lecture innate immunity Flashcards
What are PAMPs?
these are highly conserved microbial compontents that are essential for survival of microbe(difficult to alter).
Where can we recognise molecules?
- extracellular
- in the cytosol
- endosomal
What is the mechanism of TLR 4 and its activation?
- LPS binds to LPS monomer
- Binds to CD14 that is soluble
- travels as a complex to TLR4 on the membrane
- together with the MD2(helper protein) it becomes the TLR4(2)MD2CD14 complex with the antigen
- Toll IL-1 receptor (TIR) gets activated that is under the membrane of the TLR4
- MyD88 recognises the actviation of TIR
- ikB gets phosphorylated
- ikB gets ubiquinated and degraded by the proteasome
- NF-kB gets activated
- translocates to the nucleus
- activates transcription of target genes
- cytokines are synthesised
- acute inflammation and stimulation of adaptive IS
What can MyD88 also activate?
interferon regulatory factors (IRF) which then aso activates the production of type 1 IFN.
How does NF-kB get activated ( more detail)
- the TLR trigger the phosphorylation of IKK complex
-this phosphorylated complex can phosphorylated IkB - IkB can then be ubiquinated and degraded by the proteasome
- NF-kB can then translocate to nucleus.
What TLR’s are on the membrane?
TLR 1,2,4,5 and 6
What TLR’s are in the endosome?
TLR 3,7,8 and 9
Membrane bound receptor all have a different function. what are those?
- TLR
- scavenger receptors
- NK cell receptor
- lectin membrane receptor
- formyl peptide receptor
- TLR: inflammation
- scavenger: phagocytosis
- NK cell receptor: NK cell activation
- Lectin membrane receptor: inflammation + phagocytosis
- formyl peptide receptor: chemo attraction
how does an NK cell discriminate between infected cells, microbes and our healthy cells?
NK cells have an activation receptor and an inhibitory receptor (MHC 1)
1. Microbes do nothave the MHC class 1 ligand, meaning they will not inhibit the NK cell.
2. an infected cell does have the MHC1 receptor, but the activation receptor ligand can then in this case overrule the inhibitory receptor ligand
How does the formyl peptide receptor recognise microbes?
- Bacterial signal peptides are N-terminally formylated methionine to initiate translation
- eukaryote do not do this, the methionine is unformylated
What is the mechanism of NOD 1 and 2?
- NOD 1 and 2 are cytosolic receptors
- when activated, they activated RIP-2
- this activates NF-kB and c-fos-Jun
- both activate transcriptn of pro-inflammatory cytokines
What is the mechanism of inflammasomes?
- NLR recognises D/PAMPs
- NLR aggregate
- with several cofactors and proteases, pro-caspace -1 is recruited to the NLR complex which creates the inflammasome
- caspace -1 is activated
- caspace-1 cleaves pro-IL-1b into IL-1B (IL-18)
- cytokines are released from the cells through gasdermin pores
There is a difference in immune response with dead or alivee bacteria
dead bacteria > no bacterial mRNA production of IL-6 and pro-IL-1b
alive bacteria > bacterial mRNA released > activation inflammasome > IL-6 and IL-1B are released
What are the cytosolic PRRs?
- CDS
-RLR - TLR 3,7,8 and 9 (only in endosomes)
What does CDS activate?
the STING pathway which activates the IKK complex
What does the RLR activate?
the Mavs pathway, which then activates the IKK complx
What is the difference between type I and type II IFN?
type I: inhibits cell proliferation and is produced by most cells in the body
Type II: activates macrophages and mainly produced by NK cells and activated T-cells
How does RIG-1 recognise viral RNA?
- uncapped ss/dsRNA with 5’ triphosphate. mammalian cells do not have this
How does MDA-5 recognise viral RNA?
long ds RNA, these are longer than mammalian RNA
What are the soluble PRR’s and what are their function?
- pentraxin
- collectin
- ficolin
The complement system has 3 pathways, what are they?
-classical pathway (c1q to antibodies on bacteril surfaces)
- lecting pathway(ficolin)
- alternative pathway (spontaneous hydrolysis of C3)
What is the flip flop mechanism?
movement of the lipid molecules from one side to the other. FLIP> to the inside. FLOP> outside. This is controlled by the enzyme flippase and floppase
What are the effector mechanism of the complement system?
- opsonisation phagocytosis
- stimulation of inflammatory reactions
- complement mediated cytolysis
In summary, what are the steps of inflammation on the inside?
- injury/barrier break
- microbes. injury activate sentinel cells
- sentinel cells secrete inflammatory mediators
- vasodilation and increased permeability fluids
- complement, antibodies kill microbes
- adhesion molecules and chemokines cause leukocyte migration
- phagocytosis and killing of microbes
What are the steps of leukocytes migration
- leukocyte rolling
- leukocyte activation through heightening the affinity by IL-8
- firm adhesion
- transmigration (through cell layer)
- chemotaxis
What are the steps of leukocytes migration
- leukocyte rolling
- leukocyte activation through heightening the affinity by IL-8
- firm adhesion
- transmigration (through cell layer)
- chemotaxis
What is the difference between macrophage M1 and M2?
M1: are inflammatory by secretion of IL-6, 1B and TNF gamm
M2: initiate tissue repair by secretion of IL-4, 10 and TGF B. IL-10 and TGFB can inhibit inflammation
What does ILC 1 do?
ILC 1: activated by intracellular pathogens. produces IFN gamma with the stimulation of IL-12,15 and 18
What does ILC2 do?
ILC: activation by parasitic helminths, produces IL-4, 5,9 and 13 with the stimulation of IL-25,33 and TSLP
What does ILC3 do?
ILC3: activated by extracellular pathogens, produces IL-17 and 22 with the stimulation of IL-23 and 1B
What is the difference between MHC I and II?
Every nucleated cells have the class I receptor. the proteins are degraded in to aminoacids and then through the TAP protein are mounted on the MHC I. this is for CD8+
Class II is for antigen presenting cells. Pathogen is degraded by the endosome and transferred to vesicles with MHCII. when it binds, the invariantchain is dissociated (CLIP) and mounted on the membrane for CD4+
What do bacteria, protozoa and virusees activate through DC?
activate TLR 3,9 11/12. which activates DC’s. DC’s then activate Th1 with IL-12 and 27
What do helminths, venoms and allergens activate through DC?
recognised by IFN-1, TSLP and PRR signalling, this activates DC. DC produces IL-12 which activated Th2
Wh hat do fungi and bacteria activate throughDC?
recognised by TLR 2, CGRP. this activates DC. DC activates Th17 with TGFB, IL-23 and IL-6
