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119 Cards in this Set
- Front
- Back
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What happens in innate immune respone?
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Cell activation
Phagocytosis Chemokines Cytokines |
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What is innate immunity?
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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 |
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Why are microbe products recognized?
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Conserved among microbes
->PAMPs (Pathogen Ass't Molecular Patterns) |
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What recognizes PAMPs?
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PRRs in Plants and animals
.: innate response arose before the split |
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Which systems have an adaptive response?
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Vertebrates only
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Comparison of innate and adaptive immunity: Receptors
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Innate: Fixed in genome
Adaptive: Encoded in germline, rearrangement needed, memory |
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Comparison of innate and adaptive immunity: Distribution
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Innate: Non-clonal, all cells of a class identical
Adaptive: clonal, all cells of a class distinct |
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Comparison of innate and adaptive immunity: Recognition
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Innate: Conserved patterns
Adaptive: Broad, but specific |
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Comparison of innate and adaptive immunity: Self- nonself
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Innate: Perfect
Adaptive: Imperfect |
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Comparison of innate and adaptive immunity: Action time
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Innate: immediate
Adaptive: Delayed |
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Comparison of innate and adaptive immunity: Response
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Innate: Costimulatory molecules, cytokines, chemokines
Adaptive: Clonal expansion, anergy, effector cytokines |
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What are Pattern Recognition Receptors (PRRs)?
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Toll-like receptors
Mannose binding lectin (MBL) C-reactive protein Serum amyloid-P |
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What are the fcts of PRRs?
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Opsonization
Activation of complement Activation of coagulation cascades Phagoctosis Activation of proinflammatory signalling paths Apoptosis |
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Where was Toll first discovered?
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Drosophila
-> Now 11 known family members in man, 13 in mice |
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What is the similar fct btw Toll in flies and IL-1R in man?
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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) |
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What happened when Toll was deleted in flies?
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They became extremely susceptible to fungal infection. but resistant to G- infection
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Which drosophila ptn is required for G- bacteria control?
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Imd
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What do Imd and Toll induce in Drosophila?
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Drosomycin: anti-fungal
Diptericin: anti-bacterial |
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What is the insect equivalent to MyD88? IkB?
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MyD88: Tube
IkB: Cactus (both are inhibitors of NFkB) |
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What happened when Toll was deleted in flies?
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They became extremely susceptible to fungal infection. but resistant to G- infection
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What cells express TLRs?
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APCs
NK cells T-cells Level and type of expression vary with the cell type |
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Which drosophila ptn is required for G- bacteria control?
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Imd
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What do Imd and Toll induce in Drosophila?
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Drosomycin: anti-fungal
Diptericin: anti-bacterial |
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What is the insect equivalent to MyD88? IkB?
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MyD88: Tube
IkB: Cactus (both are inhibitors of NFkB) |
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What cells express TLRs?
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APCs
NK cells T-cells Level and type of expression vary with the cell type |
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Which cells have the highest level of TLR expression in humans?
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Monocytes
Macrophages |
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What are some of the bacterial products recognized by TLRs?
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LPS (usually by TLR 4)
CpG DNA P/g Lipoptns etc |
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What does TLR4 need to be active?
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Needs to be dimerized
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What does TLR2 have to heterodimerize with?
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TLR1 or TLR6
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What does TLR9 respond to?
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Unmethylated CpG DNA in bacteria
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What dos the TLR2-TLR1/6 heterodimer respond to?
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P/G (G+ bacteria)
Lipoptn Lipoarabinomannan (Mycobacterium) LPS (leptospira) GPI (Trypanosoma cruzi) Zymosan (yeast) |
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What does the TLR4-CD14-MD-2 complex respond to?
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LPS (G-)
Lipoteichoic acids (G+) RSV F ptn |
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What are the external TLRs (on the outside of the cell)?
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TLR 1
TLR 2 TLR 6 TLR 4 TLR5 |
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What are the internal TLRs on the phagosome/endosome?
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TLR 3
TLR 7 TLR 8 TLR 9 |
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How does TLR 4 work?
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As a homodimer
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What happens when there's a defect in TLR4 in C3H/HeJ mice?
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Inability to respond to LPS
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Is TLR4 the only receptor involved in LPS recognition?
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No
LPS binding ptn (LBP) in serum deliver LPS to CD14 and this complex interacts with TLR4 |
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What else does TLR4 recognize?
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Lipoteichoic acid
HSP (HSP60) |
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Which TLR recognizes the largest number of ligands?
