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Module 3 > Mechanisms of antibody mediated injury > Flashcards

Mechanisms of antibody mediated injury Flashcards

1
Q

What does the glomerular filtration barrier consist of?

A

fenestrated endothelium; BM- type IV collagen and then podocytes outside BM

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2
Q

What are the major manifestations of glomerular disease?

A

failure to filter and adequate amount of blood so that waste products are not excreted; failure to maintain barrier function leading to loss of protein and/or blood cells in the urine

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3
Q

What do immune complexes consist of?

A

lattice work of antibody and antigen

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4
Q

What does deposition of immune copmlexes in the glomerulus lead to?

A

complement activation; stimulation of inflammatory cells through Fc receptors

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5
Q

What determines the clinical disease associated with different immune complexes?

A

deposit at different rates and at different sites

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6
Q

What is the result of IC deposition in the mesangium?

A

fairly benign clinical disease

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7
Q

What is the resutl of IC deposition between the BM and podocyte (subepithlial)?

A

disrupts the foot processes totally disrupting hte barrier- nephrotic syndrome

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8
Q

What is the result of IC deposition subendothelially?

A

IC are in contact with blood so leads to lots of inflmmatory cells and blockage of hte glomerulu-and disruption of the filter and architecture- proteinuria and decreased filtration

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9
Q

How can immune complexes in the glomerulus be detected?

A

by immunohistochemistry and electron microscopy

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10
Q

What is acute GN?

A

acute inflammation of glomeruli leading to reduction in glomerular filtration

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11
Q

How does acute GN present?

A

with oliguria with urine casts containing RBCs and WBCs

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12
Q

How do glomerular crescents arise?

A

inflammatory cells release noxious substances which result in a physical break in the BM resulting in acccumulation of cells in Bowmans space compressing the glomerulus

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13
Q

What are the causes of crescentic GN?

A

immune complex; anti-GBM disease; ANCA (pauci immune)

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14
Q

What are the causes of immune complex associated crescentic GN?

A

SLE; IgA nephropathy; post-infectious GN e.g strep

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15
Q

Why is ANCA crescentic GN described as pauci-immune?

A

no appreciable amount of Ab or C’ on immunohistology

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16
Q

What is anti-GBM disease characterised by on biopsy?

A

linear deposition of IgG on the GBM

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17
Q

What is the specific antigen in anti-GBM?

A

a3 (IV) NC1 - short stretch of aa in non-collagenous domain

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18
Q

What does the strong HLA-DR15 assocation with anti-GBM suggest?

A

that you need a specific HLA type to be able to present that antigen

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19
Q

Why do antibodies have to be present in immune complexes in order to activate Fcy receptors?

A

in order to cross-linke and therefore activate the receptor

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20
Q

What is the effect of Fyc receptor activation on innate immuen cells?

A

increased phagocytosis; cytokine release; superoxides and proteases and cell killing—-damage basement membrnae

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21
Q

How is the acclerated nephrotoxic nephritic model in mice created?

A

preimmunise the mice with sheep IgG so that mouse makes anti-sheep antibodies, then give with sheep antimouse GBM which bind GBM and the anti-sheep IgG then binds creating immune complexes and crescentic GN

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22
Q

What is the inhibitory Fc receptor?

A

FcyIIb

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23
Q

What feature of the mouse activating Fc receptors allows knock out of all activating Fc recetpors?

A

share a common y chain

24
Q

What demonstrates that the Fc receptors are responsible for GN in the accelerate nephrotoxic nephritis model?

A

Fcy -/- mice have no crescent formation and are strongly protected against GN

25
Q

What is one of the first molecules in the dosntream pathway of FcR signalling?

A

Syk

26
Q

How does syk inhibitor work?

A

prevents phosphorylation of syk therefore preventing activation of the Fc receptors

27
Q

What is the effect of a syk inhibitor on WKY nephrotoxic nephritis?

A

ansimals are completely protected from GN

28
Q

Which complement factors are typiaclly present in active lupus nephritis?

A

C1q and C4

29
Q

What is seen in the complement levels of all patients with active lupus nephritis?

A

low C3 and C4

30
Q

What is the effect of C3 KO in immune complex GN?

