Chapter 2

• 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

• Lysis of microbes
• Inflammation
• Phagocytosis of complement-coated microbes

• Binds microbial phospholipids (membranes), opsonin
• Increase phagocytosis

Binds microbial carbohydrates, opsonin

• 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

• Toll-like receptors
• Mannose receptors
• Scavenger receptors

• CARD-family sensors
• Nod-like sensors

• Neutrophils
• Macrophages
• Dendritic cells
• Natural killer cells
• Eosinophls, basophils, mast cells

• Circulate in the blood
• Precursors to Macrophages and some dendritic cells
• Can get recruited to the site of infection

• Found in the tissues
• Highly phagocytic
• Take up residence and become part of the tissue
• Antigen presentation

• 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

• 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

• IL-1beta
• TNF-alpha
• IL-6
• CXCL8
• IL-12

• Activates vascular endothelium
• Activates lymphocytes
• Local tissue destruction
• Increases access of effector cells

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

• Lymphocyte activation
• Increased antibody production

Chemotactic (chemical sensing) factor recruits neutrophils, basophils, and T cells to site of infection

• Activates NK cells
• Induces the differentiation of CD4 T cells into T_H1 cells

• 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

• 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 NF_kB mediated transcription

Infections of the blood

• 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

Recognize LPS (lipopolysaccharide) on gram negative bacteria

• Recognize flagellin

• Heterodimer
• Recognizes triacyl lypopeptides

Recognize diacyl lipopeptides

• 5
• 4
• 1:2
• 2:6

• 3
• 7
• 8
• 9

• 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. I_kB dissociates from NF_kB
• 7. NF_kB goes into nucleus > txn of genes for cytokines

• 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

• NOD
• RIG

• Recognize bacterial proteoglycans in cytoplasm (intracellular)
• Activates NF_kB through RICK protein

• Cytoplasmic receptor for viral DNA
• Activate IRF3
• Leads to expression of interferons

• 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

• Detect intracelluar pathogens
• Contain cytolytic graules
• Monitor cells for identification oas self
• Kills cells infected with certain viruses or stressed cells

• 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

Macrophages

• NK cells activate macrophages by releasing inteferon
• Macrophages secreted IL-12 that activate NK cells
• Positive feed back loop

• 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