Overview of Innate Immunity Flashcards
Define the innate immune system
Immune response responsible for the confinement of infectino in the early hours of exposure.
Depends on the recognition of molecular patterns found in micro-organisms
Compare the innate and adaptive immune system with regards to:
Time
Stimulus
Memory cells
Diversity
Organism
Name 7 cells involved in the innate immunity of the lungs (name some molecules associated with them and/or describe their main function)
- Dendtritic cells - TLRs, IFNs, cytokines
- Neutrophils - phagocytosis (ROS)
- Innate Lymphoid Cells (ILCs)
- NK and NKT cells
- Macrophages - phagocytosis and scavenging
- Airway epithelium - IL-25, IL-33, TSLP
- γδ T cells - TLRs
Briefly describe the function og dendritic cells
Sample the airway mucosa and releases cytokines, chemokines, interferons as a response. It links the innate and adapive signalling together
Where are Innate Lymphoid Cells (ILCs) found and how are they different to T-cells
Sentinel cels found at mucosal surfaces.
Same effector functions to T-cells but lack TCR (T-cell receptor
Describe the three groups of ILCs, their function and cytokines they produce
ILC1 = Th1 (IFNγ, TNF-α); intracellular microbes
ILC2 = Th2 (IL-4, IL-5, IL-9, IL-13); allergic big cytokine producer
ILC3 = Th17 (IL-17A, IL-22); extracellular microbes
IL-25, IL-33, TSLP (epithelial cytokines) stimulate these ILCs
Epithelial cytokines are considered _____ because they are preformed - they are ready to be released in response to an insult. Three alarmins are: ______. Epithelial cells are mechanically sensitive
Epithelial cytokines are considered alarmins because they are preformed - they are ready to be released in response to an insult. Three alarmins are: IL-25, IL-33, TSLP. Epithelial cells are mechanically sensitive
Outline the kinetics of the immune response to acute viral infections, with regards to viral load, IFN, NK cells, T cells, IgG
Viral load increases from exposure (peaks day 2 and drops day 5)
There is a lag phase between the viral load increase and the IFN increase (INNATE)
NK cells increase follows IFN
Adaptive immune response is late (~day 4) (T cell increase)
IgG and IgA are produced much later (sharp increase at day 11)
Compare the immune response to RSV in mice, adults, infants and elderly.
Response to pathogens different and changes rapidly with age and co-morbidities
Briefly outline the role of defensins and cathelicidins
Broad bactericidal and anticiral properties - non-specific perforation of pathogen membranes (similar to complement system)
Lactoferrin (transferring family) secreted by _____ and _____ cells. It’s main function is the prevention of bacteria proliferation by _____ of _____ which bacteria rely on for oxygen capture (has best influence in anaerobic conditions).
It also has other functions:
- _____: binds to surface glycoproteins (HIV, CMV)
- Bactericidal: _____ formation on Candida sp.
- Bacteriotoxic: prevents _____ formation
Lactoferrin (transferring family) secreted by neutrophils and epithelial cells. It’s main function is the prevention of bacteria proliferation by sequestration of oxygen which bacteria rely on for oxygen capture (has best influence in anaerobic conditions).
It also has other functions:
- Anti-viral: binds to surface glycoproteins (HIV, CMV)
- Bactericidal: Pore formation on Candida sp.
- Bacteriotoxic: prevents biofilm formation
Name and describe the function of 4 Pattern Recognition Receptors (PRRs)
- Toll-like receptors (TLRs) - recognise PAMPs
- NLR - recognise dsRNA, muramyl dipeptides and peptidoglycans
- RNA helicases (RIG-I) - recognise intracellular viral dsRNA and ssRNA
- C-type lectins - recognise carbohydrates
NLR = nucleotide-binding oligomerization domain (NOD) like receptors
Name two molecules recognised by PRRs and describe their features.
-
PAMPs (Pathogens) - non-self, DNA form, dsRNA, bacterial cell wall products
- invariant molecules (products that cannot be mutated to avoid recognition)
- DAMPs (damage) - self - normal molecules but are found in laces they should not be (ATP). Can be modified-self DAMPs (citrullinated peptides act as auto-antigens and generated during inflammation)
Much of the signalling appartus is shared between PRRs and IL receptros (IRAKs)
Nam 4 TLRs found in cellular endosomes and name their ligand(s)
- TLR3 - dsRNA
- TLR7 and TLR8 - ssRNA
- TLR9 - unmethylated CpG DNA
TLRs in recognising viral invariants
Name two TLRs found exclusively in the cell surface membrane
TLR4
TLR5
What do NOD-like receptors (NLRs) recognise
dsRNA
peptidoglycans
muramyl dipeptides
(i.e. bacterial cell wall products)
Where are RNA helicasesor RIG-like helicases(RLHs) found?
In the cytosol/cytoplasm
RIG-like helicases are characterised by what?
