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Life protection > I&I the complement system > Flashcards

I&I the complement system Flashcards

1
Q

What type of system is the complement system?

A

Innate system

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2
Q

What is there activation of in the complement system?

A

Activation of small soluble heat sensitive protein that can
combine and create complexes with proteolytic activity

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3
Q

What are the 3 steps in the complement system?

A
  1. Recognition
  2. Opsonization
  3. Effector- inflammation, phagocytosis and membrane attack
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4
Q

What happens in the recognition stage in the complement?

A
  • Innate recognition of non self
  • Antibodies
  • Apoptotic cells
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5
Q

What are the 3 distinct pathways in the complement system?

A

3 Distinct pathways:
1. Antibody triggered(classical)
2. Presence of pathogen alone(Alternative)
3. Lectin type protein activation(Lectin)

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6
Q

What is the common pathway in the complement pathway?

A

Terminal pathway-lysis

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7
Q

What does C1 in the classical pathway interact with?

A

C1 interacts with Ab (IgM and IgG) bound to microbes

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8
Q

What is the effector mechanism in the classical pathway?

A

It has an effector mechanism of humoral immunity

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9
Q

What system does the alternative pathway form part of?

A

Forms part of the innate immune system

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10
Q

What system is the lectin pathway part of?

A

Part of the innate immune ststem?

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11
Q

Briefly, what is involved in the lectin pathway?

A

Mannose binding lectin (MBL) recognises terminal mannose residues on microbes, whilst ficolin recognises different microbial residues

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12
Q

What do ‘a’ and ‘b’ in the proteolytic products of the complement protein identify as?

A

‘a’ is for the smaller products
‘b’ is for the larger products

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13
Q

What does C3 convertase cleave?

A

C3 convertase cleaves C3 to C3a and C3b

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14
Q

What does C5 convertase cleave?

A

C5 convertase cleaves C5 to C5a and C5b

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15
Q

What is the classical pathway initiated by?

A

The classical pathway initiated by the binding of C1 to Ag-bound IgG or IgM

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16
Q

What is the structure of C1 and what does it consist of?

A

C1 is a multimeric protein complex, consisting of C1q, C1r and C1s

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17
Q

What does C1q bind to?

A

C1q binds to the antibodies (IgM, IgG1 and IgG3

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18
Q

What does C1 not bind to?

A

C1 does not bind to soluble (free) Ab molecules; it only binds to Ab bound to Ag

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19
Q

What does the globular head of C1q bind to?

A

The globular heads of C1q bind to the Fc domains of IgG and IgM, when the Fab domains are bound to A

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20
Q

What must every C1q molecule bind in order to be activated?

A

Every C1q molecule must bind at least 2 Ig Fc regions to be activated

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21
Q

What is the classical pathway which involves C3 convertase?

A

-After having bound to 2 or more Ag-bound Ab, the C1q can activate C1r
-C1r cleaves and activates C1s
-The C1s then cleaves C4 into C4b and C4a(the C4 molecules have a similar structure to C3, with an internal thioester bond)
-C4b binds covalently to antigens on the surface of microbes
-It acts as an opsonin, promoting phagocytosis and recruits C2
-C2 is cleaved by C1s into C2a and C2b
-In this case, C2a is the larger fragment and binds to C4b forming the C3 convertase for the classical pathway(C4bC2a)
-C2b is the smaller fragment of C2 and has no biological function

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22
Q

What are the steps involved in the classical pathway involving C5 convertase?

A

-C3 convertase(C4bC2a) cleaves more C3b molecules producing C3b and C3a
-C3a mediates biological activities
-Newly generated C3b deposits on the microbial surface, where some acts as an opsonin and some binds to the C3 convertase complex
- The resultant C4bC2aC3b is the classical pathway C5 convertase
-The C5 convertase complex cleaves C5, initiating the late steps of complement activation

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23
Q

What are the late steps in the classical pathway?