A

small decrease in survival, have increased immune complexes; increased albumin;

31
Q

What does C3 KO in immune copmlex CN suggest about its role?

A

activating C3 allows removal of IC from glomerulus

32
Q

What happens to factor B and factor D deficient mice in lupus nephritis?

A

partially protected from renal damage suggesting there is a careful balance betweeen the beneficial effects of immune complex removal and detrimental effects of alterantive pathway in amplifying local complement activation

33
Q

What is the effect of treating lupu-like AI disease in mice with anti-C5a?

A

amelioration

34
Q

What is usually seen in patients with pauci-immune crescentic GN?

A

patients have vasculitis in other organs eeg skin rash; lung haemorrhage

35
Q

What does ANCA stand for?

A

anti-neutrophil cytoplasmic antibodies

36
Q

What are the 2 forms of ANCA ?

A

p-ANCA: myeloperoxidase and c-ANCA: proteinase 3

37
Q

What is the basic lesion seen with pauci-immune crescentic GN?

A

focal and segmental fibrinoid necrosis

38
Q

What are the in vitro effects of ANCA?

A

activate primed neutrophils with release of ROS and enzymes; induce cytokine; chemokine and LT production; cytoskeletal alterations

39
Q

What does ANCA activation depend upon?

A

both the FcyR and Fab engagement

40
Q

What is the effect of hte cytoskeletal alterations seen with ANCA?

A

increased cellular rigidity and cells are more likely to get stuck as the glomerular network is very copmelx

41
Q

How is ANCA GN model created in mice?

A

MPO KO mice immunised with MPO- develop anti-MPO; then splenocytes transferred to Rag2-/- mice or purified anti-MPO given to WT mice—necrotising and crescentic GN and systemic vasculitis

42
Q

What is the effect of the classical vs alternative complement pathways in ANCA renal damage?

A

if KO factor B there are no abnormal glomeruli whereas there is no hcange with KO of C4

43
Q

What implicates C5 in ANCA renal damage?

A

C5 antibody prevents MPO-GN in mice and C6 KO was not protective implicating C5a

44
Q

What are hte actions of C5?

A

chemotaxis and MAC–mediates neutrophil activation in ANCA-GN

45
Q

What is the C5aR blocker in huamns?

A

avacopan

46
Q

What is the benefit of avacopan in ANCA vasculitis?

A

it is able to replace steroids in the treatment- avoids major SE

47
Q

What happens when neutrophils are primed?

A

display MPO or PR3 which ANCA can bind to

48
Q

What is the benefit of studying histology and animal models in GN?

A

develop much less toxic drugs for targeting those diseases

49
Q

What are other potential targets in GN?

A

anti-factorB and inhibitors of C3 activation

50
Q

What is the most common form of new-onset GN in >50s?

A

ANCA

51
Q

What is the difference between immune complex GN and anti-GBM crescentic GN on biopsy?

A

ANCA has a paucity of staining for immunoglobulin in gloermuli vs extensive localisation of Ig in glomeruli

52
Q

What suggests that ANCAs are causing the disease?

A

presence of detectable antibodies in >90% patients with systemic vasculitis ; efficiacy of immunosuppressive therapy; utility of plasmapharesis and rituximab- primary pathogenic role for autoantibodies

53
Q

What can cause neutrophil priming in ANCA vasculitis?

A

cytokines generated by a synergistic infection e.g TNF

54
Q

What are hte important immunological factors underlying ANCA disease?

A

anti-MPO IgG mouse modles- mediated by neutrophil activation, prevented by neutrophil depletion, modulated by Fcy receptor repertoire and requires amplication by the alternative pathway

55
Q

Why is there such a role for C5a?

A

strongly chemotactic for neutrophilas and primes neutrohpils for further activation by ANCAs

56
Q

How do plasma lelvels of Bb correlate with ANCA disease?

A

correlates with severity of glomerular injury- % of cellular crescents

57
Q

What has been the use of rituximab in ANCA?

A

it is noninferior for inducing remission, but adverse events were not reduced compared with cyclophosphamide, but is better than azathioprine for preventing relapse

Module 3 (33 decks)

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