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What are the characteristics is innate immune system receptors?
- 1. Specificity is inherited in the genome
- 2. Expressed by all cells of a particular type (e.g. macrophages)
- 3. Triggers immediate response
- 4. Recognizes broad classes of pathogens
- 5. Interacts with a range of molecular structures of a given type
What are the characteristics of adaptive immune system receptors?
- 1. Encoded in multiple gene segments
- 2. Requires gene rearrangement
- 3. Clonal distribution
- 4. Able to discriminate between even closely related molecular structures
What are the 4 main groups of PRR's (Pattern Recogniztion Receptors)?
- 1. Free receptors in serum
- 2. Membrane-bound phagocytic receptors
- 3. Membrane-bound signaling receptors
- 4. Cytoplasmic signaling receptors
What are the 3 main categories of phagocytic cells?
- 1. Mfs (Macrophages) - mostly in tissue
- 2. Granulocytes - neutrophils are the most active
- 3. DC's (Dedritic cells)
- a) Conventional DC's - process ingested microbes, present peptides to and activate T cells and produce cytokines
- b) Plasmacytoid DC's - produce interferons
What is the process of phagocytosis?
- 1. Macrophages have phagocytic receptors (mannose, Dectin-1 (Beta-glucan receptor), C, scavenger, lipid) that bind microbes and their components
- 2. Bound material is internalized in phagosomes and broken down in phagolysosomes
What are GPCRs?
G-protein-coupled receptors - receptors on phagocytes (Mfs, granulocytes, DC's, neutrophils) that signal the phagocyte to kill the ingested pathogen
What is the mechanism of GPCR signaling?
- 1. Before ligand (chemokine or fMet-Lec-Phe) binding, GPCR is not associated with the inactive G protein which is bound to GDP
- 2. Ligand binding causes a conformational change in the receptor which enables it to associate with the G protein which releases GDP and binds GTP
- 3. G protein dissociates into alpha and beta-gamma subunits, both of which activate antimicrobial compounds
What is respiratory burst?
- 1. Neutrophils engulf and kill the microbes to which they bind
- 2. Bacterial fMet-Lec-Phe peptides activate Rac 2 and bacteria are taken up into phagosomes
- 3. Phagosomes fuse with primary and secondary granules
- 4. Rac 2 induces assembly of a functional NADPH oxidase in the phagolysosome membrane, leading to generation of antimicrobial superoxide and hydrogen peroxide
What is the mechanism for how infection stimulates macrophages to release cytokines and chemokines that initiate an inflammatory response?
- 1. Macrophage detects invading pathogen and releases cytokines
- 2. Cytokines cause dilation of local small blood vessels
- 3. Leukocytes, plasma proteins, and fluid move from blood to tissue causing inflammation
- 4. Clotting in infected area prevents spread of pathogen
What are the 3 essential roles of inflammation?
- 1. Deliver effector molecules and cells from blood
- 2. Induce local blood clotting to prevent spreading of pathogen
- 3. Promote tissue repair
What is the mechanism of migration of monocytes from blood into inflamed and infected tissues?
- 1. Monocytes bind adhesion molecules on vascular endothelium near site of infection and receives chemokine signal
- 2. Moncytes migrate into the surrounding tissue
- 3. Once in tissue, monocytes differentiate into macrophages and migrate to the site of infection
What are TLR's?
Toll-like receptors - represent an ancient host defence signaling system in vertebrates, plants, and invertibrates and is important for defense against G+ bacteria and fungi
What are the major types of molecules that are recognized by TLRs?
- 1. TLR:TLR2 and TLR2:TLR6 heterodimers - Lipoproteins
- 2. TLR3 - dsRNA
- 3. TLR4 - LPS
- 4. TLR5 - Flagellin
- 5. TLR7 and TLR8 - ssRNA
- 6. TLR9 - DNA
- 7. TLR11 - Profilin
What are the cellular locations of mammalian TLRs?
- 1. Extracellular recognition - The cell surface of DCs, Mfs and B cells
- 2. Intracellular recognition - In the walls of endosomes
What is the mechanism of recognition of PAMPs by TLR-1 and TLR-2?
- 1. They have binding sites for triacyl lipopeptides
- 2. Binding of each TLR to the same lipopeptide induces dimerization and brings their TIR (Toll-IL-I receptor) domains close together
- 3. This initiates signaling
What is LPS
- 1. Lipopolysaccharide
- 2. Cell wall component of Gram- bacteria
- 3. In mass amounts can cause septic shock due to mass secretion of cytokines
- 4. Recognized by TLR-4
What accessory proteins are involved in TLR-4 recognition of LPS?
- 1. MD-2 binds TLR-4 to aid recognition
- 2. CD14 helps TLR-4 recognize free LPS (LPS detached from the pathogen)
What is the mechanism for TLR signaling in activating NFkB and expression of pro-inflammatory cytokines?
- 1. Dimerized TLRs recruit IRAK1 and IRAK4, activating the E3 ubiquitin ligase TRAF-6
- 2. TRAF-6 and NEMO (NFkB essential modifier) are polyubiquitinated, creating a scaffold for activation of TAK 1
- 3. TAK1 associates with IKK and phosphorylates IKKb, which phosphorylates IkB
- 4. IkB is degraded, releasing NFkB into the nucleus to induce expression of cytokine genes
What two pathways stimulate expression of antivial interferons in response to viral nucleic acids?
- 1. TLR-3 in endosome binds dsRNA and signals via TRIF to induce IFN gene expression
- 2. TLR-7 in endosome binds ssRNA and signals via MyD88 to induce IFN gene expression
How do NOD proteins activate NFkB to induce the expression of pro-inflammatory genes?