A

-The C5 convertase cleaves C5 into large C5b fragments and small C5a fragments
-C5a is a soluble fragment with several biological functions
-C5b remains bound to C5 convertase, where it recruits C6 and C7
-C7 is hydrophobic, therefore inserts into the lipid membranes of the microbes, where it recruits C8
-C8 has three chains, one of which inserts into lipid membranes of the microbe
-The complex formed by C5b-C8 then recruits C9 which polymerises, forming pores(which consist of between 10 and 16 polymerised C9 molecules)
-The C5b-C9 complex is called the MAC(membrane attack complex) which causes lysis of the microbe by allowing H20 entry via C9 pores

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24
Q

What is the lectin pathway initiated in?

A

The lectin pathway is initiated in the absence of Ab

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25
Q

What is the lectin pathway triggered by?

A

It is triggered by microbial carbohydrate recognition by PRRs

26
Q

What are the PRRs that are involved?

A

The PRRs involved are MBL (mannose binding lectin) and ficolins (which have a similar structure to C1q)

27
Q

What are the steps invovled in the lectin pathway?

A

-MBL binds to mannose residues on microbes, whilst ficolin binds to N-acetylglucosamine residues on the microbes
-Like C1q, MBL and ficolin are bound to proteases
-C1q is bound to C1r and C1s, whilst MBL and ficolin are found in a complex with MBL Associated Serine Proteases (MASP1 and MASP2)
-Binding of MBL to mannose and ficolin to N-acetylglucosamine activates the MASPs, which subsequently cleave C4 and C2
-The lectin pathway then continues in a similar way to the classical pathway

28
Q

What is the initiating event in the alternative pathway?

A

The initiating event in the alternative pathway is spontaneous cleavage of C3 in the plasma - this is called C3 tick-over

29
Q

What are the steps involved in the alternative pathway involving C3 convertase?

A

-C3 contains a reactive thioester bond (which is hidden), making it labile
-C3 cleavage induces a conformational change in C3b, exposing the thioester bond (as well as the binding site for factor B – the next component of the alternative pathway)
-The exposed bond reacts with amino or hydroxyl groups on the surface of microbes
-This leads to ester bond formation, attaching C3b to the surface of the microbe
-In the absence of covalent attachment, C3b remains in the fluid phase, in which it is unstable
-It is rapidly inactivated by hydrolysis therefore further complement activation is stopped
-Notes that when in the fluid phase, complement proteins are inactive or transiently active
-When deposited on microbes, the complement proteins are stable (i.e. they are constantly activated)
-Once bound to the surface of the microbe C3 B binds factor B
-The factor B is then cleaved into factor Ba and factor Bb by factor D (a plasma protease)
-This leaves us with C3b bound to factor Bb, the C3 convertase complex of the alternative pathway (C3bBb)
-The C3 convertase is stabilised by properdin and functions to cleave more C3 molecules, amplifying complement activation
-New generated C3b deposits on microbial surfaces act as opsonins, promoting phagocytosis
-C3a functions to mediate biological activity

30
Q

What are the steps involved in the alternative pathway involving C5 convertase?

A

-As the C3 convertase cleaves more C3 and, some of the C3b molecules produced bind to the C3 convertase
-This produces C3bBbC3b, the alternative pathway C5 convertase
-C5 convertase cleaves C5 into C5a and C5b, initiating the late steps of complement activation

31
Q

What are the late steps in the alternative pathway?

A

-The C5 convertase cleaves C5 into large C5b fragments and small C5a fragments
-C5a is a soluble fragment with several biological functions
-C5b remains bound to C5 convertase, where it recruits C6 and C7
-C7 is hydrophobic, therefore inserts into the lipid membranes of the microbes, where it recruits C8
-C8 has three chains, one of which inserts into lipid membrane of the microbe
-The complex formed by C5b-C8 then recruits C9 which polymerises, forming pores (which consist of between 10 and 16 polymerised C9 molecules)
-The C5b-C9 complex is called the MAC (membrane attack complex), which causes lysis of the microbe by allowing H2O entry via C9 pores

32
Q

What is the function of C3b and C4b?

A

Act as opsonins

33
Q

What do C3b and C4b deposit on and what does this cause?

