Complement Cascade Flashcards

0
Q

what systems does complement “complement”?

A

humoral and innate immunity

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1
Q

C’

A

complement

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2
Q

complement is central to what?

A

inflammatory reactions

triggering and amplifying inflammation, attraction of phagocytes, clearance of immune complexes, cellular activation, direct microbial killing, and important in development of the humoral responses

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3
Q

larger and smaller fragment of complement?

A

a - smaller
b - larger

b binds and a diffuses

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4
Q

anaphylotaxins

A

a fragments of complement

are chemotactic peptides

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5
Q

role of anaphylatoxins

A

play a role in initiating a localized inflammatory response

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6
Q

all pathways of complement end where?

A

formation of the MAC

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7
Q

classical pathway

A

activated by antigen binding to antigen

assists in the humoral response

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8
Q

alternative pathway

A

not necessary for a prior exposure
-doesn’t need antibody
plays a role in surveillence

more primitive than classical

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9
Q

lectin pathway

A

activated by binding of mannose binding protein in bacteria

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10
Q

initiation of classical pathway?

A

IgG or IgM antibody is bound and results in the binding of C1
-C1 binds to Fc portion of antibodies

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11
Q

overview of classical complement pathway

A

most efficient and fast

1) IgG and IgM antibodies bind antigen and Fc portion binds C1
-binds to C1q domains (cleavage of C1r and C1s)
enzymatically active C1qrs

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12
Q

structure of C1

A

one hexamer C1q subunit, two C1r, and two C1s subunits

forms a large complex
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13
Q

what activates C1?

A

cleavage of C1r and C1s
-yields active C1qrs

*the C1 is a C1q hexamer, two C1r, and two C1s subunits

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14
Q

how many of each antibody to activate classical pathway?

A

IgM is a pentamer
-only requires one to initiate cascade

IgG is a monomer
-requires at least two to initiate cascade

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15
Q

activity of enzymatically active C1qrs?

A

cleaves C4
-release C4a and C4b

C4b attaches to the cell membrane which form clusters around the area of the antibody interaction

C4a diffuses away

also cleaves C2

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16
Q

activity of C4b?

A

recruits C2, which is also cleaved by C1qrs

-C2a diffuses away and C2b binds to C4b

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17
Q

what is the C3 convertase of classical pathway?

A

C4b2b
-cleaves C3

C3b will opsonize and also associate with the C3 convertase
-forms the C4b2b3b (C5 convertase)

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18
Q

importance of C3

A

responsible for the distinction between self and non-self

self surfaces limit the deposition of C3b
-C3b rapidly associates with non-self surfaces

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19
Q

C5 convertase of the classical pathway?

A

C4b2b3b

initiates the formation of the MAC complex

C5b associates with C6 and C7 which inserts into the membrane
-forms pore - which will lead to slow lysis

C8 then bind the C5b67 which
-forms C5b678 which recruits 10-16 copies of C9
forms the MAC

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20
Q

what is the MAC complex?

A

C5b6789

creates large pores in the membrane
-results in more rapid osmotic lysis of the cell

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21
Q

alternative pathway of complement?

A

slow and less efficient

surveillence system

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22
Q

initiation of alternative pathway?

A

spontaneous conversion of C3 to C3b

-important in recognizing self from non-self

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23
Q

how is C3b involved in the recognition of self membrane?

A

sialic acid levels are high on the self membranes
-result in the inactivation of C3b

bacterial and viral envelopes have low sialic acid
-C3b remains associated with membrane

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24
Q

C3 convertase of the alternative pathway?

A

factor B binds to C3b and is cleaved
-factor D cleaves factor B

forms C3bBb (alternative C3 convertase)
	results in the cleavage of C3 (amplifies process)
25
Q

Factor B

A

binds to membrane associated C3b

cleaved by Factor D

26
Q

Factor D

A

cleaves factor B bound to C3b

-results in C3bBb (C3 convertase of the alternative pathway)

27
Q

properdin

A

binds the C3 convertase of alternative pathway and stabilizes it

*increases its half-life

28
Q

C5 convertase of alternative pathway?

A

C3bBbP3b

Properdin is stabilizing the C5 convertase

C5 convertase cleaves C5 and formation of MAC complex occurs

29
Q

lectin pathway?

A

antibody-independent

involves the lectin
-MBLs and MASPs

30
Q

activation of the lectin pathway?

