Chemokines and cytokines in autoimmunity

Question 1

What is the function of MCP-1?

Answer 1

activate monocytes/macrophages- production of IL-1 and superoxide production

Question 2

What does MCP-1 stand for?

Answer 2

monocyte chemoattractant protein-1

Question 3

Give examples of MCP-1 implicated in disease?

Answer 3

lupus nephritis; renal vasculitis

Question 4

What is the funciton of MCP-1 in disease?

Answer 4

upregulation of MCP-1 leads to migration of macrophages and T cells into the glomerulus

Question 5

How can MCP-1 levels be measured in glomerulonephritis?

Answer 5

urine

Question 6

What receptor does MCP-1 bind to?

Answer 6

CCR2

Question 7

what happens when MCP-1 is blocked pharmacologically?

Answer 7

reduces macropahge and T cell infiltration into the glomerulus; reduces crescent formation; scarring and renal impairment

Question 8

What diseases have CCR2 antagonists been used successfully in?

Answer 8

EAE; experimental inflammatory arthritis and diabetic nephropathy

Question 9

How can urinary MCP-1 be used clinically?

Answer 9

urinary MCP-1/creatinine ratio progostic of a decrease in renal function in diabetic nephropathy; non-invasive marker of glomerulonephritis

Question 10

What was the efficacy of CCR2 inhjibitors in an early clinical trial for diabetic nephropathy?

Answer 10

reduced albuminuria by 18%

Question 11

What are the functions of cytokines for B cells?

Answer 11

antibody production and switching of subclasses of immunoglobulin

Question 12

How are the functions of cytokines regulated?

Answer 12

regulation of synthesis- transcription factor; secretion- role of inflammasome and caspase 1 needed to activate IL-1b and IL18; recetpro antagonist; decoy cytokine recpetors; regulatory cytokines

Question 13

What are the best examples of applied cytokine biology in clinical practice?

Answer 13

treating RA and renal disease

Question 14

Give examples of anti-cytokine therapy in renal disease?

Answer 14

soluble receptor and receptor antagonist to IL-1 or TNF

Question 15

What was the efficacy of anti-TNF therapy in systemic vasculitis?

Answer 15

induced remission in 88% of patients

Question 16

What cytokines are important in the pathogenesis of GN?

Answer 16

TNFa and IL-1

Question 17

What cells is spleen tyrosine kinase present in?

Answer 17

Syk is found in WBCs and kidney cells

Question 18

What happens when Syk is inihited?

Answer 18

modulation of IgG Fc receptor signalling

Question 19

What is downstream of Syk signalling in DCs?

Answer 19

antigen presentation

Question 20

What is downstream of Syk in neutrophils?

Answer 20

resp burst; degranulation; adhesion

Question 21

What is downstream of Syk signalling in macrophages?

Answer 21

phagocytosis; cyokine secretion

Question 22

What is the inhibitor of Syk used?

Answer 22

Fostamtinib- active metabolite: R406- occupies the ATP binding of Syk

Question 23

What is the effect of inhiiting Syk?

Answer 23

upstream signal for many cytokines so decreases lots of them

Question 24

What happens when IgA is used to stimualte kidney mesangial cells?

Answer 24

increased production of chemoines e.g MCP-1; IL-8; inflammation- IL-6 and cell proliferation- PDGF

Question 25

What was the effect of Syk inhibitors in IgA nephropathy?

Answer 25

decreased multiple cytokine production back to normal levels

Question 26

What happened when Syk synthesis was silenced with siRNA?

Answer 26

same effect- decreased production of many cytokines

Question 27

What indicated that Syk was invovled in hte pathogenesis of IgA nephropathy?

Answer 27

increased p-Syk in the renal biopsies

Question 28

When is Syk inhibition effective?

Answer 28

tx of antibody mediated experimental glomerulonephritis even when treatment is started after onset of disease

Question 29

What is the importance of monioring autoimmunity?

Answer 29

early diagnosis of new presnetations and relapses; assess response to immunotherapy; minimise SE of tx; prognostic markers-------prevent end organ failure

Question 30

give examples of severe GN?