A

Deposit on microbial surfaces, coating them. This opsonisation promotes phagocytosis

34
Q

What is the function of C3a, C4a and C5a?

A

Trigger acute inflammation

35
Q

What do C3a, C4a and C5a bind to?

A

Bind to mast cells, causing degranulation, which releases histamine

36
Q

Why are C3a, C4a and C5a also known as anaphylaxtoxins?

A

They’re also known as anaphylatoxins because mast cell degranulation is similar to anaphylaxis

37
Q

What does C5a act as and what does this do?

A

C5a acts a chemotactic agent, attracting neutrophils and promoting ROS production

38
Q

What does C5a do to permeability and what does it promote and what does this lead to?

A

C5a increases the permeability of endothelial cells and promotes neutrophil adhesion to the endothelium, leading to WBC recruitment at inflammation sites

39
Q

Why is complement activation tightly regulated?

A

Compliment activation is tightly regulated to prevent activation affecting healthy cells, and to limit the duration of complement activation on microbes or Ag-Ab complexes

40
Q

What are the 3 mechanisms of complement regulation?

A

-Inhibiting the formation of C3 convertase
-Degrading or inactivating C3 or C5 convertase
-Inhibiting the formation of the MAC

41
Q

What is C1 INH and what does it do?

A

C1 INH is a complement regulator that inhibits C3 convertase formation

42
Q

How does C1 INH inhibit the formation of C3 convertase formation?

A

-It dissociates the proteases (C1r and C1s) from C1q
-This in turn blocks of the proteolytic activity of C1r and C1s

43
Q

What is CD59 and where is it found?

A

CD59 (protectin) in a complement regulator that is found on the surface of healthy cells

44
Q

What does CD59 inhibit and how?

A

It Inhibits MAC formation on healthy cells by binding to C5-C8

45
Q

What does the inhibition of MAC formation inhibit and what happens as a result?

A

-Inhibits the recruitment and polymerisation of C9
-As a result, no pores are formed in the cell membrane, so cell lysis cannot occur

46
Q

What does staphylococcal inhibit?

A

Staphylococcal inhibits C3 convertase assembly

47
Q

What does staphylokinase cleave?

A

Staphylokinase cleaves antibodies bound to pathogen surface
and avoids complement and phagocytosis

48
Q

What does staphylococcal complement inhibitor inhibit?

A

Staphylococcal complement inhibitor inhibits C3 convertase
activity

49
Q

What does Staphylococcal Superantigen inhibit?

A

Inhibit Fab
fragment binding to C1 complex

50
Q

How does N.meningitis block complement?

A

Factor H binding protein recruited to pathogen
surface to inactivate c3b

51
Q

What disease/manifestations arise due to a deficiency of Complement regulation
Factor I and Factor H?

A

Atypical haemolytic uraemic syndrome +
recurrent bacterial infections associated with
low C3

52
Q

What does a deficiency in DAF lead to?

A

Paroxysmal Nocturnal haemoglobinuria

53
Q

What is the triad in atypical haemolytic uraemic syndrome?

A
  • Thrombocytopenia
  • Microangiopathic haemolytic
    anaemia
  • Acute renal failure
54
Q

What is there failure to control of in atypical haemolytic uraemic syndrome?

A

Failure to control the alternative
pathway

55
Q

What mutation leads to paroxysmal nocturnal haemoglobin(PNH)?

A

Mutation in PIG-A gene

56
Q

What is there a lack of in host cell walls in PNH and what does this reduce?

A

Lack of glycosylphosphatidylinositol
protein in host cells walls reduces
anchoring of CD55 and CD59 control
factors on erythrocytes

57
Q

What is the erythrocyte more susceptible to in PNH?

A

Susceptible to lysis

58
Q

What accumulates on the surface of erythrocyte in PNH?

A

C3b accumulates on Erythrocyte Surface

59
Q

What pathway is activated and leads to the destruction of what in PNH?

A

-Activation of complement Terminal/ Mac
pathway
-Destruction of Erythrocytes

60
Q

What is the treatment of PNH?

A

Eculizumab

Life protection (12 decks)

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