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119 Cards in this Set

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What happens in innate immune respone?
Cell activation
Phagocytosis
Chemokines
Cytokines
What is innate immunity?
Universal form of host defense against infection
Limited number of germline encoded receptors in the host
-> Defects in these receptors, although rare, are almost always lethal
Recognize conserved products of microbial metabolism produced by the microbe but not th host
.: Recognition of "infectious" non-self
Why are microbe products recognized?
Conserved among microbes
->PAMPs (Pathogen Ass't Molecular Patterns)
What recognizes PAMPs?
PRRs in Plants and animals
.: innate response arose before the split
Which systems have an adaptive response?
Vertebrates only
Comparison of innate and adaptive immunity: Receptors
Innate: Fixed in genome
Adaptive: Encoded in germline, rearrangement needed, memory
Comparison of innate and adaptive immunity: Distribution
Innate: Non-clonal, all cells of a class identical
Adaptive: clonal, all cells of a class distinct
Comparison of innate and adaptive immunity: Recognition
Innate: Conserved patterns
Adaptive: Broad, but specific
Comparison of innate and adaptive immunity: Self- nonself
Innate: Perfect
Adaptive: Imperfect
Comparison of innate and adaptive immunity: Action time
Innate: immediate
Adaptive: Delayed
Comparison of innate and adaptive immunity: Response
Innate: Costimulatory molecules, cytokines, chemokines
Adaptive: Clonal expansion, anergy, effector cytokines
What are Pattern Recognition Receptors (PRRs)?
Toll-like receptors
Mannose binding lectin (MBL)
C-reactive protein
Serum amyloid-P
What are the fcts of PRRs?
Opsonization
Activation of complement
Activation of coagulation cascades
Phagoctosis
Activation of proinflammatory signalling paths
Apoptosis
Where was Toll first discovered?
Drosophila
-> Now 11 known family members in man, 13 in mice
What is the similar fct btw Toll in flies and IL-1R in man?
Both can induce NF-kB

(Conserved fct btw the 2 because NF-kB is rapidly induced in the fly as well, in response to infection)
What happened when Toll was deleted in flies?
They became extremely susceptible to fungal infection. but resistant to G- infection
Which drosophila ptn is required for G- bacteria control?
Imd
What do Imd and Toll induce in Drosophila?
Drosomycin: anti-fungal
Diptericin: anti-bacterial
What is the insect equivalent to MyD88? IkB?
MyD88: Tube
IkB: Cactus (both are inhibitors of NFkB)
What happened when Toll was deleted in flies?
They became extremely susceptible to fungal infection. but resistant to G- infection
What cells express TLRs?
APCs
NK cells
T-cells

Level and type of expression vary with the cell type
Which drosophila ptn is required for G- bacteria control?
Imd
What do Imd and Toll induce in Drosophila?
Drosomycin: anti-fungal
Diptericin: anti-bacterial
What is the insect equivalent to MyD88? IkB?
MyD88: Tube
IkB: Cactus (both are inhibitors of NFkB)
What cells express TLRs?
APCs
NK cells
T-cells

