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What are toll-like receptors?
- Innate receptors that recognize pathogens and their products and stimulate production of cytokines and chemokines in receptor-bearing cells
- They are important for resistance to viral, bacterial, and fungal infection
Give 5 examples of PAMPs recognized by TLRs
- 1. Lipoteichoic acids: gram+ cell walls
- 2. Lipopolysaccharide (LPS): gram- outer membrane
- 3. Bacterial flagella
- 4. Unmethylated repeats of CpG: abundant in bacterial DNA (methylated in mammalian DAN)
- 5. Double-stranded RNA: many viruses can produce, not a mammalian characteristic
Examples of cells that express TLRs
- dendritic cells
- NK cells
- B cells
- epithelial cells
- ***NOT T-cells
Describe the basic structure of mammalian TLRs
- Leucine-rich repeat (LRR): extracellular region
- creates horseshoe-shape
- recognizes ligands on outside and inside of this shape
- Toll-IL-1-receptor (TIR): cytoplasmic tail
- interacts with other TIR-like domains (often from other signaling molecules) to produce signal
What are the important (discussed) TLRs and what PAMPs activate them?
- TLR 1,2,6: lipoteichoic acid of gram+, diacyl and triacyl lipoproteins of gram-
- TLR 3: long-strand dsRNA
- TLR 3,7,9: viral RNA and DNA via the endocytic pathway
- TLR 4: LPS of gram-
- TLR 5: Bacterial monomeric flagellin
How is signaling initiated in TLRs?
- Ligand binding (direct or indirect) induces formation of dimers (heterodimers OR homodimers)
- Close TIR domains initiate signaling
What are NOD-like receptors? How do they work? What do they recognize?
- NLRs are intracellular sensors for microbial products (in the cytoplasm)
- activate NFκB to initiate the same inflammatory response as TLRs
- NOD1: recognize γ-glutamyl diaminopimelic acid (breakdown product of gram- in the cytoplasm)
- NOD2: recognizes muramyl dipeptide (peptidoglycan constituent of gram+ and gram-)
- NLRP subfamily recognizes muramyl dipeptide, bacterial DNA (non-methylated CpG repeats), and dsRNA
What are the RIG-I-like helicases? MDA-5? How do they work? What do they recognize?
- Retinoic acid-inducible gene I: sense the unmodified 5'-triphosphate end of ssRNA (eukaryotic RNA is typically "capped") in the cytoplasm
- melanoma differentiation-associated 5: similar in structure, but senses dsRNA
- Recognition in these proteins activates a signaling pathway resulting in IFN-α and IFN-β
Signaling by mammalian TLRs and NLRs induce intracellular responses that together result in production of....
- Inflammatory cytokines (TNF-α, IL-1β, IL-6)
- Antimicrobial peptides
- Antiviral cytokines - the type I interferons (IFN-α and IFN-β)
What are the cytokines/chemokines produced by activation of the NFκB (via TLR and NLR) that influence the ADAPTIVE immune response
- IL-12: activates NK cells
- induces differentiation of CD4T into TH1
- Co-stimulatory molecules: CD80 and CD86 on the surface of dendritic cells
- required along with the peptides displayed by MHC molecules to activate naïve CD4T
- TNF-α: stimulates antigen-presenting dendritic cells to migrate to lymph nodes and activate naïve T cells
What changes occur in a Langerhans cell activated through TLR 4 signaling?
- 1. Activated cells migrate, enter lymphatic system, travel to regional lymph node, become mature dendritic cells
- 2. Mature dendritic cells lose the ability to ingest antigen, but gain ability to stimulate T cells
What are the 3 ways a cytokine can act?
- autocrine: affect same cell that released
- paracrine: affect adjacent cells (cytokine is unstable)
- endocrine: affect distant cells (cytokine is stable)
What are the important cytokines and chemokines? What are their local and systematic effects?
