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IHO Week 2 > Complement > Flashcards

Complement Flashcards

1
Q

complement system is heat ______

A

labile (not stable)

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2
Q

Important functions of complement

A 
Lysis
Opsonization
Solubilization and clearance of immune complexes and apoptotic cells
Augments stimulation of the B cell 
Mediators of inflammatory response
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3
Q

complement and immune complex diseases

A

In deficiencies of
classical pathway components, particularly C1q, the risk of immune complex disease is clearly increased both because
immune complexes are not eliminated and because of the potential for increased autoantibody production. C1q binds to surface bound DNA on apoptotic blebs. In the absence of C1q binding, apoptotic cells are not cleared and may increase the risk of exposure to autoantigens and development of autoimmune disease.

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4
Q

Issues with C1, 2, 4

A

immune complex diseases (SLE, glomerulonephritis) (classical, lectin and alternative - opsonization key)

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5
Q

Issues with C5, 6, 7, 8

A

neisseria (requires alternative pathway and terminal lytic)

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6
Q

Issues with C3

A

recurrent infections (classical pathway) and immune complex diseases

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7
Q

what is complement

A

plasma protein system, synthesized mainly by liver and tissue macrophages, epi cells, fibroblasts, monocytes

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8
Q

3 pathways of activation

A

classical - Ag/ab
Mannose-binding lectin - mannose
alternative - LPS, carbohydrates, etc

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9
Q

which complement proteins are cleaved

A

C1 - 5

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10
Q

which comp proteins are not cleaved

A

c6 - 9

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11
Q

Which fragments when cleaved stay and are active in complex

A

smaller = a, larger = b
larger (b) stay in complex for next step

exception is C2 (C2a stays and is largeR)

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12
Q

activators of classical pathway

A

ag/ab complexes

IgG (2) or IgM OR by apoptotic cells binding C1q

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13
Q

order of classical pathway (just numbers)

A

142356789

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14
Q

Cq present in plasma as

A

inactive C1qr2s2 complex

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15
Q

how to activate C1

A

binding of two arms of complex to Ig (2IgG or IgM) changes shape of C1q –> C1r change –> 2nd C1r change –> C1s change = active

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16
Q

C1s active cleaves

A

C4

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17
Q

absence or mutation in C1 inhibitor (controls C1 esterase)

A

leads to hereditary angiodema

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18
Q

IgG or IgM better activator of complement

A

IgM

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19
Q

activation of C4 classical

A

C1 esterase cleaves C4

C4b thioester region binds activation surface = opsonin

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20
Q

Activation of C2 classical

A

C2 interacts with C4b and is cleaved by C1s, forming a C4b2a complex on the surface.
C4b2a is the classical pathway C3 convertase

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21
Q

Classical pathway C3 convertase

A

C4b2a

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22
Q

C3 activation classic

A

C4b2a cleaves C3

thioester C3b binds to surface

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23
Q

key points classical pathway

A

Activation in conjunction with specific antibody
C3b and C4b covalently bind via thioester bonds
Enzymatic cleavage of proteins with amplification