Level and type of expression vary with the cell type
Which cells have the highest level of TLR expression in humans?
Monocytes
Macrophages
What are some of the bacterial products recognized by TLRs?
LPS (usually by TLR 4)
CpG DNA
P/g
Lipoptns
etc
What does TLR4 need to be active?
Needs to be dimerized
What does TLR2 have to heterodimerize with?
TLR1 or TLR6
What does TLR9 respond to?
Unmethylated CpG DNA in bacteria
What dos the TLR2-TLR1/6 heterodimer respond to?
P/G (G+ bacteria)
Lipoptn
Lipoarabinomannan (Mycobacterium)
LPS (leptospira)
GPI (Trypanosoma cruzi)
Zymosan (yeast)
What does the TLR4-CD14-MD-2 complex respond to?
LPS (G-)
Lipoteichoic acids (G+)
RSV F ptn
What are the external TLRs (on the outside of the cell)?
TLR 1
TLR 2
TLR 6
TLR 4
TLR5
What are the internal TLRs on the phagosome/endosome?
TLR 3
TLR 7
TLR 8
TLR 9
How does TLR 4 work?
As a homodimer
What happens when there's a defect in TLR4 in C3H/HeJ mice?
Inability to respond to LPS
Is TLR4 the only receptor involved in LPS recognition?
No
LPS binding ptn (LBP) in serum deliver LPS to CD14 and this complex interacts with TLR4
What else does TLR4 recognize?
Lipoteichoic acid
HSP (HSP60)
Which TLR recognizes the largest number of ligands?
TLR2
When does TLR2 recognize its ligands?
When its heterodimerized with TLR 1 or 6
What are ligands of TLR2?
P/g
Bacterial lipoptns
LPS from Prophyromonas gingivitis and Leptospira interrogans (structurally different from the LPS of G- bacteria)
How does TLR5 act?
As a homodimer
What does TLR5 recognize?
Bacterial flagellin (a ptn ligand, unlike the other ligands) and the conserved hydrophobic core is recognized
--> Flagellin is essential for the bacteria and is conserved by various bacteria
What does TLR9 recognize?
Recognizes unmethylated DNA with a CpG motif (found in bacteria)
-->Most bacteria lack the enz to methylate, whereas most mammalian DNA is methylated
Is CpG immunostimulatory?
Yes
It can be used in vaccines to boost the immune response`
Where does recognition of CpG occur?
Intracellularly in the endosome
Where is CpG expressed?
On the internal surface of the organelle
What happens when the TLRs ligate to the cognate ligand?
TLRs induce the expression of host defense genes
What is the Toll signalling path similar to?
IL-1R path (since the cytosolic TIR domain is in common)
Which adaptor ptn is recruited to the the Toll complex?
MyD88
What does MyD88 then associate with?
IRAK
What is IRAK?
A serine threonine kinase
What happens when MyD88 associates with IRAK?
IRAK autoP
Attracks TRAF6
What does TRAF6 do?
Causes the degradation of IkB, freeing NF-kB to translocate to the nucleus
Is there specificity between TLRs and their ligands?
Yes
i.e. each TLR and IL-1 induce different target genes (but we don't know what confers the specificity)
What happens in MyD88 -/- mice?
They can't activate MAP kinase and NF-kB or upregulate surface expression of MHC and costimulatory molecules in response to IL-1 and many TLR ligands
Cannot produce IL-12 in response to any tested ligand
Can MyD88-/- mice still respond to LPS?
Yes, through TLR4, but with different kinetics and seem to use a unique adapter ptn TIRAP (aka TRIF)
What does this suggest?
There are 2 different paths for TLR4
--> TRIF and MyD88
What does TIRAP do?
Reacts with LPS to produce:
IFN inducible gene expression +CASPASE activation
What is MyD88 for/what reaction does it produce?
Mostly for cytokines
Look at figures, pg 13
look at figures pg 13
What does the MyD88 dependent path produce?
Cytokines
Costimulatory molecule induction
What does the MyD88 independent path produce?
IFN-inducible gene expression
CASPASE activation
Costimulatory molecule induction
What happens after NF-kB translocates?
Costimulatory molecules (CD80/86) on the surface of APCs (macs and DC) are induced
What happens to MHC after TLR engagement?
Increased expression of MHC

Both Costimulatory molecules and MHC are required for adaptive immunity
How is adaptive immmunity activated by innate immunity?
Microorganism bound by phagocytic receptor
Gets engulfed by phagosome
Antigens released and captured by MHC/TCR etc
What does IL-12 promote a naive T cell to become?
Th1
What does Th1 send out?
IFN-y
Which IL's do Th2 cells secrete?
IL-4: Humoral immunity
IL-5:Humoral immunity
IL-13:Humoral immunity
Il-10: immunosuppression
What happens to DCs in MYD88-/- mice when they are activate by alll PAMPs other than LPS? Why?
They do NOT mature
See blocks in expression of costimulatory molecules and MHC and these cells cannot prime Ag-specific T cells
What happens to these mice in response to Ag + adjuvant (that contains bacterial products)?
NO IFN-y or IgG2a Ab are made
DO make IgG1 and IgE (because these are relatedto Th2 type cell)
What does this say about MyD88 responses?
Needed for mounting a Th1 response
(without MyD88, defect in Th1 response)
MHC expression depends on MyD88
What kind of T cell response does activation through TLR induce?
Th1 response
Can activation through TLR induce a Th2 response?
Yes, but it is dependent on the:
cell type
antigen
adjuvant
What Th2 response is TLR-4 critical for?
Critical for the Th2 response induced to ovalbumin (OVA) with an alum (aluminum hydroxide hydrate) adjuvant, in the lung
What kind of ptns are TLRs?
Integral Mb proteins
What are the new cytoplasmic surveillance proteins/
Nucleotide-binding Oligomerisation Domain (NOD) ptns
NOD 1 and NOD2
What is the structure of the NOD ptns?
NOD1
N-term --- CARD---- NBD ---- LRRs ---- C-term
NOD2
N-term--- CARD--CARD--- NBD----LRRs--- C-term
What do the CARDs recognize?
Caspases
What is the ligand for NOD?
Peptidoglycan (p/g or PGN)
What is PGN?
Major component in G+ cell wall, thin layer in periplasmic space of G-
Glycan chains alternating GlcNAc and MurNAc linked by peptide bridges
What linkage does NOD1 recognize? NOD2?
NOD1: rec'z mesoDAP
NOD2: rec'z mesoDAP and L-Lys
What is the pathway for NOD signalling?
PGN --> NOD1 or 2--> NOD1 or 2 stack interacts with RLL2 --> Rll2 interacts with the IKK complex ---> IKK no longer interacts with NF-kB
--> IKK goes to proteasome
--> NF-kB migrates to the nucleus where it activates transcription
Where is NOD2 expressed?
Paneth cells of intestine
Why do enteric bacteria induce a-defensins through NOD2?
To kill luminal microbes
What happens with mutant NOD2?
It produces and processes more IL-1B leading to more inflammation
-> Less control in killing the bacteria
Some ppl with Crohn's disease have less IL-1B
What are cytokines?
Ptns produced in response to innate and adaptive IRs
What kind of activity do cytokines have?
Pro or anti-inflammatory

