Innate Response_1

Innate Response_1

1. Physical

   • Epithelia
     • Skin
       • Epidermis
         • Tightly packed & Keratin
           • Shedding
           • Waterproof
       • Dermis
         • Connective tissue & other functional components
     • Tight Junctions
   • Mucous Membranes
     • +
     • If infection
   • Secretions trap and wash away pathogens
     • Mucus clearing by cilia and coughing in respiratory tract
     • Mucus, tears, saliva, urine, milk, GI tract loss takes pathogens

2. Chemical

   • Acidic pH
     • Stomach, Vagina
   • Antimicrobial proteins, peptides
     • Surfactants --> collectins
   • Enzymes/enzymatic degradation
     • Lysozyme
       • Saliva, tears, respiratory tract

3. Phagocytes

   • Dendritic Cells (DCs)
     • Initiation of Adaptive Responses
       • T-Cell, B-Cell Activation
     • Engulfment and presentation via MHC
   • Neutrophils
   • Macrophages
     • Recognize PAMP/DAMP
       • Engulf
         • Phagosome forms and fuses with Lysosome
           • Degrade microbe (enzymatic, antimicrobial, ROS, RNS)
   • Pattern Recognition Receptors (PRRs)
     • Cytosolic
       • • Inside Lysosomes & Endosomes
       • RIG-I-Like Receptors (RLRs)
         • Recognize viral double stranded DNA
           • RNA helicases
           • IRF pathway
             • Interferons
           • NFkB
             • antimicrobials and inflammatory cytokines
       • Nod-Like Receptors (NLRs)
         • LRR
         • Nuclear Binding Domain (NBD)
         • activates caspase-1 protease
           • Cleaves IL-1/IL-18 into active forms
             • Inflammation
     • Surface
       • Toll-Like Receptors (TLRs)
         • Extracellular Leucine-Rich Repeats (LRRs)
           • forms dimers to bind P/DAMPs; capable of binding many P/DAMPs so location determines what it binds
             • Pathways
               • NFkB activation
                 • Inflammatory Cytokines, antimicrobials, Interferons
               • Interferon Regulating Factor (IRF) pathways
                 • Interferons
               • MAP Kinase Pathway
                 • AP-1 transcription
                   • Interferons
             • TIR domains
         • Membrane Spanning Protein
       • C-type Lectin Receptors (CLRs)
         • Recognize cell wall carbohydrates (mannose, fucose, glucans)
         • Phagocytosis, Innate, Inflammatory Responses
           • NFkB and AP-1
             • Inflammatory Cytokines, antimicrobials, Interferons
   • Cytokines/Chemokines secreted
     • Inflammatory Response
       • Redness
       • Heat
       • Swelling
       • Pain
       • increased vascular permeability and recruitment of immune cells
       • Acute Phase Responses (APRs) [induced by cytokines]
         • Liver increase output of MBL, C-reactive protein, complement
         • Out of Control Response
           • Severe Damage (Multiple Organ Failure) Leading to Death
           • Ongoing release of microbial toxins
           • No or little immune system regulatory activities
     • Soluble proteins, membrane bound proteins
       • 6 families
         • IL-1
           • proinflammatory; macro & DC; APRs; binds to heterodimer receptor
           • IL-1Ra ihibits
           • IL-18 redundancy
           • IL-33 affects T, B, mast, eosinophil
           • MyD88, IRAK, TAK1
             • AP-1, NFkB
               • Cytokines
         • Hematopoietin (Class I)
           • Secreted by many cells; 4 antiparallel helices;
             • Beta or FNIII domain
           • IL-2R
             • High affinity during activation
           • Beta chain subfamily
             • IL-3, IL-5, GM-CSF receptors
               • redundancy
           • GP130 subfamily
             • Monomeric (IL-6) and Dimeric (IL-12)
         • Interferon (Class II)
           • Anti-viral & modulators
           • Type I, II, III
             • II: heterodimers
               • JAK-STAT
         • Structures & Pathways
         • Tumor Necrosis Factor
           • IR Development, Effector, Homeostasis
           • TNF receptors
             • CRD in extracellular region
               • Fas/FasL --> FADD --> Caspase --> Apoptosis (shut down IR)
             • TNFR1
               • Caspase-8 VS cFLIP
         • IL-17
           • Pro-inflammatory
             • receptors on neutrophils, keratinocytes, non-lymphoid cells
             • NFkB, MAPK to stabilize mRNA, and C/EBP for IL-6
           • newest
           • 7 Receptors are 5 protein chains arranged in different ways
         • Chemokines
           • Chemoattractant; leuk. migration
           • small; conserved disulfide bonds;
           • 6 categories
           • G protein GTP
             • Ras/MAPK (AP-1), NFkB, Rho (movement), JAK/PKC (survival)
       • Released by one cell and bind to receptors on another cell to induce effect
         • Movement
         • Enzyme and transcription regulation
         • Survival or Death
         • Endocrine, Paracrine, Autocrine
         • Pleiotropy, Redundancy, Synergy, Antagonism, Cascade Induction
           • Effects occurring simultaneously determine strength of response
             • Cytokine binding
               • Chemokine receptors
               • Stimulated cells migrate
               • Upregulate receptors and proliferation of stimulated cells
       • Innate Response Cytokines
         • IL-1, TNFalpha, IL-12, IL-6, IFN-alpha, IFN-beta, CXCL8
       • Adaptive Response Cytokines
         • IL-2, IL-4, IL-5, IL-17, TGF-beta, IFN-gamma
       • Inhibition
         • Natural Inhibitors (IL-1Ra
         • Pathogen-derived Inhibitors
       • Over-response
         • Superantigens
           • Bacterial Toxic Shock
         • Myeloid, Lymphoid Cancers
         • H1N1 cytokine storms
         • Transplant
   • Membrane Opsonin Receptors
   • Pathogen Escape
     • Avoid detection by PRR
       • mutation/alteration in cell surface components
       • Inhibit PRR transcription
     • Block PRR signaling pathways
     • Prevent killing or replication inhibition
       • Rupture phagosome
       • Prevent phagosome fusion with lysosome

4. Spleen

   • Red pulp, white pulp, PALS

5. MALT, M cells

6. GALT

7. Natural Killer Cell

   • Direct destruction

8. Opsonins

   • MBL, Ficolins, C1

9. Basic Barrier Mechanism