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24
Q

does MBL pathway require specific antibody

A

no

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25
primary constituent of MBL pathway
is the plasma protein mannose binding lectin (also called the mannan binding lectin).
26
MBL path triggered by
polysaccharide structure of microbes (Salmonella, Listeria, Neiserria, Candida, etc bind MBL)
27
what does MBL pathway lead to
C1 independent formation of the classical pathway C3 convertase (C4b2a)
28
MBL analogs
MBL interacting with MASP-1 and MASP-2 is similar to C1q interaction with C1r and C1s --> C4 cleavage....
29
alternative pathway triggered by
recognition of foreign surface structures by complement itself (no ab)
30
A: C3 tickover
spontaneous conformational change of a few C3 molecules, leading to water hydrolyzing the thioester bond of C3 to form C3(H20) = C3b
31
Order alternative pathway
C3(H2O) + FB --> C3(H2O)B + FD --> C3bBb = C3 convertase - cleaves C3 and C3b put onto surface of cell (activating --> amplification)
32
Properdin
acts to stabilize alternative pathway C3 convertase C3bBb
33
Alternative pathway C3 convertase
C3bBb
34
Add C3bBb and C3b get
C3bBbC3b = C5 convertase
35
2. Activation of the complement system by antibody coated Streptococcus pneumoniae leads to the formation of a C3 convertase enzyme. The subunit composition of this enzyme is most likely:
C4b2a
36
Which complement proteins covalently binds to surfaces after enzymatic cleavage and exposure of an internal thioester bond?
C4 and C3
37
formation of membrane attack complex
C5 convertases generate C5b --> attachment of C6, C7, C8 to C5b --> c9 unfolds --> poly 9 on C5b-C8
38
if no C9?
still can have lysis, slower
39
if MAC not in the membrane
still important | C3b4b still in membrane - can result in effects by interaction w/ CR1-4
40
things that limit complement activation
short half-life of enzymes formed properties of non-activator surfaces inhibitors
41
fluid phase inhibitors
so active fragments don't go too far
42
membrane bound inhibitors
On our own membranes | So C3b and C4b don’t attach or don’t lead to lysis of our own cells
43
C1inh
plasma - binds active C1s and C1r so C4 not cleaved
44
S protein
plasma - binds soluble C5b-7 and blocks membrane binding
45
Factor H
inhibits alternative pathway at C3bBb (Decay acceleration and cofactor for Factor I)
46
C4BP
inhibits classical pathway at C4b2a
47
MCP(CD46)
membrane cofactor protein -- - help Factor I dissociate both C3 convertases (A and C)
48
DAF (CD55)
Decay accelerating factor -- dissociate both C3 convertases
49
what makes a surface non-activating
sialic acid
50
deficiencies in Factor H
Atypical hemolytic uremic syndrome (aHUS) | Age related macular degeneration
51
aHUS
Uncontrolled alternative pathway complement activation systemically Can also be due to mutations in C3, Factor B or MCP (CD46) Leads to systemic thrombotic microangiopathy Formation of blood clots in small blood vessels throughout the body which can lead to stroke, heart attack, kidney failure…
52
what happens if you lack control?
Consequences of activation – lysis etc Consumption of the complement components leading to the consequences of secondary complement deficiency (IC disease and infections)
53
C1 inh deficiency
HAE Recurrent episodes of localized edema in skin, GI tract, or larynx Uncontrolled complement activation leads to consumption of C4 and C2. Possibility of immune complex disease as well
54
C1 Inh deficiency tx
Anabolic steroids to increase synthesis of C1 INH Purified C1 INH Kallikrein inhibitors and bradykinin B2 receptor inhibitors Evidence for excess kinin formation responsible for the episodes of edema
55
Deficiency in DAF (CD55)
Defect in a post-translational modification of the peptide anchors that bind the proteins to the cell membrane Increased susceptibility of erythrocytes to MAC-mediated lysis
56
things C4b and C3b can do
MAC --> lysis interact w/ CR1 -- opsonization degraded to fragments - interact with CR2 and CR3 - opsonization, clearance of IC, augmentation of humoral immunity
57
CR1 (CD35) major ligands
C3b, C4b
58
CR1 on
Monocytes, macrophages, PMN, Eosinophil, RBC, B and T cells | RBC - transport of immune complex
59
CR1 promotes
immune adherence (binding of opsonized microbes to primate RBCs) Promotes phagocytosis in cooperation with Fc receptors Blocks formation of C3 convertase
60
immune complex disease
High incidence of IC disease SLE in individuals who are deficient in C1, C4, C2 or C3 Excess immune complexes cause pathological complement activation -- inflammation, tissue damage IC not solubilized and cleared
61
what gets IC to reticuloendothelial system for clearance
CR1 receptors on the erythrocyte The immune complex coated with C3b is transferred from the RBC CR1 receptor to the macrophage CR1 receptor. The immune complex is then internalized and degraded.
62
what interferes with lattice formation, limits its growth, prevents precipitation of the antigen antibody complexes and keeps them soluble.
binding of C3b to antigen/ab complex
63
CR2 major ligans
C3d, C3dg, iC3b
64
CR2 role
CR2 forms an additional signal with antibody to augment stimulation of the B cell to increase the humoral immune response (CR2/CD19/CD81).
65
CR2 and EBV
CR2 has high affinity for an envelope protein of Epstein Barr virus, allowing the virus to enter the B cell.
66
CR3 and 4 (CD11b/c / CD18)
Major ligand iC3b Monocytes, macrophages, PMN, NK cells, T cells Phagocytosis, cell adhesion
67
Numerous C3b molecules are deposited on the surface of bacteria X. The C3b favors the phagocytosis of the bacteria by neutrophils by binding to what
CR1
68
anaphylatoxins
C3a and C5a can mimic the symptoms of inflammation and anaphylaxis Chemotaxis, smooth muscle contraction, increased vascular permeability, degranulation of mast cells, etc

IHO Week 2 (13 decks)

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