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TLR2
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When does TLR2 recognize its ligands?
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When its heterodimerized with TLR 1 or 6
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What are ligands of TLR2?
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P/g
Bacterial lipoptns LPS from Prophyromonas gingivitis and Leptospira interrogans (structurally different from the LPS of G- bacteria) |
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How does TLR5 act?
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As a homodimer
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What does TLR5 recognize?
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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 |
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What does TLR9 recognize?
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Recognizes unmethylated DNA with a CpG motif (found in bacteria)
-->Most bacteria lack the enz to methylate, whereas most mammalian DNA is methylated |
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Is CpG immunostimulatory?
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Yes
It can be used in vaccines to boost the immune response` |
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Where does recognition of CpG occur?
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Intracellularly in the endosome
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Where is CpG expressed?
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On the internal surface of the organelle
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What happens when the TLRs ligate to the cognate ligand?
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TLRs induce the expression of host defense genes
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What is the Toll signalling path similar to?
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IL-1R path (since the cytosolic TIR domain is in common)
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Which adaptor ptn is recruited to the the Toll complex?
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MyD88
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What does MyD88 then associate with?
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IRAK
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What is IRAK?
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A serine threonine kinase
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What happens when MyD88 associates with IRAK?
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IRAK autoP
Attracks TRAF6 |
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What does TRAF6 do?
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Causes the degradation of IkB, freeing NF-kB to translocate to the nucleus
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Is there specificity between TLRs and their ligands?
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Yes
i.e. each TLR and IL-1 induce different target genes (but we don't know what confers the specificity) |
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What happens in MyD88 -/- mice?
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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 |
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Can MyD88-/- mice still respond to LPS?
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Yes, through TLR4, but with different kinetics and seem to use a unique adapter ptn TIRAP (aka TRIF)
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What does this suggest?
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There are 2 different paths for TLR4
--> TRIF and MyD88 |
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What does TIRAP do?
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Reacts with LPS to produce:
IFN inducible gene expression +CASPASE activation |
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What is MyD88 for/what reaction does it produce?
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Mostly for cytokines
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Look at figures, pg 13
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look at figures pg 13
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What does the MyD88 dependent path produce?
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Cytokines
Costimulatory molecule induction |
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What does the MyD88 independent path produce?
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IFN-inducible gene expression
CASPASE activation Costimulatory molecule induction |
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What happens after NF-kB translocates?
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Costimulatory molecules (CD80/86) on the surface of APCs (macs and DC) are induced
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What happens to MHC after TLR engagement?
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Increased expression of MHC
Both Costimulatory molecules and MHC are required for adaptive immunity |
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How is adaptive immmunity activated by innate immunity?
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Microorganism bound by phagocytic receptor
Gets engulfed by phagosome Antigens released and captured by MHC/TCR etc |
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What does IL-12 promote a naive T cell to become?
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Th1
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What does Th1 send out?
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IFN-y
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Which IL's do Th2 cells secrete?
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IL-4: Humoral immunity
IL-5:Humoral immunity IL-13:Humoral immunity Il-10: immunosuppression |
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What happens to DCs in MYD88-/- mice when they are activate by alll PAMPs other than LPS? Why?
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They do NOT mature
See blocks in expression of costimulatory molecules and MHC and these cells cannot prime Ag-specific T cells |
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What happens to these mice in response to Ag + adjuvant (that contains bacterial products)?
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NO IFN-y or IgG2a Ab are made
DO make IgG1 and IgE (because these are relatedto Th2 type cell) |
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What does this say about MyD88 responses?
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Needed for mounting a Th1 response
(without MyD88, defect in Th1 response) MHC expression depends on MyD88 |
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What kind of T cell response does activation through TLR induce?
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Th1 response
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Can activation through TLR induce a Th2 response?
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Yes, but it is dependent on the:
cell type antigen adjuvant |
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What Th2 response is TLR-4 critical for?
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Critical for the Th2 response induced to ovalbumin (OVA) with an alum (aluminum hydroxide hydrate) adjuvant, in the lung
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What kind of ptns are TLRs?
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Integral Mb proteins
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What are the new cytoplasmic surveillance proteins/
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Nucleotide-binding Oligomerisation Domain (NOD) ptns
NOD 1 and NOD2 |
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What is the structure of the NOD ptns?
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NOD1
N-term --- CARD---- NBD ---- LRRs ---- C-term NOD2 N-term--- CARD--CARD--- NBD----LRRs--- C-term |
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What do the CARDs recognize?
