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Immunology > Complement System > Flashcards

Complement System Flashcards

1
Q

Definition of complement

A

Heat liable component of the blood (alexin) that complements the heat stable antibody in the killing of bacteria.

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2
Q

What complement pathways produce C2aC4b convertase?

A

Classical and lectin

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3
Q

Features of classical pathway

A

Commonly generally antibody mediated, occurs in the secondary response.

Generates C2aC4b

Components: C1q,r,s C4 and C2.

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4
Q

Features of lectin pathway

A

Requires carbohydrate recognition.

Generates C2aC4b.

Components: MBL, MASP1-3.

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5
Q

Features of alternative pathway

A

Spontaneous.

Generates C3bBb

Components: Factor D, B, C3 (and Factor P).

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6
Q

Outcomes of complement activation.

A

Inflammation
Phagocytosis
Membrane attack complex (MAC)

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7
Q

Components of MAC

A

C5b C6 C7 C8 and C9

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8
Q

Function of fragment C3a

A

Anaphylatoxin which can activate mast cells, histamine release and vascular permeability, chemotaxins (attract phagocytes like neutrophils and mononuclear phagocytes.

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9
Q

Function of fragment C5a

A

Anaphylatoxin which can activate mast cells, histamine release and vascular permeability, chemotaxins (attract phagocytes like neutrophils and mononuclear phagocytes.

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10
Q

What are the two types of C3 convertase

A

C2aC4b and C3bBb

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11
Q

What are the two types of C5 convertase

A

C2aC4bC3b and C3bBbC3b

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12
Q

How does C3b bind to antigen surfaces?

A

Thioster bond to surfaces.
Activated thioester carbonyl becomes exposed and can react with -OH group on antigen surface forming a covalent ester linkage.

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13
Q

Step by step of classical pathway

A
  1. C1q part of the C1 complex binds to the Fc region on bound antibodies. (Requires two).
  2. C1r activates C1s which is a proteinase.
  3. C1s cleaves C4 to produce C4b which binds to pathogen surface and C4a which is a weak inducer of inflammation.
  4. C1s cleaves C2 to produce C2a which binds to pathogen surface and C2b (inactive).
  5. C4b + C2a make the C3 convertase.
  6. C4bC2a cleaves C3 producing C3b which binds to the pathogen surface and C3a which is a mediator of inflammation.
  7. C4bC2a + C3b = C5 convertase
  8. C4bC2aC3b cleaves C5 into C5b and C5a which is a mediator of inflammation.
  9. For Gram+ve this cascade ends here, there is no cell lysis.
  10. C5b connects to C6, which then connects to C7, C8 and C9.
  11. This is the MAC and it forms a pore allowing for cell lyis of Gram-ve.
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14
Q

Complement is fixed by antibodies with low affinity.

A

IgM>IgG3>IgG1>IgG2»IgG4

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15
Q

Membrane attack complex

A

Forms pores in lipid bilayers microbial membranes.

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16
Q

What does the MAC kill?

A

Gram negative bacteria.
Envolved viruses.
Some protozoan parasites.

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17
Q

How do Gram postive bacteria protect themselves from complement mediated lysis?

A

Thick peptidoglycan cell walls

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18
Q

How do fungi protect themselves from MAC?

A

Thick chitin cell walls

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19
Q

What do mannose/GlcNAc bound lectins (MBL) activate?

A

MASP1 then MASP2.

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20
Q

What is the structure of MBL/ficolin similar to?

A

C1q

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21
Q

What is the structure/function of MASP similar to?

A

C1r

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22
Q

What does the family of collectins include?

A

Ficolin, MBL, Sp-A and Sp-D.

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23
Q

What is the function of Sp-A and Sp-D

A

Modulate infection and inflammation mediated by other viruses

24
Q

MASP

A

Mannan binding lectin Associated Serine Proteinases

25
Q

Step by step of lectin pathway

A
  1. MBL binds to the mannose in the fungal/bacterial cell wall.
  2. MASP-1 then MASP-2 bind to the MBL. This activates the MASP1-2.
    3.MASP-1 MASP-2 enzyme complex then cleabes C4 and C2.
  3. The C4bC2a C3 convertase is formed.
  4. C3 is cleaved and the C4bC2aC3b C5 convertase is formed.
  5. C5 is cleaved and the casacde follows on to form the MAC.
26
Q

C3; alternative pathway. Location and function

A

C3 is constantyl activated in serum unless it meets a surface to form a thioester bond with. It is then spontaneously hydrolysed.

27
Q

Where is the alternative pathway activation confined to?

A

Areas where C3 convertase is needed; like on microbes, debris and dying cells.

28
Q

What is the oldest pathway.

