Microbes-L9-Innate Immunity and Inflammation

how does the immune system recognise pathogens very early on?

• innate immediate-1-2 hours- this happens ALL the time

• epithelial cells recognise this- macrophages respond quickly and release preformed molecules

• this induces innate immune response

how does the innate immune response work?

1. innate immune- needs recognition from macrophages

2. once they recognise- they respond by making inflammatory proteins: cytokines and interferons in viruses

   • prevents growth of pathogen and to recruit and activate other cells

   • causes a cacacse

3. if pathogen isn’t cleared in 0-3 days- adaptive system is triggered

discuss inflammation- good and bad

• good and bad

• innate immune- fluid and cells move in that want to get rid of pathogen- fluid causes swelling

• if swelling persists- we get meningitis, IBD etc

discuss the 5 features of inflammation- 5

1. pain

2. heat

3. swelling

4. Redness

5. loss of function

early on- loss of vasculature- immune cells can move from blood vessels to tissue

in tissue make more cytokines- pain as cytokines can cause tissue damage and loss of function

what does inflammation do?

after detection-

• trigger microbial molecule

• receptor: pathogen recognition receptor- PRR

responding to this

• immune cell activation, proliferation and chemotaxis

• cytokines

regulation

• cytokines, steroids and metabolism

resolution

• macrophages

how does the innate immune cells detect and respond to microbes?

detection happens with microbes bind to: pathogen recognition receptors

• detection is conserved to microbial patterns

• microbes detected are called microbe associated molecular patterns

what are MAMPs and examples

microbe associated molecular patterns- bind to PRR’s and trigger detection

• LPS and nucleic acids-TR4

what are TLR’s

toll like receptors- recognises MAMP

PRR’s are toll like receptors

• recognise one or more molecular patterns

• such as TLR4- LPS on gram NEG

• TLR5- flagellin

• TLR3- dsRNA

expression of TLR’s and where?

• on innate cell types- macrophages

• liver-kupffer cells

• skin-langerhans

• lung-alveolar

also TLR’s are expressed by dendritic cells- epithelial cells

• cell surface receptors

• intracellularly in endosomes- microbes

how does TLR signalling work?

• once TLR- binds to ligand(MAMP) pathway is activated

activation of:

• TF NF kappa B- drives expression of something else- from cytoplasm to nucleus

• IRF-interferon regulatory factor- another pathway!!

makes:

• interferons

• chemokines

• cytokines

• antimicrobial peptides

what is made by TLR signalli

interferons

chemokines

cytokines

antimicrobial peptides

discuss the interferon pathway- type 1 TLR signalling- first wave and what is triggered

important for protection against viruses

• type 1- direct antiviral contact

1. first wave:PRR and TLR recognise PAMP/MAMPS

2. IRF3 phosphorylation and Nf kappa B activation-makes type 1 interferon- IFN- alpha and beta

3. which induces IRF7 phosphorylation- more IFN

4. these IFN binds to IFN receptors- triggers JAK/STAT pathway

5. expression of 500 genes- anti viral immune activity- including NK cells which make Type 2 interferons

how are type 2 interferons made?

• by lymphoid cells- effects the innate immune cells and amplify adaptive immune response

• made by T cells and NK cells and effect T cells, B cells, macrophages and epthelial cells

what do cytokines do and a mean type of cytokine

produce systemic inflammation

• IL-6 has effect on liver cells

• create the acute phase - make IL-6 receptors and make proteins called SERUM amyloid A, CRP and mannose binding lectin

• mannone binding lectin binds mannose - bacterial surfaces- making them likely to be phagocytose

• CRP does this too- binds to phosphocholine

explain the Il-6 signalling pathway and what it does

drive acute phase when you’re ill- active in the liver

• IL-6 and Il-6 receptor- bind to gp130

• gp130 creates signalling through the JAK-STAT pathway

• leads to TF STAT3- binds to DNA moieties in promotor regions

• switched off by suppressor of cytokine signalling SOCS

what do chenokines do?

also inflammatory proteins- call immune cells to site

• IL-8 drives neutrophils from blood vessels

• there is a gradient and move in a specific direction

• have DISULPHIDE bonds

what do antimicrobial peptides do? some examples

very quick effect- disrupt bacteria membrane- d

• defensins and cathelicidins

how are inflammatory responses regulated?

• cell signalling inhibitors

• immunomodulatory cytokines and glucocorticoids

• apoptosis

explain cell signalling inhibitors- SOCS

• suppressor of cytokine signalling-SOCS

• limit JAK/STAT pathway by:

1. SOCS inhibit JAK-bind to signalling receptor

2. SOCS stops it by substrate competition

3. SOCS- suppers signalling pathways by targeting associated substrates-or degradation through ubiquitation

explain cell signalling inhibitors- soluble receptors

IL-1R and TNFR- decoy receptors-inhibit and mop up cytokines- bind to TNF

1. binding ligands

2. keeping it from binding to its regular receptor

explain cell signalling inhibitors- immunomodulatory cytokines and glucocorticoids

• TGF beta- blocks iNOS- in macrophages- stops IL-6 signalling

• il-10 inhibits NF kappa B

explain cell signalling inhibitors- apoptosis

• FAS and FASLR interaction- ligand binds to activated immune cell FAS and drives cell death