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Serum Proteins
- Bind to microbes to increase visibility by the immune system
- Recognize foreign presence
- Soluble pattern recognition receptors - bind to pathogen assoicated molecular patterns (PAMPS)
- Complement proteins
- Mannose-binding lectins
- C-reactive proteins
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Complement mechanisms
- Lysis of microbes
- Inflammation
- Phagocytosis of complement-coated microbes
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C-reactive protein
- Binds microbial phospholipids (membranes), opsonin
- Increase phagocytosis
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Mannon-binding Lectins
Binds microbial carbohydrates, opsonin
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3 ways to activate complement
- Alternative pathway - pathogen surface creates local environment conducive to complement activation (first to act)
- Lectin pathway - mannose-bidning lectin binds to pathogen surface
- Classical pathway - C-reactive protein or antibody binds to specific antigen on pathogen surface
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Cell surface Receptors
- Toll-like receptors
- Mannose receptors
- Scavenger receptors
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Cytoplasmic Receptors
- CARD-family sensors
- Nod-like sensors
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Cells that express pattern recognition receptors
- Neutrophils
- Macrophages
- Dendritic cells
- Natural killer cells
- Eosinophls, basophils, mast cells
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Monocytes
- Circulate in the blood
- Precursors to Macrophages and some dendritic cells
- Can get recruited to the site of infection
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Macrophages
- Found in the tissues
- Highly phagocytic
- Take up residence and become part of the tissue
- Antigen presentation
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Macrophage Receptors
- LPS receptor and Toll-like receptor 4: bind LPS a cell wall component of gram negative bacteria
- CR3,4 complement: bind complement coated bacteria
- Scavenger receptor: bind to negatively charged polymers
- Mannose receptor: bind sugars unique to bacteria, activates C'
- Glucan receptor: bacteria carbohydrates
- Other TLRs
- Chemokine receptors: mediate macrophage migration
- Cytokine receptors
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Neutrophils
- Most common WBC
- Granulocytes
- Short lived
- Same receptors as macrophages
- Engulf and digest bacteria
- Do not live in tissues! Have to be recruited to site
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Receptor mediated phagocytosis
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Types cytokines secreted by macrophages
- IL-1beta
- TNF-alpha
- IL-6
- CXCL8
- IL-12
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IL-1beta
- Activates vascular endothelium
- Activates lymphocytes
- Local tissue destruction
- Increases access of effector cells
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TNF-alpha
Activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes
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IL-6
- Lymphocyte activation
- Increased antibody production
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CXCL8
Chemotactic (chemical sensing) factor recruits neutrophils, basophils, and T cells to site of infection
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IL-12
- Activates NK cells
- Induces the differentiation of CD4 T cells into TH1 cells
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Systemic effects of cytokines
IL-1/IL-6/TNF-alpha
- Liver - acute-phase proteins > activation of complement opsonization
- Bone marrow endothelium - neutrophil mobilization > phagocytosis
- Hypothalamus - increased body temp > decreased viral and bacterial replication
- Fat, muscle - protein and energy mobilization to generate increased body temp > decreased viral and bacterial replication
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Toll-like receptors
- Detect pathogen-specific molecular patterns
- Extracellular domain: recognize pathogen (contains Leucine Rich Region-LRR)
- Cytoplasmic signaling domain: conveys that info to inside of cell (Toll-interleukin receptor)
- TLR binding leads to activation of NFkB mediated transcription
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Sepsis
Infections of the blood
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Septic Shock
- Dilation of blood vessels and massive leakage of fluid into tissues throughout the body (decreased BP)
- Widespread blood clotting in capillaries > vital organs lack blood supply
- Caused by too much production of TNF-alpha
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TLR-4
Recognize LPS (lipopolysaccharide) on gram negative bacteria
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TLR-1:TLR-2
- Heterodimer
- Recognizes triacyl lypopeptides
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TLR-2:TLR-6
Recognize diacyl lipopeptides
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Signaling Pathway of NFkB
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Steps in NFkB activation
(Extracellular bacteria)
- 1. LPS binds to TLR-4, MD2, CD14 complex
- 2. TIR domain of TLR4 binds to MyD88
- 3. MyD88 recruits IRAK4 (protein kinase)
- 4. IRAK4 phosphorylates TRAF6
- 5. Lead to activation of IKK
- 6. IkB dissociates from NFkB
- 7. NFkB goes into nucleus > txn of genes for cytokines
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Alternate TLR4 pathway
(Viral infection)
- 1. TRIF, TRAM forms complex with TLR4
- 2. Phosphorylate TRAF3
- 3. Lead to phosphorylation of IFR3
- 4. IFR3 goes into nucleus
- 5. Secretion of type I interferons
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Cytoplasmic Pathogen Recognition Receptors
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NOD2
- Recognize bacterial proteoglycans in cytoplasm (intracellular)
- Activates NFkB through RICK protein
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RIG-I
- Cytoplasmic receptor for viral DNA
- Activate IRF3
- Leads to expression of interferons
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Dendritic Cell
- Phagocytic and pinocytic
- Found in tissues and in secondary lymphoid organs
- When they encounter a pathogen, they are activated to travel to the local secondary lymphoid organs and become good antigen presenters
- Upon activation, they secrete cytokins, mature, and travel to local lymph node to activate T cells
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Natural Killer Cells
- Detect intracelluar pathogens
- Contain cytolytic graules
- Monitor cells for identification oas self
- Kills cells infected with certain viruses or stressed cells
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NK Receptors
- 1. Inhibitory receptors: tell them NOT to kill a target cell
- 2. Activating receptors: tell them to kill a target
- When they lose inhibitory signals or receive high levels of activating signals, they kill infected cell
- Always ready to kill but can be better stimulated by cytokines
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Who is making the cytokines that activate NK cells?
Macrophages
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- NK cells activate macrophages by releasing inteferon
- Macrophages secreted IL-12 that activate NK cells
- Positive feed back loop
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Type I Interferons
- IFN-alpha and IFN-beta
- 1. Induce resistnace to viral replication in all cells
- 2. Increase expression of ligands for receptors on NK cells
- 3. Activate NK cells to kill virus-infected cells
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