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Module 3 > SLE- the role of inherited and acquired complement deficiencies > Flashcards

SLE- the role of inherited and acquired complement deficiencies Flashcards

1
Q

How does complement act as a bridge between humoral adaptive immune system and innate immunity?

A

many of the effector activities of antibody are mediated by the activation of complement to immune complexes; augments antibody responses

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2
Q

What are the function of the classica complement pathway?

A

immune complexes; apoptotic cells; certain viruses and bacteria; CRP

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3
Q

What is the C3 inhibitor?

A

factor I

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4
Q

What are the functions of C3?

A

opsonin; anaphylatoxin; leucocyte activation; natural dajuvant

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5
Q

What is the result of C3 deficiency?

A

recurrent pyogenic infections

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6
Q

What is the result of deficiencies in the terminal complement pathway (C5-9)

A

meningococcal infection

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7
Q

What inhibits MAC?

A

CD59

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8
Q

What is the traditional view of inflammation in SLE?

A

autoantibodies form immune complexes with autoantigens which fix complement which causes tissue injury

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9
Q

Why doesn’t the traditional view of the pathogenesis of inflammation in SLE fit?

A

complement deficiencies would protect rather than predispose to SLE

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10
Q

What % of patients with a C1q deficiency get SLE?

A

93%

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11
Q

What is the sibling concordancy of SLE in C1q deficiency?

A

90%

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12
Q

What do the figures about C1q deficiency indicate about the role of complement in SLE?

A

a physiological activity of the early part of hte classical pathway protects against the devleopmnet of SLE

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13
Q

What are the actions of C1q?

A

helps clear apoptotic cells; downregulates autoreactive B cell function; acts as adjuvant and increases humoral immune repsonse

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14
Q

Where are lupus autoantigens concentrated?

A

surface of apoptotic blebls and bodies

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15
Q

What is the waste disposal hypothesis in SLE?

A

SLE associated wtih C1q deficiency may be caused by an impairment of the clearance of dying cells and/or immune complexes which cause inflammation and provide a source of autoantigens

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16
Q

What supports that there is defective waste disposal in C1q deficiency?

A

in C1q -/- mice you can see apoptotic cells in kidney biopsy- which normally wouldn’t as cleared. % of macrophages ingesting apoptotic bodies is lower- not as effective

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17
Q

What happens when there is impaired clearance of apoptotic cells?

A

develop secondary necrosis- lose membrane integrity and release of intracellular contents

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18
Q

How does C1q regulate cytokine expression?

A

suppresses IFN-a responses to ICs directly on pDCs and monocytes

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19
Q

What indicates that IFNa is upregulated in SLE?

A

SLE patietns have lots of expression of genes induced by IFNa

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20
Q

What suggests that increased IFNa in C1q deficiency is not solely responsible?

A

C4 and C2 deficiency are associated with increased SLE risk but do not inhibit IFNa

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21
Q

What are the unconventional complement activation independent actions of C1q

A

pro-angiogenesis; carinogenesis; trophoblast invasion; role in neurodegeneration and ageing

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22
Q

What effect does C1q have on CD8 T cells?

A

acts through the mitochondria to act on the metabolism and result in uncontrolled proliferation and lots of granzyme production–tissue damage–epitope spreadign

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23
Q

What are the acquired complement deficiencies of SLE?

A

consumption :decreased C4 and C3

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24
Q

How does complement relate to disease activity in SLE?

A

reflects sever disease; increase after treatment; bippsies show deposits of C3 and C4

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25
Q

What are the difficulties with complement assays?

A

serum levels vary widely in heatlhy individuals; rise with acute phase response (infection); loca activation may not be reflected in circulating components

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26
Q

What is the SLE paradox with C1q?

A

genetic deficiency of C1q is associated with SLE and patients with SLE develop antibodies to C1q

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27
Q

How were the anti-C1q antibodies in SLE first detected?

A

when trying to create an assay to detect immune complexes, by having plate bound C1q which then bound antibody

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28
Q

Why do anti-C1q antibodies only bind C1q in solid phase?

A

neoepitope when C1q is in its bound form

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29
Q

What does the fact that the anti-C1q antibodies are high affinity suggest?

A

they are the result of an antigen-driven response

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30
Q

What type of antibody are nati-C1q antibodies?

A

mainly IgG2

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31
Q

What part of the C1q molecule do the antibodies recognise?

