What does C5 bind to in the terminal pathway?
What happens next?
Binds to C3b(2)Bb
(= the *active *version of C3bBb that had two C3b’s bound to it)
- The C5 is split into C5b and C5a
- –> C5b sets off the terminal pathway
What is recruited by C5b? What does this result in?
combines with C6, 7, 8, 9 to make the Membrane attack complex
*The pore is lined with C9, so many are recruited per C5b
Functions of C7 and C8 in MAC formation?
Both expose hydrophobic regions
C7 allows attachment to membrane
C8 allows insertion into membrane
Why doesnt the MAC get formed in all cells that have C3b2Bb?
CD9 can’t bind in human cells because C5b678 is bound by** CD59**
(CD59 = CI factor 5)
PNH?
- Main feature/ pathophysiology
- Defective expression of ____ and ____
- Somatic mutation in _____ gene
Paroxysomal Nocturnal hemoglobinuria
- Intermittent intravascular hemolysis
- No CD55 (DAF) or CD59
- Mutation of PIGA gene (X-linked)
PNH path:
DAF defect causes ______
CD59 defect causes ______
DAF = extravascular hemolysis
CD59 = intravascular hemolysis –> Free Hb –> NO scavenging = fatigue, esophageal spasms, thrombosis
**both result in anemia
PNH treatments
- Bone marrow transplantation
- Eculizumab
- (Soliris, a humanized anti-C5 antibody)
- prevents C5 activation by C5 convertase (C3b(2)Bb)
Anaphylatoxins
- potencies
- act on ____ to increase_____
- also causes migration of…
C5a > C3a > C4a
act on vessels to increase vascular permeability
MQ and PMN into tissue from bloodstream
Two types of C3 convertase
ALt = C3bBb
Classical = C2aC4b
Classical C3 pathway steps (4)
- Immune complex’s Fc receptor recruits C1q,r,s
- C4 and C2 are cleaved, giving C4b2a (C4a and C2b leave…mediate inflammation)
- C4b2a (= C3 convertase) cleaves C3 into C3b (C3a leaves, also mediates inflamm.)
- Forms C4b2aC3b = C5 convertase (classical)
Classical pathway can be activated by…
How?
antibodies and CRP
- If CRP binds to phosphocholine on the pathogen surface, it can recruit C1 in the same way as IgM
Initiation of the classical pathway involves binding of _____
Binding of IgM to antigen on a pathogen surface
IgM binds in ___ conformation to bacterial cell surface
staple
(soluble form is planar)
Can IgG activate complement classical pathway?
Yes. Multiple IgG are required for activation
- IgG binds to surface antigen –> C1q binds to two or more IgG and initiates complement
OR
- IgG binds to soluble multivalent antigen –> C1q binds to soluble immune complex and initiates complement activation
Amplification by _______
Steps?
Alt. C3 convertase
- C1 binds to immune complex
- Deposition of C4b (by C1)
- Deposition of C3b (by C4b2a and C3bBb)
Ability of isotypes to activate complement (rank)
- IgM best
- then IgG 3 > 1 > 2
- Then IgA 1+2
“So M31212”
C4 haplotype - people can have ______ genes (and what are the combos)
Absence of C4A =
Absence of C4B =
People can have 1, 2, or 3 genes. (A/B, AA/BB/AB, AAB/ABB)
C4A = SLE susceptibility
C4B = increased infections
C1 r + s (in classical pathway) are ____
serine proteases
Lectin pathway steps
- MBP binds bacterial surface
- MASP1 and 2 are recruited
- C4 activated
- C2 activated
- C4b2a is formed (as in the classical pathway
What are MASP1/2?
MBP-associated serine proteases
Hereditary angioedema lab tests
C1 inhibitor deficiency
Low serum C4
Normal C3
- Hereditary angioneurotic edema = deficiency of _____
- Genetics
- Increase of ____, decrease of ___ and ___
- Low functional C1-INH
- Autosomal dominant
- increaed bradykinin, decreased C4 + C2
HAE Sx
Why do these patients NOT have increased susceptibility to infectious disease?
Recurrent edema of Skin, GI, UG, larynx
Abdomal/pelvic pain, suffocation
*Because C3 is still active = Alternative pathway still intact and you still have antibodies doing their thing
C1 inhibitor inhibits activation of ___ and ___ (among severeal other steps)
kallikrein and plasminogen
C2 Kinin =
a vasoactive peptide generated by C2b cleavage from plasmin
*results in edema