DEAD box protein - conserved motif: Asp-Glu-Ala-Asp (DEAD)
Name three RIG-like helicases, describe their structure and name their ligands/function
- RIG-I - has RNA helicase domain and CARD. short dsRNA and 5’phospho ssRNA
- MDA5/Helicard - has RNA helicase domain and CARD. Lond ds RNA
- LGP2 - RNA helicase domain. Inhibitory helicase (no CARD)
RIG-I = retinoic acid inducible geneI; CARD = Caspase Recruitment Domain; MDA5 Melanoma differentiation associated gene; LGP2 = Laboratory of genetics and physiology 2
Outline in 3 steps the PRR signalling
- Receptor
- Adaptor
- Transcription Factor
What is needed when RIG-I and MDA5 bind to their ligand to go through conformational shpe change
ATP
Name the adpator protein that RNA helicase uses for signalling
VISA/CARDIF/MAVS/IPS
Same adaptor, four different names
_V_eronica _C_an’t _M_ove _I_n
What Transcription factors do RIG-I and MDA5 (RNA helicases) activate and what proteins o they upregulate
NF-κB - pro-inflammatory (TNF, IL-8)
IRF-3 (1, 3, 7)- interferon, antivirals (IFN-B)
IRF-3: Interferon Regulatory Transcription Factor 3
Name the signalling complex associated with activation of IRF-3 TF by the RIG-5/MDA5 pathways
TANK
IKK-ι/ε
TBK-1
TBK = TANK binding kinase
Name the signalling complex associated with activation of NF-kB TF by the RIG-5/MDA5 pathways
NEMO
IKK-α
IKK-β
Describe the complete PRR signalling involved in IFN-β transcription
- Viral material enters cell (TLR4)
- Material in cytoplasm (recognised by RIG-I and MDA5) or in endosome (TLR3, 7, 8, 9)
- Adaptor protein binding (VISA/CARDIF/MAVS/IPS)
- Signalling complex binds (TANK/IKK-i/e/TBK-1)
- Phosphorylation and activation of IRF-3 and binding to nuclear binding site to upregulate the transcription of IFN-β (NOT expression)
Decribe the downstream effects of secreted IFN-β in neighbouring cells
- IFN-β binds to its receptors (IFNAR1/2)
- Activation of kinase cascade involving JAK1/2 and STAT1/2.
- Phosphorylation of IRF7 and IRF9 and binding to nuclear binding site
- Increase transcription of Interferon Stimulated Genes (ISGs - e.g. OAS and RNAse L)
Interferons are not antivira - it is their effects on target cells which mediates antiviral response
How many types of human interferons are there and provide examples with what type of cells secreting these IFNs
- Type I: IFN-β (all nucleated cells)
- Type II: IFN-γ (strictly leukocytes)
- Type III: IGN-λ (most nucleated cells)
Name 5 Interferon stimulated genes and theri function
- PKR: binds viral dsRNA and stops host cell translation
- Viperin: prevents viral protein trafficking
- MxA: GTPase preventing viral replication
- RNAseL: degrades viral dsRNA
- OAS: activates RNAse L with 2’-5’ oligoadenylate
OAS - 2’-5’ oligoadenylate synthetase
Describe the mechanism of function of RNAse L and OAS
OAS = 2’-5’ oligoadenylate synthetase
- IFN-B signalling upregulates the transcription of IFN stimulated genes (ISG)
- OAS is one of these ISGs and it recognises viral dsRNA.
- OAS activates and arms RNAse L with 2-5A.
- Active RNAse L degrades the RNA, thereby blocking replication
Describe 6 effects of IFN-β on the immune system
- Induce anti-viral state through ISGs(OAS and RNAse L)
- ↑other IFNs (IFN-αs)
- ↑RNA helicases (↑IFN-β transcription)
- T Cell cytokines (CCL5, CXCL10)
- Apoptosis of infected cell
- Activates dendritic cells
These are energetically expensive processes and damage host cell replication - so they are inducible
Dendritic cells link the innate and adaptive immune response. Name the two types of dendritic cells and their function
-
Plasmacytoid DCs (pDCs)
- Peripheral (circulation)
- IFN-α/β producers
- ↑PRRs (TLR7/8/9)
- Poor activation of Th1 cells
-
Conventional DCs (cDCs)
- In tissue
- Activators of Th cells
- ↑integrins and PRRs
- Further subdivided into CDC11c
Describe the three main ways in which dendritic cells link innate and adaptive immunity
- PRRs recognise PAMPs
- Respond to signals from infected cells
- Mediate T cell function
Explain how RNA interfaces (RNAi) can regulate/silence gene expression
siRNA or miRNA (RNAi) are delivered or naturally produced in the cell, respectively
DICER cleaves siRNA and miRNA into smaller sections
AGO binds to these and degrades one strand
The ss and AGO complex is called RISC
RISC finds its match (siRNA - perfect; miRNA seed matching therefore lots)
Cleaves at point of match
Briefly describe 4 virus/gene or protein which counterats the innate immune response
- Modification of host proteins (Vaccinia B8R is IFNAr1 homolog - doesn’t function)
- Hep C cleaves CARDIF/IPS-1
- Influenza/ NS1 complexes with RIG-I and prevents ligation with adaptors (CARDIF-IPS)
Describe the features of a deficiency in IFN-β and IFN-γ
HIgher viral load
greater decrease in lung function
Describe the features of IL-1 Receptor Associated Kinase (IRAK)-4 - an adapter kinase downstream of TLRs
↓produce inflammatory cytokines
↓IFN-a/B and IFN-λ
Recurrent infections with pyogenic bacteria
normal immunity to viruses