A

the collagenous part

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32
Q

How many pateints have anti-c1q antibodies?

A

around 30%

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33
Q

What do the anti-C1q antibodies highly correlate with?

A

lupus nephritis; hypocomplementaemia

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34
Q

What other diseases are anti-C1q antibodies found in?

A

rheumatoid vasculitis; Felty’s sydnrome

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35
Q

What is the thought to be the reason for devleopment of anti-C1q antibodies?

A

C1q binds to dying cells and beomces part of autoantigenic complexes

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36
Q

What was the initial question posed by the finding of anti-C1q antibodies in SLE?

A

are they pathogenic or an epiphenomenon

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37
Q

What was the effect of administering anti-C1q mAb to naive mice?

A

mouse didn’t develop albuminuria

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38
Q

What was the effect of administration of anti-C1q mAb to anti-GBM pretreated mice?

A

developed proteinuris

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39
Q

What did the effect of anti-C1q antibodies in context of goodpastures suggest about their role in SLe?

A

amplify damage if there are immune complexes already present- cause increased inflammation, increased complement fixation and influx of immune cells

40
Q

Give an example of complement therapeutic effective in SLE?

A

anti-C5a

41
Q

What are the 3 type of complement deficiency that can cause increased susceptibility to pyogenic infections?

A

deficiency of the opsonic activities of the complement system; any deficiency that compromises the lytic activity of complement and deficiency function of the MBL pathway

42
Q

What type of infection is increased with deficient opsonic activity of complement?

A

general susceptibility topyogenic organsims

43
Q

What type of infection is increased with compromised lytic activity of complement?

A

neisserial infections

44
Q

Give examples of pyogenic bacteria?

A

h.influenzae and strep. pneumoniae

45
Q

What is the normal pathway of defense against pyogenic bacteria?

A

opsonisation with antibody activation of copmlement; phagocytosis; intracellular killing

46
Q

What are the most important complement opsonins in the defense against bacterial infection?

A

C3b and iC3b- the covalently bound cleavage fragments of C3

47
Q

What is extracellular lysis a major mechanism of killing neisseria?

A

they are capable of intracellular survival

48
Q

What MBL homologos in structure to?

A

C1q

49
Q

What does the low levels of MBL in young children with recurrent infections suggest?

A

the MBL pathway is important during the interval between the loss of maternal antibody and acquisition of a mature immunologic repertoire

50
Q

Why may low levels of MBL partially protect against mycobacterial infection?

A

opsoinsation of intracellular organisms eg mycobacteria enhances entry of such pathogens into cells

51
Q

How do mycobacteria manipulate the complement system?

A

synthesise a C4-like molecule that binds the serine esterase fragment of C2, C2a, leading to cleavage of C3 and deposition of C3b on mycobacterial-cell membranes enhancing uptake into macraophges

52
Q

Give an example of a virus that uses complement to gain entry into the cell?

A

uses CD21 (CR2) as a cellular receptor for its envelope glycoprotein gp350/220- trposim for B cells with CR2

53
Q

How do group A streptococci manipulate complement?

A

use the M protein to bind factor H which increases catabolism of C3b and reduces formation of C3 convertase enzymes

54
Q

How does vaccinia virus evade complement?

A

has complement-control protein which acts as a cofactor to factor I which cleaves C4b and C3b inhibiting activation of complement

55
Q

How does HIV evade complement?

A

incorporates complement regulatory proteins into the viral env

56
Q

What does activation of the internal thioester bond of C3 bind to?

A

hydroxyl groups on carbohydrates and proteins

57
Q

How is C3b which doesn’t bind inactivated?

A

binding to water molecules

58
Q

What does the amplification step of C3 deposition require?

A

facto B

59
Q

What activates factor B bound to C3b ?

A

factor D to form C3bBb

60
Q

What does binding of factor H to C3b allow?

A

degradation of C3b by factor I into iC3b and C3f

61
Q

What determines the relative affinity of C3b for factor H or factor B?

A

the carbohydrate environment of the surface on which teh C3b is deposited

62
Q

What type of carbohydrate environemnt favours factor H binding to C3b rather than factor B?

A

sialic acids

63
Q

What disease is defective regulation of C3 typically associated with?

A

glomerulonephritis

64
Q

What causes the defective regulation of C3 in GN?

