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IHL Exam 2 > Complement Cascade > Flashcards

Complement Cascade Flashcards

1
Q

Complement system

A

Collection of circulating and cell membrane proteins

complements the humoral branch of innate and adaptive immunity

coordinated enzymatic cascade –> seqeuntial proteolytic cleavage of C’ proteins (zymogens)

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2
Q

C’ functions

A

triggers and amplifies inflammation rxns

attraction of phagocytes by chemotaxis

clearance of immune complexes

cellular activation

Direct microbial killing

Development of humoral responses

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3
Q

what are the components activated by cleavage into peptide fragments

A

smaller fragment “a” - away

  • anaphylatoxins
  • diffuse AWAY from site
  • helps initiate localized inflammatory response

larger fragment “b”

  • active complement component
  • BINDS to target near site of activation
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4
Q

what does a bar over a symbol mean in the nomenclature of C’ system

A

it means the complex (such as C4b2b3b) is activated and has enzymatic activity

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5
Q

Complement system activation differs in the stimulus that triggers the cascade but all merge into a common pathway leading to the formation of what?

A

lethal membrane attack complex (MAC)

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6
Q

What are the three different C’ activation pathways?

A

Classical
Alternative
Lectin

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7
Q

What activates the classical pathway

A

antibody binding to antigen

antibody defines the target antigen

this is part of humoral arm of adaptive immunity

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8
Q

Alternative pathway

A

Independent of antibody

  • not necessary for the host to have had prior exposure (so innate)
  • constant trickle (surveillance)
  • don’t have exquisite specificity that you have to have in classical pathway
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9
Q

Lectin Pathway

A

activated when a carbohydrate-binding plasma protein, mannose-binding lectin (MBL), binds to terminal mannose residues on the surface glycoproteins of microbes.

component of innate immunity

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10
Q

What are the initiation steps of Classical pathway

A

Antibodies bind antigens

C1 component

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11
Q

What is C1 and what does it bind to?

A

C1 is a hexamer (6 globular domains) associated to two C1s and C1r molecules

binds to antigen/antibody complex

binds 1 IgM

binds 2 IgG

***Classical pathway

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12
Q

what does C1qrs cleave?

A

C4

C2

generates an amplification b/c it cleaves and activates many C4 and C2 molecules

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13
Q

C4b2b

A

aka C3 convertase

cleaves many molecules of C3

responsible for the distinction b/w self and non-self b/c C3b deposits deposits rapidly on non-self surfaces which leads to opsonization

self surfaces limit the deposition of C3b

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14
Q

C4b2b3b

A

aka C5 Convertase

this brings in C5 and cleaves it to C5b and C5a

initiates the final series of events leading to MAC formation

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15
Q

C5b67 complex

A

Inserts itself into the membrane and forms a small pore

eventually leads to slow lysis of target cells

association of C5b67 can occur in fluid phase as well as on membrane… so that means this complex can diffuse and insert itself into other near by membranes

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16
Q

C8

A

associated with C5b67

C8 recruits 10-16 copies of C9

C9 forms hole in membrane and leads to lysis of cell

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17
Q

MAC

A

C5b67 with C8 and C9

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18
Q

Alternative pathway

A

Protects from pathogens in the absence of antibody

slow. less efficient

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19
Q

initiation of alternative pathway?

A

spontaneous conversion of C3 to C3b in serum

if there is a microbe in the area then C3b will deposit itself onto the membrane surface of the microbe

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20
Q

How does C3 identify self from non self

A

Self membranes

  • high levels of sialic acid
  • rapidly inactivates bound C3b molecules on host cells

Non self membranes

  • bacterial cell walls, yeast walls and viral envelopes
  • low levels of sialic acid
  • bound C3b will remain active longer
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21
Q

what does factor B bind to

A

binds to deposited C3b on microbe surface

alternative pathway

cleaved by Factor D

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22
Q

Complex C3bBb

A

aka C3 convertase

cleaves more C3 into C3b

alternative pathway

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23
Q

what does factor D do…

A

cleaves factor B into Bb and Ba

alternative pathway

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24
Q

Alternative C5 convertase?