- 1. Cytoplasmic NOD proteins reside in the cytoplasm in an inactive form
- 2. Binding of bacterial ligands to NOD proteins induces recruitment of RIPK2, which activates TAK1, leading to NFkB activation
What is the inflammasome and how does it activate the release of mature cytokines?
- 1. Efflux of K+ ions from damages cells induces dissociaton of cytoplasmic proteins from NALP3
- 2. NALP3 dimerization recruits PYCARD, causing aggregation and proteolytic activation of caspase 1
- 3. Caspase 1 releases mature inflammatory cytokines such as IL-1 and IL-18 from their proproteins
What are RLH's?
RIG-I-like helicases - they detect cytoplasmic viral RNA and stimulate interferon production
What is the mechanism of RLH (RIG-I-like helicase) sensing of cytoplasmic RNA?
- 1. Cytoplasmic replication of virus produces uncapped RNA with a 5'-triphosphate
- 2. Viral RNA binding to RIG-I induces RIG-I to associate with the adaptor MAVS, causing dimerization
- 3. MAVS induce production of inflammatory cytokines and interferons via activation of NFkB and IRF's
What changes in gene expression are triggered by TLR and NLR activation?
- 1. Immature DC's ingest pathogens
- 2. They migrate to lymph nodes
- 3. Increased expression for cell surface molecules B7.1 (CD 80) and B7.2 (CD 86) that stimulate T-cells
Discuss the similarity of TLR signaling in Drosophila with that in humans?
- 1. Extracellular recognition receptors activate a protease cascade leading to cleavage of Spatzle
- 2. Ceaved Spatzle homodimer binds to Toll, causing its dimerization
- 3. The TIR domains of Toll recruit the adaptor dMyD88, which activates a signaling pathway similar to the NFkB pathway
List and distinguish between the 3s way in which cytokines can act.
- 1. Autocrine manner - affect the behavior of the cell that releases the cytokine
- 2. Paracrine manner - affect the behavior of adjacent cells
- 3. Endocrine manner - affect the behavior of distant cells
What are the basic actions of IL-1Beta, TNF-alpha, IL-6, CXCL8, and IL-12?
- 1. TNF-alpha - induces local inflammation and fever
- 2. CXCL8 - induces local inflammation by attracting neutrophils
- 3. IL-1Beta, IL-6 - induces fever and acute-phase response in liver
- 4. IL-12 - activates NK cells and induces differentiation of CD4 T cells into TH1 cells
What is the major structural difference between the 2 major types of chemokines?
- 1. CC chemokines - have 2 adjacent cysteine residues near the amino terminus
- 2. CXC chemokines - have 2 cycteine residues near the amino terminus that are separated by a single amino acid
What is the funciton and cell-type locaion of selectins, integrins, and ICAMs?
- 1. Selectins - Bind carbs; initiate leukocyte-endothelial interaction; located in endothelium
- 2. Integrins - Bind to cell-adhesion molecules and extracellular matrix; located in monocytes, T cells, Mfs, neutrophils, DCs, and NK cells
- 3. ICAMs - ligands for integrins; located in activated leukocytes and endothelial cell-cell junctions
What are the 4 steps involved in extravasation induced by inflammation?
- 1. Rolling adhesion
- 2. Tight binding
- 3. Diapedesis
- 4. Migration
Distinguish between the action of TNF-alpha locally vs. systemically.
- 1. Mfs activated to secrete TNF-alpha in tissue
- 2. Increased release of plama proteins into tissue; increased phagocyte and lymphocyte migration into tissue; increased platlet adhesion to blood vessel wall
- 3. Phagocytosis of bacteria; local vessel occlusion; plasma and cells drain to local lymph node
- 4. Removal of infection - adaptive immunity
- Systemic (Sepsis)
- 1. Mfs activated in the liver and spleen secrete TNF-alpha into the bloodstream
- 2. Systemic edema causing decreased blood volume, hypoproteinemia, and neutropenia, followed by neutrophilia; decreased blood volume causes collapse of vessels
- 3. Disseminated intravascular coagulation leading to wasting and multiple organ failure
- 4. Death
How is the acute-phase response induced and what are the major functions of C-reactive protein and MBL in this capacity?
- 1. Bacteria induce Mfs to produce IL-6, which acts on hepatocytes to induce synthesis of acute-phase proteins
- 2. C-reactive protein binds phosphocholine on bacterial surfaces, acting as an opsonin, and also activating C
- 3. Mannose-binding lectin binds mannose residues on bacterial surfaces, acting as an opsonin, and also activating C
What are the 3 main systems that help inhibit viral replication that are induced by interferons?
- 1. They activate gene (Mx proteins, oligoadenylate sysnthetase, and PKR) that cause the destruction of mRNA and inhibit the translation of viral proteins
- 2. They induce MHC I expression in infected cells which makes them more susceptible to being killed by CD8 cytotoxic T cells
- 3. They activate NK cells which selectively kill virus-infected cells
Describe the basic role of NK cells in innate immune response.
Activated NK cells serve to contain virus infection while the adaptive immune response is generating Ag-specific cytotoxic T cells and neutralizing Abs that can clear the infection.
What is the balance of activating vs inhibiting receptors that determines the ability of NK cells to kill their targets?
- 1. MHC I on normal cells is recognized by inhibitory receptors that inhibit signals from activating receptors - NK cell does not kill the normal cell
- 2. Absent MHC I can't stimulate a negative signal; the NK cell is triggered by signals from activating receptors - Activated NK cell releases granule contents, inducing apoptosis in the target cell
What are the basic roles of the innate-like lymphocytes?
- 1. B-1 Cells - Make Ab
- 2. Epithelial y:g cells - Produce cytokines rapidly
- 3. iNKT cells - Produce cytokines rapidly