- IL-1β,IL-6,TNF-α: induce acute-phase response in liver and induce fever
- TNF-α: inducer of local inflammatory response
- can have harmful systemic effects
- IL-12: activates NK Cells and favors differentiation of CD4T to TH1
- CXCL8: local inflammatory response
- helps to attract neutrophils to site of infection
- ONLY CHEMOKINE ON THIS LIST
What are the 3 roles of inflammation in combating infection?
- Deliver additional effector molecules and cells: complement and acute-phase proteins, monocytes and neutrophils
- Induce local blood clotting: block the spread of infection from bloodstream
- Promote repair: of injured tissue
Give two examples of NON chemokines/cytokines that are involved in inflammation w/ description.
- c5a (from complement):
- promotes inflammation by increasing vascular permeability and inducing adhesion molecules on endothelium
- Lipid mediators (from damaged tissue): induce vascular permeability, pain, fever, and chemotaxis of neuotrophils
- eg. prostaglandins and leukotrienes
What are the four types of change in local blood vessels during inflammation?
- 1. Dilation of local blood vessels and changes on the walls in endothelial cells
- 2. Movement of leukocytes (neutrophils and monocytes) to periphery of blood vessel because endothelial cells increased adhesion molecules on their surface
- 3. extravasation: leukocytes move out of the blood vessel and into the infected tissue
- 4. blood clotting: proteins move from blood into tissues for healing
What are examples of endogenous pyrogens? How do they work?
- TNF-α, IL-1β, and IL-6
- cause fever by inducing synthesis of prostaglandin E2 which acts on the hypothalamus resulting in an increase in heat production by brown fat and vasoconstriction
List the spectrum of activities that TNF-α, IL-1β, and IL-6 coordinate to help the body during infection (no description)
- Elevation of body temperature
- Acute-phase response
- Stimulation of dendritic cell migration
What is the acute phase response? Describe it in detail based on each component
- TNF-α, IL-1β, and IL-6 induce liver hepatocytes to produce acute phase proteins
- C-reactive protein: binds to phosphocholine in bacterial and fungal cell walls (opsonize, activate complement)
- Mannose-binding lectin: binds to annose residues on bacterial surfaces (opsonize, activate complement)
- Surfactant proteins SP-A and SP-D: produced by the liver and a variety of epithelia (opsonize)
What are the two types of interferon w/ description?
- Type I (IFN-α and IFN-β): synthesized by all nucleated cells after infection by virus
- Type II (IFN-γ): synthesized by activated Tcells (mainly TH1) and NK cells
How can type I interferons be induced in infected and noninfected cells?
- Infected cell: cytoplasmic sensors of viral RNA, RIG-I, and MDA-5
- Uninfected cell: TLR-3 in membrane or endosome recognizes viral material produced by an infected cell
How do Type I interferons affect cells after binding to interferon receptors?
- 1. Induce resistance to viral replication by activating genes: cause destruction of mRNA, inhibit translation of viral and host proteins
- 2. Induce MHC class I expression and antigen presentation in most cell types: make them more susceptible to CD8 Tctyo
- 3. Activate dendritic cells and macrophages: enables activation of specific immunity
- 4. Activate NK cells: selectively kill virus-infected cells more efficiently
What are the important enzymes in NK cytotoxic granules?
- granzymes: induce apoptosis
- perforin: forms pore
How is IFN-γ different than IFN-α and IFN-β?
- It is produced predominantly by NK during innate response and by CD4 TH1 and CD8 Tcyto during adaptive response
- Production by NK cells may induce differentiation of mature CD4 to TH1 which can activate macrophages
Describe how an NK cell detects and destroys an infected cell
- Sense changes in the expression of MHC class I molecules
- Activating receptor: triggers NK to kill target cell in response to changes in cell glycoprotein composition
- Inhibitory receptor: inhibit killing by overruling activating receptor in response to proper MHC class I molecules
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