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adv immunology > control of inflam > Flashcards

control of inflam Flashcards

1
Q

importance of inflam

A

controls infection
wound healing
tumour prevention

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2
Q

w/o inflam regulation

A

septic shock
chronic inflam
fibrosis
tumour growth

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3
Q

kinetics of inflam

A

pathogens drive immune activation
fast robust response to the pathogen
replication of the pathogen can be very fast
fast response is needed even if pathogen is very small
too small a response may allow the pathogen to escape
the immune system
too big a response may damage tissues
immune system must be deactivated after pathogen clearance

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4
Q

no feedback to inflam

A

response to low no of pathogen may be too weak or too slow to control infection

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5
Q

+ve feedback to inflam

A

amplifies response
faster and stronger inflam response to low pathogen no
more likely to control infection
difficult to turn off once inflam has started

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6
Q

-ve feedback to inflam

A

suppressive response
prevents excessive inflam
immune system may be turned off before all pathogens are cleared

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7
Q

+ve and -ve feedback to inflam

A

enables fast and strong initial response
limits maximal level of inflam
allows deactivation of immune system once pathogens are clear

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8
Q

chronic inflam leads to…..

A 
diabvetes
autoimmune disorders
copd, asthma
cardiovascular disease
autoinflam disorders
neurodegeneration
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9
Q

autoimmune disorders

A

80-100 known
23.5 americans suffer from autoimmune diseases
health care cost is in the range of 100 billion dollars
in the top 10 causes of death in women under 64

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10
Q

treatments for autoimmunity

A

corticosteroids - weight gain, increased risk of diabetes, cataracts and osteoporosis
NSAIDs - stroke, cardiac dysfunction
anti-proliferative drugs - increased risk of infect, bone marrow suppression and increased cancer risk
biological - increased risk of infection and cancer

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11
Q

anti inflammatory mechanisms

A

cell based -
immunosuppressive cells - t regs and b regs, pro resolution cells - alternatively activated/ m2b macrophages

molecule based -
anti inflam cytokines - IL10 and IL-1ra
liquid mediators - resolvins and prostoglandins

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12
Q

il-10 background

A

protein made of alpha helices
18 AA signal peptide required for il-10 secretion
represses pro-inflams
suppresses t cells and inhibs production of cytokines by macros and dendritic cells
product of th2
family includes il-26,24,22,20 and 19

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13
Q

il-10 function

A

inhibs cytokine production by macros and dendritic cells
promotes differentiation and func of t regs
may promote antibody production by b cells

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14
Q

il-10 ko

A

loss results in the development of colitis
dependent on components of gut microbiota flora
loss of func mutations occur in il10 and il10 receptor
very early onset colitis is treated via bone marrow transplant

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15
Q

therapeutic use of il10

A

has powerful immunosuppressive effects
RA - no clinical benefit
Chrons disease - best response at 5-8 mg/kg, higher is deterous
Psoriasis - early trials were promising by larger studies show limited efficacy
Vasculitis - not reported

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16
Q

experimental autoimmune encephalitis

A

EAE
mouse model used for MS
t cel independent immune reaction in cns
demyelination of nerves leading to loss of motor func

17
Q

il-10 in EAE

A

over expression of il10 transgenic mice are resistant
intravenous il10 exacerbate eae
intracerebral infection with il10 expression virus protects against eae
b cells are required for the remission phase of eae
t cells producing il10 inhibs eae onset

18
Q

il10 producing cells

A 
cd4 t cells
cd8 t cells 
reg b cells
macros
myeloid dendritic cells
mast cells
19
Q

studying il10 producing cells

A

adoptive transfer

  • transfer of immune cells from one mouse to another
  • allows mice to be generated that lack il10 specific subsets

conditional kos
- flank the gene of interest with loxP sequences
cross mice to transgenic mice expression cre recombinase in specific cell type

20
Q

regulation of il10 production

A

controlled at level of transcription
reg of il10 promoter is complex and cell type specific
diff promoter elements operate in diff cell types even if stimulus is similar

21
Q

reg of il10 production in t cells

A

reported in both cd8 and cd4
il10 production is not a general feature of all t cells
th2 and t reg cells are main subsets linked to il10 production
molecular mechanisms are unclear. 2 steps
1. polarisation of cd4 t cells into a phenotype capable of producing il10
2. signal to induce il10
work has used ko mice but can be difficult to asign a func to polarisation of direct activation of il10 promoter

22
Q

reg of il10 production in macrophages

A

stimulated by tlr agonist
leads to activation og erk and p38 pathways
leads to activation of msk 1/2 resulting in pCREB
pCREB activates its ability yo induce transcription and is required to promote il10 transcription in macros
loss of msk or creb mutation greatly reduced macro il10 production

23
Q

il10 producing b cells

A 
b cell main func = antibody production 
most bs dont produce il10 
bs express tlrs
b cells that produce il10 are b10 or bregs
adoptive transfer is protective
proportion of b regs varies in tissues
24
Q

control of il10 transcription by tlrs is cell type dependent

A
  1. isolate peritoneal cells
  2. stimulate with lps in the presence of agents that block cytokine secetion
  3. 5h stain with antibodies for il10 and macrophage/ b cell markers
  4. analyse by FAC5
25
Q

regulation of il10 production in b cells

A

doesnt require msk or creb
regulated in b cells by rsk1/2 downstream of erk1/2
how they control is unknown

26
Q

il10 action

A

acts on all cells expressing il10 receptor
activates the jak stat pathway
can act in autocrine or paracrine matter
strongly suppresses cytokine production in macros or dendritic cells
promotes t reg devo and function

27
Q

il-1b

A

highly inflammatory
sources: macros, dendritic cells, monocytes, NKs and Bs
production regulated at 2 points
1 synthesis of pro il-1b
2 inflammasome activation and cleavage of pro il-1b

28
Q

function of il-1b

A

activates gene expression

  • ptgs2/cox2 required for the production of prostoglandins
  • il1 elevates prostoglandin production

stimulates endothelial cells to express adhesion molecules and chemokine ssuch as mcp1
- promotes monocyte/ neutrophil recruitment

stimulates cytokine production
- induces il6 and il1

promotes th17 cell production
- implicated in autoimmunity

29
Q

il1b and disease

A

muckle wells symdrome

  • causes sensorineural deafness, recurrent hives and leads to amyloidosis
  • episodic fever, chills and painful joints

familial cold autoinflammatory syndrome
- rash, conjunctivitis, fever and chills and athralglias

neonatal onset multisystem inflammatory disease
- periodic fever snydrome causing uncontrolled inflam in multiple parts of the body

activating muts can result in increased il1b production

30
Q

DIRA

A

deficiency of il1 receptor antagonist

early onset
neonatal early onset of sterlie multifocal osteomyelitis - inflam lesions and pain in bones
periostitis - inflam of connective tissue around bone
pustulosis - infla mskin blisters

31
Q

anakinra

A

recombinant for human il=1ra protein
develop as therapy for RA
fda approved for moderate to severe ra that doesnt response to dmards
highly effective at reducing symptoms of dira - long term therapy is required

32
Q

il-1ra

A

produced by tlr activcated in macros
2 isoforms produced via alternate promoters
- 1 is cytoplasmic the other is scereted
acts as an inhibitors of il1 signalling

33
Q

mechanisms to inhib il1 signalling

A

membrane bound receptor il1r11 - no itr domain so cant signal
soluble forms of il1r11 and sil-ira that dinb il1 in serum before it can stimulate cells

adv immunology (12 decks)

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