A

Alternative

29
Q

Step by step of the alternative pathway:

A

C3 spontaneously makes C3b which binds to the antigen surface, coating it.
Factor B then binds to C3b to make C3bB.
Factor D then cleaves factor B into Ba and Bb.
C3bB is converted into C3 convertase C3bBb.
Factor P (properdin) stabilises the C3 convertase allowing it to stay bound to the surface.
C3bBb then cleaves C3, this is the amplification step.

30
Q

Function of C3b fragment?

A

C3b is an opsonin which sticks on the external side of bacteria and so enables phagocytes to recognise and bind antigens to phagocytose them.

31
Q

Where are C3a and C5a released into?

A

The serum, where they bind to receptors on mast cells leading to degranulation and inflammation.

32
Q

How is phagocytosis of microbes enchanced by C3b?

A

C3b interacts with C3b receptors on phagocytes. This enchances the uptake of antigens for presentation by DC cells, macrophages, B cells and B cell memory via antigen complexes.

33
Q

Regulation of complement; Binding to fluid phage C5b-C6,C7 (C5b67).

A

Factor 1, Co-factor H and Vitronection.

Prevent the C5b67 complex binding to cell membrane

34
Q

Regulation of complement; cell surface proteins: CR1

A

Binds C3b, Bb and inhibits C3 convertases.
Found on RBCs and WBCs.

35
Q

Regulation of complement; cell surface proteins: Membrane cofactor proteins

A

Binds C4b and acts as a cofactor for Factor 1.
Found on WBCs.

36
Q

Regulation of complement; cell surface proteins: CD59

A

Prevents formation of MAC on homologous cells

36
Q

Regulation of complement; anaphylatoxin inactivator

A

DAF: Decay accelerating factor.
Binds C3b, displaes Bb and inhibits C3 convertases.

37
Q

How is negative regulation achieved?

A

Factor H, Factor I, DAF (CD55) and MCP (CD46).

38
Q

Function of Factor I

A

Highly specigic serine proteinase. Concerned with regulation of C3 convertase of alternative pathways.

39
Q

How does factor I and co-factor H cease C3 convertase activity?

A

Factor H is a co-factor for I which displaces Bb.
Factor I cleaves small frgament from C4b (c3f) to give rise to C3bi which is inactive.

40
Q

How does cofactor H and factor I inactivate C3b?

A

Factor I is helped by co-factor H to split the alpha chain of C3b into C3c and C3d. Leaving an inactive fragment of iC3b.

41
Q

How are C5a and C3a inactivated?

A

The removal of the terminal arginine by a carboxypeptidase N.
C3a becomes inactive.
C5a experiences reduced activity.

42
Q

How is the C3b activated/regulated through a balance of factors.

A

Factor B> Factor H = amplification alternative pathway

Factor B< Factor H = inactivation and degradation by Factor I

43
Q

How does CD59 negatively regulate the complement system?

A

Prevents final assembly at the C8 to C9 stage of MAC formation

44
Q

Signal augementation and cross talk: C3d formation

A

Factor I cleaves C3b to produce C3d.
C3d remains coated in antigen.
sIg recongises antigen.
Co-receptor CR2 binds C3d.

45
Q

What does signal augmentation and crosstalk mean for B cells?

A

The dual recognition/signal increased B-cell sensitivity to an antigen by 1000-10000x.

46
Q

How do complement deficiencies present?

A

Inability to control infections.

47
Q

Complement deficiency: Factor I

A

Genetic deficiencies of factor I:
Individuals will continually use up C3 available in serum via. spontaneous unchecked C3bBb activity.

48
Q

Complement deficiencies: Inflammatory thrombotic conditions

A

Uncontrolled C5a in antiphospholipid syndrome.

49
Q

What can deficiencies in immune complex clearance lead to?

A

Systemic lupus or glomerulonephritis

50
Q

Systemic lupus erythematosus is due to

A

Due to a failure of clearance which leads to autoimmunity.

51
Q

How does systemic lupus erythromatosus manifest

A

Skin rashes, chronic fatigue, arthritis, glomerulonephritis and neurological issues.

52
Q

How does systemic lupus erythematosis occur?

A

Autoantibodies directed against DNA and histones induce complement activation. General Fc gamma receptor mediated response.

Autoantibodies form immune complexes that deposit in kidney glomeri; activate classical complement pathway leading to tissue damage and lupus nerphritis.

53
Q

Failure of regulation: atypical heamolytic uremic syndrome. aHUS

A

Mutations in factors H and I, CD48, thrombomodulin and C3.

Chronic activation complement.
Vascular injury and complement.

54
Q

Failure of regulation: Paroxysmal noctural haemoglobinuria PNH.

A

Abnormal CD55- and CD59- RBCs will be lysed by activated complement.

55
Q

Example of complement inhibitor.

A

Eculizumab.

56
Q

Evasion strategies of pathogen.

A

Antibody inactivation.
Convertase decay.
MAC inhibition.
C1-5 inhibition.
C5a-receptor antagonism.
C3b degradation.

Immunology (12 decks)

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