A

C3 nephritic factor

65
Q

What is the function of C3 nephritic factor?

A

increases the stability of the C3 convertase enzymes or reduced function of factor H or I

66
Q

What is C3 nephritic factor?

A

autoantibody that binds to and stbailises C3 convertase C3Bb

67
Q

What disease does C1 inhibitor deficiency result in?

A

recurrent angioedema

68
Q

What is the function of C1 inhibitor in copmlement?

A

inactivates serine esterases C1r and C1s

69
Q

Give an example of a disease related to a failure to regulate the formation of MAC?

A

paroxysmal nocturnal haemoglobinuria

70
Q

What causes the failure of regulation of MAC in PNH?

A

lack proteins which prevent anchoring CD55 and CD59

71
Q

What is the function of CD55?

A

regulates the formation of C3 convertase

72
Q

What is the principal way of activating hte classical pathway of the complement system?

A

formation of immune complex

73
Q

what demonstrated that complement plays a role in the induction of antibody responses?

A

formation of antibodies against T-cell-dependent antigens was reduced in animals in which C3 had been depleted

74
Q

Why could copmlement be used as an adjuvant?

A

binding to C3dg to complement receptors reduces the threshold for activation of the B cell

75
Q

What type of antibody is important for binding complement intiially?

A

natural IgM antibodies

76
Q

What indicates the importance for natural IgM antibodies in stimulating an antibody response?

A

mice lacking serum IgM have suboptimal responses of IgG antibody to low doses of antigen

77
Q

What are hte 2 ways by which complement is actiated in tissues?

A

through immune complexes and through tissues ischaemia and reperfusion which exposes phospholipids and mitochondrial proteins which bind C1q or MBL; natural IgM or CRP

78
Q

How is hereditary angioedema linked to SLE?

A

excessive cleavage of C4 and C2 by C1s caused by a deficiency of C1INH leads to acquired deficiency of C4 and C2 resulting increased risk of SLE

79
Q

What od macrophages secrete in response to engulding apoptotic cells?

A

TGFb

80
Q

What animal models support the waste disposal hypothesis?

A

mice lacking serum amyloid P component which binds to extracellular chromatin and apoptotic cells develop SLE; also mice lacking DNase1 which digests extracellular DNa

81
Q

Why is IFa particularly produced in SLE?

A

in absence of C1q, instead of Ics binding to monocytes that preferentially engage pDC generating IFN; lack of C1q increases NET degradation which promote type I IFN production and source of antigen for formation of ICs

82
Q

How do complement proteins protect against infeciton?

A

promote phagocytosis; direct pathogen lysis; promoting chemotaxis; stimulating antibody production

83
Q

What is the paradox of complement in SLE?

A

complete activation of the complement pathway promotes tissue injury, yet deficiency of classical complement components predisposes to SLE

84
Q

How does IFNa contribute to autoimmunity?

A

autoantigens taken up by DCs- DC activated by IFNa- activation of T and B cells

85
Q

What part of C1q binds to phagocytic receptors?

A

collagenous

86
Q

What may explain why C4 and C2 deficiency predisposes to SLE?

A

C1q activation of apoptotic cells rpomotes apoptotic cell clearance by activating the classical pathway with deposition of C3b

87
Q

What supports the C3 model of SLE?

A

C1q did not enhance ingestion of apoptotic cells in the absence of fresh serum

88
Q

What is efferocytosis?

A

ingestion of apototic cells

89
Q

How may NETosis be induced in SLE?

A

by ICs and/or IFNa

90
Q

Why may SLE patients be less able to degrade NETs?

A

lower DNase1 levels

91
Q

Describe the C1q molecule?

A

collagen-like region that sprouts in 6 globular heads

92
Q

What are anti-C1q antibodies directed against?

A

neoepitopes- epitopes not accessible in the native protine but when bound - collagen-like region

93
Q

What type of IgG is the most potent activator of C1q?

A

IgG3

94
Q

How can the types of autoantibody in SLE be divided?

A

thos directed against nuclear components; those against membrane phospholipids (anticardiolipin); antibodies against serum proteins (b2-glycoprotein)

95
Q

How can anti-C1q antibodies be used in SLE?

A

predict a renal relapse better than dsDNA; will not develop severe lupus nephritis if don’t have anti-C1q antibodies

Module 3 (33 decks)

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