Answer 30

Goodpastures; systemic vasculitis; SLE

Question 31

Waht type of GN is the most sever form of inflammation?

Answer 31

crescentic GN

Question 32

What found on biopsy indicates the severity of crescentic GN?

Answer 32

infiltration by monocytes/ macropahges

Question 33

How are antibodies in goodpastures detected?

Answer 33

renal biopsy; serum

Question 34

What are the advantages of measuring autoantibodes?

Answer 34

support diagnosis; fall in titre correlates with clinical improvement; rising titre may associate or precede clinical relapse; some patients have persisten high level during remission- higher risk of relapse

Question 35

How are circulating anti-GBM antibodies detected?

Answer 35

ELISA coated with glomerular basement membrane; Western blotting

Question 36

What is the target of hte antibody in anti-GBM disease?

Answer 36

a3 domain of type IV collagen

Question 37

What is seen on renal biopsy with immunofluoresnce in goodpastures?

Answer 37

linear deposition of autoantibodes to GBM

Question 38

What are the methods of detecting ANCA vascultitis>

Answer 38

indirect immunofluorescence; ELISA

Question 39

What is indirect immunofluorescence?

Answer 39

detection of antibody binding to alcohol fixed neutrophil preparation

Question 40

What antibody is assocaited iwth cANCA?

Answer 40

anti-proteinase 3

Question 41

What antibody is associated wtih pANCA?

Answer 41

anti-MPO

Question 42

What is the benefit of the bead based immunoassay?

Answer 42

different types of beads are coated with different autoantigen which allows detection of miltple antibodies simultaneously

Question 43

How is inflammation traditionally assessed?

Answer 43

complement activation/consumption; CRP; ESR

Question 44

What are new methods of measuring inflammation?

Answer 44

detection of new protein markers in urine; plasma or serum using ELISA or luminex assays for known targets; proteomics for novel markers

Question 45

give ane xample of urinary MCP-1 being used in a clinical trial?

Answer 45

used as a biomarker in testing a C5a receptor inhibitor in renal vasculitis

Question 46

What other urinary marker can MCP-1 be combined with to improve detection of subtle renal flare in ANCA vasculitis?

Answer 46

CD163

Question 47

`What type of lupus nephritis is MCP-1 raised in?

Answer 47

proliferative lupus nephritis

Question 48

What suggests that inflammation is part of hte pathogenesis of diabetic nephropathy?

Answer 48

increased in numer of macrophages in renal biopsies

Question 49

What is the function of CTGF in diabetic nephropathy?

Answer 49

mediates some of hte effects of TGF-b in deposition of ECM

Question 50

What does CTGF stand for?

Answer 50

connective tissue growth factor

Question 51

What cells produce CTGF?

Answer 51

mesangial and tubular epithelial cells

Question 52

How is CTGF related to diabetic nephropathy clinically?

Answer 52

increased expression in all stages of diabetic nephropathy; increased in urine; anti-CTGF has reduced urinary ACR by almost half in a clinical trial

Question 53

How is urinary CTGF tested for?

Answer 53

ELISA

Question 54

Why is MCP-1 increased in urine of patients with diabetic nephroapthy?

Answer 54

secreted by glucose stimulated mesangial cells; AGE induces MCP-1 production from podocytes in mice

Question 55

The ratio of what and MCP-1 correlated with the rate of dall in kidney function better than urinary MCP-1/creat in patients with diabetic nephropathy?

Answer 55

urinary epidermal growht factor (uEGF)

Question 56

How can the production of cytokines be measured?

Answer 56

mRNA or protein

Question 57

How can mRNA be assessed?

Answer 57

northern blots; RT-PCR; RNAseq

Question 58

How can protein cytokine production be assessed?

Answer 58

immunostaining; culture of tissues in vitro

Question 59

How can the function of cytokines be assessed?

Answer 59

inhibition of synthesis- siRNA; knockout; inhibition of signalling; blockade of receptor interactions- specific anti-cytokine antibodies; receptor antagoniost