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Caspases
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What is the ligand for NOD?
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Peptidoglycan (p/g or PGN)
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What is PGN?
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Major component in G+ cell wall, thin layer in periplasmic space of G-
Glycan chains alternating GlcNAc and MurNAc linked by peptide bridges |
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What linkage does NOD1 recognize? NOD2?
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NOD1: rec'z mesoDAP
NOD2: rec'z mesoDAP and L-Lys |
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What is the pathway for NOD signalling?
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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 |
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Where is NOD2 expressed?
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Paneth cells of intestine
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Why do enteric bacteria induce a-defensins through NOD2?
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To kill luminal microbes
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What happens with mutant NOD2?
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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 |
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What are cytokines?
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Ptns produced in response to innate and adaptive IRs
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What kind of activity do cytokines have?
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Pro or anti-inflammatory
->cytokines generall have an ordered appearance with important roles in the early or late phases of the response |
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What kind of receptors do cytokines have?
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Specific or shared
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Look at figure pg 19
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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 |
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What is an inflammatory response?
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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 |
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What characterizes inflammatory response?
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Swelling
Redness Inc in T Inc in pain All these subside with healing |
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What is the acute phase response?
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Early and immediate set of reactions induced by invasion of the pathogen
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What makes acute phase ptns?
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Liver (many made here)
Macrophages |
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What do the reactive O2 products (NO) and arachidonic acid (AA) cascade lead to?
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Cause a change in vascular tone
This is caused b dilation and leakage (tissue edema, redness) |
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How is pain mediated?
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Through brandykinin, which is liberated from kininogen by kallikrein during the clotting cascade
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What mediates fever?
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Prostaglandin E2
Measurable APP (acute phase ptns) produced by the liver in 24-48 hours |
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What kind of APPs are there?
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Complement components
Coagulation Ptns: Fibrinogen Proteinase Inhibitors Metal-binding proteins: Haptoglobin Major APRs: C-reactive ptn, serum amyloid P Others: LBP, lipoptn A, MBL |
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How are type 1 (C-reactive P/ complement C3) controlled?
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Induced by IL-1, TNF
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How are type 2 (haptoglobin, ceruloplasmin) controlled?
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Induced by IL-6, LIF (leukemia inhib factor), oncostatin M
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What upregulates type 1 and 2 APPs?
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Glucocorticoids enhances the cytokines effect
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What downregulates type 1 and 2 APPs?
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Insulin, hepatocyte growth factor, fibroblast growth factor
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What does IL-1RA do?
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Downregulates IL-1
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What does sTNFR?
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Downregulated TNF
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What does IL-4 do?
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DOWNregulates: TNF, IL-1/8, release of PGE2, superoxide anion
UPregulates: IL-1RA, VCAM Enhances apoptosis of macrophages |
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What does IL-10 do?
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Inhibits the synthesis of IL-1/6/8, TNF
UPregulates IL-1RA |
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What are chemokines?
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Small polypeptides: less than 100 aa, ~7-16 kDA
Chemoattractant cytokines Four families: CXC, CC, C, CX3C (38kDA) |
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How are chemokines produced?
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As inactive precursors
-> enzymatically cleaved intracellularly and secreted rapidly into circulation |
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What can chemokines bind?
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The BASIC part of chemokines can bind GAG on endothelial cells, connective tissue and extracellular matrices
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Describe chemokine receptors.
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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 |
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What is the receptor for IL-8? What is IL-8 responsible for?
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CXCR1: receptor for IL-8
Mostly responsible for attracting neutrophil to the area of infection |
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What produces CXC chemokine?
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Macrophage
neutrophils fibroblasts endothelial cells keratinocytes NK cells T-cells Smooth muscle cells |
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What are the stimnulants of IL-8?
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LPS
Bacteria IL-1 TNF |
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What are the target cells of IL-8?
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Neutrophils**
Resting T-cells Endothelial cells NK cells Basophils |
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What does IL-8 do?
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Activate neutrophil adhesion
Cause shape change in T-cells Enzyme release Respiratory burst |
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What do inhibitors of IL-8 do?
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Limit angiogenesis and neutrophil infiltration
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What is Rantes?
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CC chemokine
Chemoattracts T-cells and mast cells but not neutrophils |
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What produces Rantes?
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T cells
Endothelial cells Platelets |
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Characteristics of Rantes
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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 |
