Mechanisms of antibody mediated injury

Question 1

What does the glomerular filtration barrier consist of?

Answer 1

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

Question 2

What are the major manifestations of glomerular disease?

Answer 2

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

Question 3

What do immune complexes consist of?

Answer 3

lattice work of antibody and antigen

Question 4

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

Answer 4

complement activation; stimulation of inflammatory cells through Fc receptors

Question 5

What determines the clinical disease associated with different immune complexes?

Answer 5

deposit at different rates and at different sites

Question 6

What is the result of IC deposition in the mesangium?

Answer 6

fairly benign clinical disease

Question 7

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

Answer 7

disrupts the foot processes totally disrupting hte barrier- nephrotic syndrome

Question 8

What is the result of IC deposition subendothelially?

Answer 8

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

Question 9

How can immune complexes in the glomerulus be detected?

Answer 9

by immunohistochemistry and electron microscopy

Question 10

What is acute GN?

Answer 10

acute inflammation of glomeruli leading to reduction in glomerular filtration

Question 11

How does acute GN present?

Answer 11

with oliguria with urine casts containing RBCs and WBCs

Question 12

How do glomerular crescents arise?

Answer 12

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

Question 13

What are the causes of crescentic GN?

Answer 13

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

Question 14

What are the causes of immune complex associated crescentic GN?

Answer 14

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

Question 15

Why is ANCA crescentic GN described as pauci-immune?

Answer 15

no appreciable amount of Ab or C’ on immunohistology

Question 16

What is anti-GBM disease characterised by on biopsy?

Answer 16

linear deposition of IgG on the GBM

Question 17

What is the specific antigen in anti-GBM?

Answer 17

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

Question 18

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

Answer 18

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

Question 19

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

Answer 19

in order to cross-linke and therefore activate the receptor

Question 20

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

Answer 20

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

Question 21

How is the acclerated nephrotoxic nephritic model in mice created?

Answer 21

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

Question 22

What is the inhibitory Fc receptor?

Answer 22

FcyIIb

Question 23

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

Answer 23

share a common y chain

Question 24

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

Answer 24

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

Question 25

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

Answer 25

Syk

Question 26

How does syk inhibitor work?

Answer 26

prevents phosphorylation of syk therefore preventing activation of the Fc receptors

Question 27

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

Answer 27

ansimals are completely protected from GN

Question 28

Which complement factors are typiaclly present in active lupus nephritis?

Answer 28

C1q and C4

Question 29

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

Answer 29

low C3 and C4

Question 30

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

Answer 30

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

Question 31

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

Answer 31

activating C3 allows removal of IC from glomerulus

Question 32

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

Answer 32

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

Question 33

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

Answer 33

amelioration

Question 34

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

Answer 34

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

Question 35

What does ANCA stand for?

Answer 35

anti-neutrophil cytoplasmic antibodies

Question 36

What are the 2 forms of ANCA ?

Answer 36

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

Question 37

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

Answer 37

focal and segmental fibrinoid necrosis

Question 38

What are the in vitro effects of ANCA?

Answer 38

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

Question 39

What does ANCA activation depend upon?

Answer 39

both the FcyR and Fab engagement

Question 40

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

Answer 40

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

Question 41

How is ANCA GN model created in mice?

Answer 41

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

Question 42

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

Answer 42

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

Question 43

What implicates C5 in ANCA renal damage?

Answer 43

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

Question 44

What are hte actions of C5?

Answer 44

chemotaxis and MAC--mediates neutrophil activation in ANCA-GN

Question 45

What is the C5aR blocker in huamns?

Answer 45

avacopan

Question 46

What is the benefit of avacopan in ANCA vasculitis?

Answer 46

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

Question 47

What happens when neutrophils are primed?

Answer 47

display MPO or PR3 which ANCA can bind to

Question 48

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

Answer 48

develop much less toxic drugs for targeting those diseases

Question 49

What are other potential targets in GN?

Answer 49

anti-factorB and inhibitors of C3 activation

Question 50

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

Answer 50

ANCA

Question 51

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

Answer 51

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

Question 52

What suggests that ANCAs are causing the disease?

Answer 52

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

Question 53

What can cause neutrophil priming in ANCA vasculitis?

Answer 53

cytokines generated by a synergistic infection e.g TNF

Question 54

What are hte important immunological factors underlying ANCA disease?

Answer 54

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

Question 55

Why is there such a role for C5a?

Answer 55

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

Question 56

How do plasma lelvels of Bb correlate with ANCA disease?

Answer 56

correlates with severity of glomerular injury- % of cellular crescents

Question 57

What has been the use of rituximab in ANCA?

Answer 57

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