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Module 3 > Chemokines and cytokines in autoimmunity > Flashcards

Chemokines and cytokines in autoimmunity Flashcards

1
Q

What is the function of MCP-1?

A

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

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2
Q

What does MCP-1 stand for?

A

monocyte chemoattractant protein-1

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3
Q

Give examples of MCP-1 implicated in disease?

A

lupus nephritis; renal vasculitis

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4
Q

What is the funciton of MCP-1 in disease?

A

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

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5
Q

How can MCP-1 levels be measured in glomerulonephritis?

A

urine

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6
Q

What receptor does MCP-1 bind to?

A

CCR2

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7
Q

what happens when MCP-1 is blocked pharmacologically?

A

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

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8
Q

What diseases have CCR2 antagonists been used successfully in?

A

EAE; experimental inflammatory arthritis and diabetic nephropathy

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9
Q

How can urinary MCP-1 be used clinically?

A

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

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10
Q

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

A

reduced albuminuria by 18%

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11
Q

What are the functions of cytokines for B cells?

A

antibody production and switching of subclasses of immunoglobulin

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12
Q

How are the functions of cytokines regulated?

A

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

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13
Q

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

A

treating RA and renal disease

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14
Q

Give examples of anti-cytokine therapy in renal disease?

A

soluble receptor and receptor antagonist to IL-1 or TNF

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15
Q

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

A

induced remission in 88% of patients

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16
Q

What cytokines are important in the pathogenesis of GN?

A

TNFa and IL-1

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17
Q

What cells is spleen tyrosine kinase present in?

A

Syk is found in WBCs and kidney cells

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18
Q

What happens when Syk is inihited?

A

modulation of IgG Fc receptor signalling

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19
Q

What is downstream of Syk signalling in DCs?

A

antigen presentation

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20
Q

What is downstream of Syk in neutrophils?

A

resp burst; degranulation; adhesion

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21
Q

What is downstream of Syk signalling in macrophages?

A

phagocytosis; cyokine secretion

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22
Q

What is the inhibitor of Syk used?

A

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

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23
Q

What is the effect of inhiiting Syk?

A

upstream signal for many cytokines so decreases lots of them

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24
Q

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

A

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

25
Q

What was the effect of Syk inhibitors in IgA nephropathy?

A

decreased multiple cytokine production back to normal levels

26
Q

What happened when Syk synthesis was silenced with siRNA?

A

same effect- decreased production of many cytokines

27
Q

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

A

increased p-Syk in the renal biopsies

28
Q

When is Syk inhibition effective?

A

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

29
Q

What is the importance of monioring autoimmunity?

A

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

30
Q

give examples of severe GN?

A

Goodpastures; systemic vasculitis; SLE

31
Q

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

A

crescentic GN

32
Q

What found on biopsy indicates the severity of crescentic GN?

A

infiltration by monocytes/ macropahges

33
Q

How are antibodies in goodpastures detected?

A

renal biopsy; serum

34
Q

What are the advantages of measuring autoantibodes?

A

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

35
Q

How are circulating anti-GBM antibodies detected?

A

ELISA coated with glomerular basement membrane; Western blotting

36
Q

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

A

a3 domain of type IV collagen

37
Q

What is seen on renal biopsy with immunofluoresnce in goodpastures?

A

linear deposition of autoantibodes to GBM

38
Q

What are the methods of detecting ANCA vascultitis>

A

indirect immunofluorescence; ELISA

39
Q

What is indirect immunofluorescence?

A

detection of antibody binding to alcohol fixed neutrophil preparation

40
Q

What antibody is assocaited iwth cANCA?

A

anti-proteinase 3

41
Q

What antibody is associated wtih pANCA?

A

anti-MPO

42
Q

What is the benefit of the bead based immunoassay?

A

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

43
Q

How is inflammation traditionally assessed?

A

complement activation/consumption; CRP; ESR

44
Q

What are new methods of measuring inflammation?

A

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

45
Q

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

A

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

46
Q

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

A

CD163

47
Q

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

A

proliferative lupus nephritis

48
Q

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

A

increased in numer of macrophages in renal biopsies

49
Q

What is the function of CTGF in diabetic nephropathy?

A

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

50
Q

What does CTGF stand for?

A

connective tissue growth factor

51
Q

What cells produce CTGF?

A

mesangial and tubular epithelial cells

52
Q

How is CTGF related to diabetic nephropathy clinically?

A

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

53
Q

How is urinary CTGF tested for?

A

ELISA

54
Q

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

A

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

55
Q

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?

A

urinary epidermal growht factor (uEGF)

56
Q

How can the production of cytokines be measured?

A

mRNA or protein

57
Q

How can mRNA be assessed?

A

northern blots; RT-PCR; RNAseq

58
Q

How can protein cytokine production be assessed?

A

immunostaining; culture of tissues in vitro

59
Q

How can the function of cytokines be assessed?

A

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

Module 3 (33 decks)

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