Anti-GBM disease

Question 1

What is the global burden of glomerulonephritis?

Answer 1

20% of patients requiring dialysis or transplantation

Question 2

What other name is cresenteric GN known as?

Answer 2

rapidly progressive GN

Question 3

What are the types of rapidly progressive GN?

Answer 3

vasculitic-ANCA; Goodpasture’s

Question 4

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

Answer 4

massive fibrin deposits with disruption of hte tubules

Question 5

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

Answer 5

unknown

Question 6

Waht is Goodpasture’s?

Answer 6

rapidly progressive GN with or without lung haemorrhage

Question 7

What is Goodpasture’s disease defined by?

Answer 7

circulating and deposited anti-GBM autoantibodies of proven pathogenicity

Question 8

What is the autoantigen in Goodpastures?

Answer 8

NC1 domain of the a3 chain of type IV collagen

Question 9

What is the strong HLA association with Goodpasture’s?

Answer 9

HLA DR15

Question 10

What HLA is negatively associated with Goodpasture’s?

Answer 10

DR7

Question 11

What is the current available treatment for Goodpastures?

Answer 11

pred; cyclophosphamide; plasma exchange

Question 12

What is the glomerular basement membraen?

Answer 12

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

Question 13

Where is NC1 found in the collagen network?

Answer 13

hidden in the collagen molecule but with inflammation is revealed

Question 14

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

Answer 14

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

Question 15

How was the EAG originally induced?

Answer 15

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

Question 16

What was the problem with the original method of EAG?

Answer 16

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

Question 17

What is the current animal model of EAG?

Answer 17

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

Question 18

What is seen in EAG?

Answer 18

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

Question 19

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

Answer 19

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

Question 20

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

Answer 20

T cells then macropahge infiltration and glomerular injury

Question 21

How can EAG be transferred?

Answer 21

by anti-GBM antibodies or by T cells

Question 22

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

Answer 22

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

Question 23

What is seen histologically in lung haemorrhage?

Answer 23

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

Question 24

What is the evidence for T cell involvement in EAG?

Answer 24

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

Question 25

What type of T cells are implicated in EAG?

Answer 25

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

Question 26

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

Answer 26

development of proteinuria and linear deposits of IgG on GBM

Question 27

How has targeting costimulatory molecules been used in EAG?

Answer 27

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

Question 28

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

Answer 28

good at preventing disease but not effective at treating establihsed disease

Question 29

Which cells express PD1?

Answer 29

activated T cells; B cells and myeloid cells

Question 30

What does engagement of PD1 lead to?

Answer 30

inhibition of prolfieration and cytokine production; apoptosis

Question 31

How was the effect of PDL1 fusion protein determined?

Answer 31

immunised mice were given PDL1 from day 18 to day 28

Question 32

What was the result of PDL1 immuntherapy on B cells?

Answer 32

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

Question 33

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

Answer 33

reduced alumbinuria and number of severely affected glomeruli

Question 34

What was the effect of PDL1 fusion protein on immunohistology?

Answer 34

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

Question 35

What family is ICOS a member of?

Answer 35

CD28

Question 36

When is ICOS expressed?

Answer 36

on activated T cells

Question 37

When is ICOSL expressed?

Answer 37

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

Question 38

When is PDL1 expressed?

Answer 38

activated monocytes and DCs; endothelial cells

Question 39

What is the result of ICOS engangement?

Answer 39

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

Question 40

How was the efficacy of anti-ICOSL determined?

Answer 40

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

Question 41

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

Answer 41

no reduction in circulating antibodies; small effect on deposited antibodies

Question 42

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

Answer 42

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

Question 43

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

Answer 43

suggests possible induction of antigen-specific tolernace

Question 44

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

Answer 44

reduced the number of severe glomeruli

Question 45

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

Answer 45

no changein glomuerli

Question 46

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

Answer 46

reduced severe glomeruli

Question 47

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

Answer 47

whole spleen

Question 48

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

Answer 48

protects recipients from EAG

Question 49

What other diseases is anti-ICOSL being used in?

Answer 49

preclinical trials in RA and MS

Question 50

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

Answer 50

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

Question 51

When was Goodpasture's disease first identified?

Answer 51

pathologist- Ernest Goodpasture in the early 20th century

Question 52

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

Answer 52

John Reynolds