->cytokines generall have an ordered appearance with important roles in the early or late phases of the response
What kind of receptors do cytokines have?
Specific or shared
Look at figure pg 19
Th1/2 types of cytokines
Th1 mediated immunity: IL-12/18, IFN-y
Th2 mediated immunity: IL-4/13/10
Lymphocyte stimulator: IL-6
Antiviral/microbial immunity: IFN-a/b
Proinflammatory effects: TNF-a
What is an inflammatory response?
Homeostatic process
Series of reaction by the host to prevent tissue damage, to isolate and destroy the infective organisms and to repair the damage and return the organism to normal fct
What characterizes inflammatory response?
Swelling
Redness
Inc in T
Inc in pain
All these subside with healing
What is the acute phase response?
Early and immediate set of reactions induced by invasion of the pathogen
What makes acute phase ptns?
Liver (many made here)
Macrophages
What do the reactive O2 products (NO) and arachidonic acid (AA) cascade lead to?
Cause a change in vascular tone
This is caused b dilation and leakage (tissue edema, redness)
How is pain mediated?
Through brandykinin, which is liberated from kininogen by kallikrein during the clotting cascade
What mediates fever?
Prostaglandin E2

Measurable APP (acute phase ptns) produced by the liver in 24-48 hours
What kind of APPs are there?
Complement components
Coagulation Ptns: Fibrinogen
Proteinase Inhibitors
Metal-binding proteins: Haptoglobin
Major APRs: C-reactive ptn, serum amyloid P
Others: LBP, lipoptn A, MBL
How are type 1 (C-reactive P/ complement C3) controlled?
Induced by IL-1, TNF
How are type 2 (haptoglobin, ceruloplasmin) controlled?
Induced by IL-6, LIF (leukemia inhib factor), oncostatin M
What upregulates type 1 and 2 APPs?
Glucocorticoids enhances the cytokines effect
What downregulates type 1 and 2 APPs?
Insulin, hepatocyte growth factor, fibroblast growth factor
What does IL-1RA do?
Downregulates IL-1
What does sTNFR?
Downregulated TNF
What does IL-4 do?
DOWNregulates: TNF, IL-1/8, release of PGE2, superoxide anion
UPregulates: IL-1RA, VCAM
Enhances apoptosis of macrophages
What does IL-10 do?
Inhibits the synthesis of IL-1/6/8, TNF
UPregulates IL-1RA
What are chemokines?
Small polypeptides: less than 100 aa, ~7-16 kDA
Chemoattractant cytokines
Four families: CXC, CC, C, CX3C (38kDA)
How are chemokines produced?
As inactive precursors
-> enzymatically cleaved intracellularly and secreted rapidly into circulation
What can chemokines bind?
The BASIC part of chemokines can bind GAG on endothelial cells, connective tissue and extracellular matrices
Describe chemokine receptors.
Leukocytes can express 1+ receptors
Receptors bind 1+ chemokines
Signal transduction from the receptor via G-ptn
--> leads to killing of intracellular microbes
also: actin polym, adhesion, shape changes, chemotaxis, NADPH oxidase (for H2O2) degranulation. Depends on cell target and chemokine
What is the receptor for IL-8? What is IL-8 responsible for?
CXCR1: receptor for IL-8
Mostly responsible for attracting neutrophil to the area of infection
What produces CXC chemokine?
Macrophage
neutrophils
fibroblasts
endothelial cells
keratinocytes
NK cells
T-cells
Smooth muscle cells
What are the stimnulants of IL-8?
LPS
Bacteria
IL-1
TNF
What are the target cells of IL-8?
Neutrophils**
Resting T-cells
Endothelial cells
NK cells
Basophils
What does IL-8 do?
Activate neutrophil adhesion
Cause shape change in T-cells
Enzyme release
Respiratory burst
What do inhibitors of IL-8 do?
Limit angiogenesis and neutrophil infiltration
What is Rantes?
CC chemokine
Chemoattracts T-cells and mast cells but not neutrophils
What produces Rantes?
T cells
Endothelial cells
Platelets
Characteristics of Rantes
Early T-cell product which promotes mononuclear cell (mac, T-cell) infiltration
Mitogenic for T-cels (CD4>CD8), in contrast MIP1a favors CD8
Induces IL2-Ra
Can induce histamine release