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Module 3 > Anti-GBM disease > Flashcards

Anti-GBM disease Flashcards

1
Q

What is the global burden of glomerulonephritis?

A

20% of patients requiring dialysis or transplantation

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2
Q

What other name is cresenteric GN known as?

A

rapidly progressive GN

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3
Q

What are the types of rapidly progressive GN?

A

vasculitic-ANCA; Goodpasture’s

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4
Q

What is seen on light microscopy of hte glomerulus with crescenteric GN?

A

massive fibrin deposits with disruption of hte tubules

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5
Q

Why do some patients get lung haemorrhage and others don’t?

A

unknown

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6
Q

Waht is Goodpasture’s?

A

rapidly progressive GN with or without lung haemorrhage

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7
Q

What is Goodpasture’s disease defined by?

A

circulating and deposited anti-GBM autoantibodies of proven pathogenicity

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8
Q

What is the autoantigen in Goodpastures?

A

NC1 domain of the a3 chain of type IV collagen

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9
Q

What is the strong HLA association with Goodpasture’s?

A

HLA DR15

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10
Q

What HLA is negatively associated with Goodpasture’s?

A

DR7

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11
Q

What is the current available treatment for Goodpastures?

A

pred; cyclophosphamide; plasma exchange

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12
Q

What is the glomerular basement membraen?

A

separates the endothelial cells from the podocytes- type IV collagen network

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13
Q

Where is NC1 found in the collagen network?

A

hidden in the collagen molecule but with inflammation is revealed

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14
Q

What is the evidence for T cell involvement in Goodpasture’s?

A

T cells present in kidney biopsies; T cells from the peripheral blood of patients proliferate to Goodpasture antigen; precursor freq of autoreactive T cells specific for NC1 is higher than controls; MHC-II genes are associated with development

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15
Q

How was the EAG originally induced?

A

mash up rat kidneys then degrade with collagenase to reveal NC1 domain and then immunise the rats

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16
Q

What was the problem with the original method of EAG?

A

some rat strains didn’t respond so created a recombinant rat a3(IV) NC1

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17
Q

What is the current animal model of EAG?

A

animal model induced in WKY rats by immunisation with recombinant a3 (IV) NC1

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18
Q

What is seen in EAG?

A

characterised by circulating deposited anti-GBM antibodies, focal necrotising GN and variable lung haemorrhage

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19
Q

What is suggested in rat models about a cause of lung haemorrhage?

A

animals that had a higher number of pathogens in the lungs had hgiher rate of lung haemorrhage

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20
Q

What are the first cells to infiltrate the glomerulus in EAG?

A

T cells then macropahge infiltration and glomerular injury

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21
Q

How can EAG be transferred?

A

by anti-GBM antibodies or by T cells

22
Q

What is the evidence that the EAG model is a good model for Goodpasture’s?

A

the animal have high numbers of circulating and deposited antibody; strong linear deposits on biopsy; high alubmin secretion; 100% of glomeruli in the rats are abnormal; massive infiltration of T cells and macrophages

23
Q

What is seen histologically in lung haemorrhage?

A

surfactant and RBCs in air spaces; lots of immune infiltration and disruption of hte lung basement memrbane

24
Q

What is the evidence for T cell involvement in EAG?

A

glomerular infiltration of T cell precedes influx of macropahges; splenic T cells from EAG animals proliferate to a3 (IV)NC1; T cells can transfer crescentic nephritis to naive recipients; immuntherapy against T cells is effective in devleopment of EAG

25
Q

What type of T cells are implicated in EAG?

A

at week 2 there are high numbers of CD4 cells but low numbers elsewhere; CD8 cells gradually rise to high levels at weeks 3 and 4

26
Q

What is seen after transfer of T cells to naive recipients?

A

development of proteinuria and linear deposits of IgG on GBM

27
Q

How has targeting costimulatory molecules been used in EAG?

A

blocking CD28/B7 and CD40/CD40L prevents the development of EAG

28
Q

What is the problem with the anti-CD40L and anti-CTLA4 immunotherapies?

A

good at preventing disease but not effective at treating establihsed disease

29
Q

Which cells express PD1?

A

activated T cells; B cells and myeloid cells

30
Q

What does engagement of PD1 lead to?

A

inhibition of prolfieration and cytokine production; apoptosis

31
Q

How was the effect of PDL1 fusion protein determined?

A

immunised mice were given PDL1 from day 18 to day 28

32
Q

What was the result of PDL1 immuntherapy on B cells?

A

no effect on ciruclating or deposited antibodies (by day 18 its T cell mediated disease)

33
Q

What was the effect of PDL1 fusion protein on disease severity?

A

reduced alumbinuria and number of severely affected glomeruli

34
Q

What was the effect of PDL1 fusion protein on immunohistology?

A

on LM- markedly better; reduced 50% numbers of T cell and macropahge infiltration

35
Q

What family is ICOS a member of?

A

CD28

36
Q

When is ICOS expressed?

A

on activated T cells

37
Q

When is ICOSL expressed?

A

constitutively on resting B cells; DCs; macropahges and parenchymal cells

38
Q

When is PDL1 expressed?

A

activated monocytes and DCs; endothelial cells

39
Q

What is the result of ICOS engangement?

A

T cell proliferation; cytokine production and idfferentitiation into an effector state

40
Q

How was the efficacy of anti-ICOSL determined?

A

immunsied mice were given anti-ICOSL at days 18 to 28

41
Q

What was the effect of anti-ICOSL on B cells?

A

no reduction in circulating antibodies; small effect on deposited antibodies

42
Q

What was the effect of anti-ICOSL on disease severity?

A

reduced albuminuria; 2/3rds reduction in severe glomeruli; decreased T cell prolfieration from spleen cells

43
Q

What does the reduction in T cell prolfieration assay suggest about anti-ICOSL

A

suggests possible induction of antigen-specific tolernace

44
Q

What was the effect of transferring CD4 cells from treated donors to immunised mice?

A

reduced the number of severe glomeruli

45
Q

What was the effect of transferring CD8 cels from treated donors to immunised mice?

A

no changein glomuerli

46
Q

Waht was the effect of transferring CD25 cells from treated donors to immunsied mice?

A

reduced severe glomeruli

47
Q

What had the biggest effect on severity of gleomuli affected in T cell transfers with anti-ICOSL?

A

whole spleen

48
Q

Overall what is the effect of transferring splenocytes from anti-ICOSL treated donors?

A

protects recipients from EAG

49
Q

What other diseases is anti-ICOSL being used in?

A

preclinical trials in RA and MS

50
Q

What is the result of the rat studies with ICOSL/PD1?

A

can be of value in designing new therapetuic strategies for patietns with anti-GBM - can treat with ICOSL then isolate and expand Tregs and reinfuse into patients

51
Q

When was Goodpasture’s disease first identified?

A

pathologist- Ernest Goodpasture in the early 20th century

52
Q

Who has done all the rat mucosal immunity studies with Goodpastures?

A

John Reynolds

Module 3 (33 decks)

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