control of inflam Flashcards
importance of inflam
controls infection
wound healing
tumour prevention
w/o inflam regulation
septic shock
chronic inflam
fibrosis
tumour growth
kinetics of inflam
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
no feedback to inflam
response to low no of pathogen may be too weak or too slow to control infection
+ve feedback to inflam
amplifies response
faster and stronger inflam response to low pathogen no
more likely to control infection
difficult to turn off once inflam has started
-ve feedback to inflam
suppressive response
prevents excessive inflam
immune system may be turned off before all pathogens are cleared
+ve and -ve feedback to inflam
enables fast and strong initial response
limits maximal level of inflam
allows deactivation of immune system once pathogens are clear
chronic inflam leads to…..
diabvetes autoimmune disorders copd, asthma cardiovascular disease autoinflam disorders neurodegeneration
autoimmune disorders
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
treatments for autoimmunity
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
anti inflammatory mechanisms
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
il-10 background
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
il-10 function
inhibs cytokine production by macros and dendritic cells
promotes differentiation and func of t regs
may promote antibody production by b cells
il-10 ko
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
therapeutic use of il10
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
experimental autoimmune encephalitis
EAE
mouse model used for MS
t cel independent immune reaction in cns
demyelination of nerves leading to loss of motor func
il-10 in EAE
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
il10 producing cells
cd4 t cells cd8 t cells reg b cells macros myeloid dendritic cells mast cells
studying il10 producing cells
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
regulation of il10 production
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
reg of il10 production in t cells
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
reg of il10 production in macrophages
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
il10 producing b cells
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
control of il10 transcription by tlrs is cell type dependent
- isolate peritoneal cells
- stimulate with lps in the presence of agents that block cytokine secetion
- 5h stain with antibodies for il10 and macrophage/ b cell markers
- analyse by FAC5
regulation of il10 production in b cells
doesnt require msk or creb
regulated in b cells by rsk1/2 downstream of erk1/2
how they control is unknown
il10 action
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
il-1b
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
function of il-1b
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
il1b and disease
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
DIRA
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
anakinra
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
il-1ra
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
mechanisms to inhib il1 signalling
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