A

C3bBb3bP

formed when a second C3b binds to the C3BbP complex (which is the C3 convertase stabilized by a P)

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25
Q

Lectin pathway

A

innate immune response (antibody independent)

another surveillance method

plasma contains Collectin Family

  • Mannose-binding lectin (MBL) or ficolins
  • MBL- associated serine proteases (MASPS)
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26
Q

what is MBL

A

used in lectin pathway

Mannose binding lectin attaches to microbes
structurally similar to C1 in classical pathway and acts to activates C4

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27
Q

what is MASP in the lectin pathway equivalent to in the classical pathway

A

C1qrs complex

so it needs to be activated and then cleaves C4 as well as C2

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28
Q

Activation of lectin pathway

A

MBL binds mannose residues on bacterial surface polysaccharides

MBL/MASP complex cleaves C4 and C2 components

steps following are similar to classical pathway in that it leads to formation of C3 convertase

29
Q

C’ regulation

A

required to prevent:

  • consumption of components (C shit) through unregulated amplification
  • protect host and host self cells

regulation occurs during activation, amplification, and membrane attack

30
Q

Two main effector functions of regulation

A

binding with complement molecules to cause dissociation

proteolytic digestion to decrease half life

31
Q

first control of convertases is…..

A

decay acceleration- components of complement under go spontaneous inactivation as they diffuse away from the site of activation

rapid hydrolysis of C3b

also happens to C4b

32
Q

Factor H

A

prevents the formation of C5 convertase

Factor H/C3b complex is also a target for Factor I

binds to C3b only if the C3b has been deposited on the surface of a host cell

33
Q

Protected site concept of C3b

A

Deposition of C3b on a microorganism

C3b is then protected from Factor H–> activates the alternative pathway

C3b on a host cell is a target for factor H and subsequently for factor I

34
Q

S protein (Vitronectin)

A

binds to fluid phase form of C5b67

prevents binding to membranes

DOES NOT prevent association with C8 and the C9 proteins so still building a MAC just not poking holes in anything

35
Q

C1 inh

A

binds Clr and Cls in classical

removes MASP from MBL complex in lectin path

prevents these from becoming active so helps in early regulation of C’

36
Q

Factor I

A

C3b inactivator

cleaves C4b or C3b

requires cofactors such as:
C4-bp, MCP or CR1

prevents formation of C3 or C5 convertases

37
Q

C4-bp

A

prevents C4b from associating with C2b

also causes C4b to dissociate from C3 convertase

cofactor for Factor I

38
Q

CR1

A

binds to C3b molecules on the surface of cells

allows cleavage by factor I

mechanism for distinguishing between self and non-self b/c pathogens don’t have self markers

39
Q

MCP (CD46)

A

co-factor for factor I

binds to either C4b or C3b

MCP is found on “self” membranes

“self” verses “non-self” recognition

40
Q

DAF

A

Promotes dissociation of the C3 convertase

C2b from C4b in classical

Removes Bb from C3b in alternative pathway

41
Q

CD59

A

Blocks C9 binding to C5bC678 complex on the cell surface

42
Q

Functions of complement

A

Opsonization and phagocytosis/ waste management
Osmotic lysis of microbes (via MAC)
Stimulation of inflammatory reactions (due to anaphylatoxins the “a” C’ particles)

43
Q

Opsonization

A

WShower of C4b and C3b in the area of activation

  • coats antigens/microbes
  • these C4b or C3b bind to one of the complement receptors (CR1-CR4) on phagocytic cells
  • leads to enhanced phagocytosis

ALSO
Anaphylatoxins (C5a in particular) increased the number of complement receptors on the cell surface which greatly facilitates their phagocytosis of C3b-coated antigens

44
Q

Opsonins in body

A

C3b (main)

C4b

45
Q

C5a anaphylatoxin

A

increases the number of complement receptors on the cell surface which greatly facilitates their phagocytosis of C3b-coated antigens

46
Q

Waste management (steps?)