A

MBL binds MASP on bacterial surface polysaccharides

this structure is similar to the C1q
-cleaves C4 and C2

forms C4b2b (C3 convertase of the classical pathway)
	-everything occurs as classical pathway
forms the C3 convertase  C4b2b
31
Q

RCA proteins?

A

regulators of complement activation

32
Q

two main function of RCA?

A

bind and cause dissociate

cause the proteolytic cleave of components

33
Q

first level of control of convertases?

A

decay acceleration

34
Q

decay acceleration

A

many of the components have short half lives

C3b is hydrolyzed rapidly**

35
Q

C1inh

A

in both classical and lectin pathway

binds to the C1r and C1s to dissociate them from C1q

removes MASP enzymes from MBL complex

36
Q

Factor I

A

plasma protein

cleaves C4b or C3b

has several cofactors - C4-bp, MCP, CR1

prevents formation of C3 and C5 convertases

- C3 - C4 degradation
- C5 - C3 degradation
37
Q

cofactors of Factor I

A

C4-bp, MCP, CR1

38
Q

C4-binding protein

A

binds to C4b

- prevents its association with C2b
- causes C4b to dissociate from the C3 convertase

C4-bp/C4b is target for digestion by Factor I

39
Q

Complement Receptor I

A

binds C3b and allows for the cleavage by Factor I

**mechanism for distinguishing between self and non-self

(CR1;CD35)

40
Q

Membrane Co-factor protein

A

MCP;CD46

co-factor for factor I
binds to either C4b or C3b

found on self membranes
*allows self vs. non-self recognition

41
Q

Factor H

A

analagous to C4-bp

binds to C3b and prevents C5 convertase formation

Factor H/C3b is a target for factor I

42
Q

protected site concept

A

factor H binding only occurs if the C3b has been deposited on surface of cell

43
Q

decay-accelerating factor

A

DAF;CD55

promotes the dissociation of the C3 convertase

- C2b from C4b and Bb from C3b
- in classical and alternative pathways
44
Q

CD59

A

blocks C9 binding to C5b678 on cell surface

45
Q

vitronectin (S protein)

A

binds to the fluid phase (C5b67)
-prevents binding to membrane

* *doesn't prevent C8 or C9 association
	- forming MAC, but they aren't in the membrane
46
Q

opsonization

-major one in body?
A

major one is C3b

C4b is also an opsonin

Complement receptors on the phagocytic cells bind to the C3b or C4b

- increases phagocytosis
	- also the a fragments increase phagocytosis
47
Q

activity of anaphylatoxins?

A

increase the number of complement receptors on the cell surface of phagocytes
greatly facilitate their phagocytosis of complement opsonized cells

48
Q

waste management

A

removal of immune complexes from circulation

-antibodies bind extracellular antigens

antibody with bound C3b

- binds to erythrocytes complement receptor
- taken to the spleen and liver (degradation)
	- erythrocytes offload the antibody/complement
49
Q

MAC activity on erythrocytes?

A

only single MAC to lyse an RBC

50
Q

nucleated cells and MAC?

A

usually requires several MACs

there are certain cells that can internalize the MAC and degrade it

51
Q

complement and inflammation?

A

instrumental role

activation of complement results in influx of fluid

52
Q

anaphylatoxins function?

A

increase inflammation

bind to receptors on mast cells and basophils - histamine
smooth muscle contraction - vascular permeability
monocytes and neutrophils to adhere to endothelial cells

53
Q

C5a

A

most potent in mediating the processes of inflammation in response to complement cascade

54
Q

C2a

A

prokinin

cleaved by plasmin to yield kinin
-results in edema

55
Q

C3 deficiency

A

can lead to life-threatening situations
-noticed early after birth

can be mimicked by deficiency in factor H and factor I

**why?

56
Q

MAC deficiency?

A

C5, 6, 7, 8, 9
generally healthy

except infection by Neisseria gonorrhoeae and N. meningitidis

57
Q

deficiency in C1, 2, and 4

A

most common is C2
-patients have a high degree of systemic lupus erythematois
SLE

58
Q

C1inh deficiency

A

HANE

chronic low levels of C4 and C2

swelling with no obvious cause

commonly involves the extremities

59
Q

DAF deficiency

A

decay-accelerating factor

leads to paroxysmal nocturnal hemoglobinuria

hemolytic disorders
-degrades RBCs

treat with erythropoietin

60
Q

viruses and complement?

A

use them to increase its infectivity

epstein-barr - CR2 as a receptor for attachment
measles - MCP as a receptor
West Nile virus - C3b to gain entry into cells via CR3 recepor