A

Removal of immune complexes from circulation

1) Immune complexes form in circulation (Antibody/antigen)

2) IC is opsonized with C3b/C4b
classical or alternative

complement binds to C’ receptors of the Fc portion of the antibody (C3b)

3) IC binds to RBC C’ receptor I
4) RBC’s then travel to liver and spleen where they offload opsonized antibody C’ complex to phagocytes in liver or spleen

very large complex in capillaries (immune complex disease)

47
Q

Antibodies bind…

A

bind extracellular antigens

48
Q

Cell Lysis

A

done with the MAC

can do this to:
microorganisms
erythrocytes (just takes 1 MAC)
nucleated cells (requires multiple MAC’s)

49
Q

what is responsible for the inflammatory response of complement?

A

Anaphylatoxins -the small diffuseable “a” fragments

50
Q

Functions of Anaphylatoxins

A

Bind to receptors on mast cells and blood basophils–> degranulation/histamine release

induce smooth muscle contraction
-increase vascular permeability

induce monocytes and neutrophils to adhere to vascular endothelial cells (by upregulating adhesion molecules on endothelial cells)
CHEMOTACTIC

C5a is most potent in mediating these proceses (C3a and C5b67 can do this to)

51
Q

C2a

A

Prokinin
cleaved by plasmin to yield kinin

which results in edema

52
Q

C3 deficiency

A

life-threatening problems
severe recurrent infections soon after birth

central role of C3b plays in opsonin of infectious particles

53
Q

Deficiencies in Factor H and Factor I mimic C3 why?

A

b/c unregulated C3b generation completely exhausts C3 from the serum

54
Q

MAC deficiencies (C5-C9)

A

Generally healthy

except increase infection by Neisseria gonorrhea and N. meningitidis

55
Q

deficiencies in early C’ activation

A

C1, C2, C4

C2 deficiency most common
pt’s have high degree of systemic lupus erythematosis (SLE)
can’t efficiently clear circulating immune complexes
IC’s deposit in blood vessel walls and tissues

56
Q

C1inh deficiency

A

C1 is not regulated properly –> so C4 and C2 levels are low

physical trauma and emotional stress and precipitating factors

HANE (hereditary angioneurotic edema)
(swelling of face, GI tract, extremities)

treat with androgens (transcriptional expression problem)

57
Q

DAF deficiency

A

causes Paroxysmal nocturnal hemoglobinuria (PHN)
-bright red urine in the morning

spontaneous episodes of RBC lysis
RBC’s, leukocytes, and platelets have increased sensitivity to C’ lysis (MORE MACs)

Treat with Erythropoietin

DAF normally promotes dissociation of C2b from C4b and Bb from C4b

what are the levels of C’ stuff when you have a DAF deficiency??

58
Q

what is causing edema in the HANE

A

c2a or other anaphyatoxins

59
Q

Viruses and C’ pathway

A

can be used to enhance infectivity

60
Q

Epstein-Barr virus

A

uses CR2 as a receptor for attachment

61
Q

Measles virus

A

uses MCP (CD46) as a receptor

62
Q

West nile virus

A

C3b coats viral particle

gains entry into cells via the CR3 receptor

63
Q

classical pathway deficiencies result in…

A

tissue inflammation

why?

64
Q

Deficiencies of MBL are associated with…

A

infections in infants

65
Q

Alternative pathway and C3 deficiencies are associated with…

A

bacterial infections

66
Q

Terminal pathway deficiencies …

A

predispose to Gram-negative bacterial infections

67
Q

C1 inhibitor deficiency leads to …

A

hereditary angioedema

68
Q

Deficiencies in alternative pathway regulators produce …

A

a secondary loss of C3

IHL Exam 2 (14 decks)

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