innate immunity

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Author:
mfawcett
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187526
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innate immunity
Updated:
2012-12-06 08:52:30
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innate immunity immune bod pathology
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Innate immunity
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  1. Define parenchyma/stroma
    • Parenchyma: Main functional cell type within a tissue eg hepatoctes in liver
    • Stroma: connective tissue/nerve/adipose
  2. Reversible cell injury
    • Fatty change: accumulation of lipid droplets in cytoplasm
    • Due to disruption of aerobic glycolysis and beta-oxidation of fat, meaning that fatty acids are not broken down and glycerol is esterified to form triglycerides
  3. Necrosis
    • Karyolysis: complete dissolution of the chromatin matter of a dying cell due to the activity of DNase � nucleus disappears
    • Proteins denature ('coagulative necrosis')� cytoplasm becomes more eosinophilic
  4. Cytological changes of apoptosis
    • Cell shrinkage
    • Loss of cell-to-cell contact
    • Condensation of chromatin at periphery of nucleus
    • Nuclei are pyknotic: smaller, denser, strongly basophilic
    • Karyorrhexis: nuclear fragmentation
  5. 2 death pathways and caspases involved
    • mitochondrial: BCL2
    • death receptor: Fas, TNF
  6. Which antibacterial peptides are present in the lung?
    Defensins: present in surfactant, but inactivated in high salt conditions of CF
  7. Name 7+ initial barriers to infection
    Skin (with keratin, squamous epithelium), mucous, cilia, flow of air/fluid, peptides, enzymes (pepsin, defensin, lysozyme), commensals
  8. Inflammation a response to what 2 things?
    • Microbial infection
    • Tissue injury (can be sterile)
  9. 5 stages of innate inflammatory response
    • 1) recognition of infection by PRRs
    • 2) vascular response to injury: acute inflammatory exudate
    • 3) elimination of pathogen
    • 4) resolution of inflammation, repair, return to homeostasis
    • 5) [induction of adaptive response via DCs]
  10. What process generates leukocytes in bone marrow in adults?
    Haematopoesis
  11. Lymphoid lineage gives rise to:
    B, T, NK cells
  12. Myeloid lineage gives rise to:
    • 1) Granulocytic: neutrophils, eosinophils, basophils
    • 2) Myelomonocytic: monocytes, macrophages, dendritic cells, mast cells
    • 4 functions of complement
    • Opsonisation
    • Lysis of target cells
    • Activation of inflammation (C3a and C5a are anaphylotoxins)
    • Clearance of immune complexes (C1 binds antibody-bound antigen; C3 binds to antigen, transported to liver via erythrocytes
  13. Outline alternative pathway
    • C3: spontaneous tickover hydrolysis to C3a and C3b (cleavage of thioester bond)
    • C3b is either bound to H20 or to pathogen surface (via LPS etc, or just not inhibited by DAF and MCP on host cells)
    • Factor B binds and is cleaved by Factor D to Ba and Bb
    • Ba is released
    • C3Bb is stabilised by Properdin (serum protein)
    • C3bBbP is a C3 convertase and cleaves more C3
  14. Outline classical pathway
    • C1q attaches to pathogen (directly, via CRP (binds to phosphocholine component of LPS), or via Fc of IgM and IgG)
    • Proteases C1r and C1s bind
    • C1 is involved with cleaving C2 to form C4b2a
  15. Outline lectin pathway
    • MBL (an APP) forms oligomers with mannose and fucose residues on pathogen carbohydrates
    • MASPs (MBL associated serine proteases) associate and are activated
    • C4 and C2 are activated
    • C4b2a is a C3 convertase
  16. Describe MAC, inc inhibitor
    • C5b binds with C6, C7, C8 and hydrophobic regions are exposed and bind to pathogen cell membrane
    • C9 polymerises to form a pore: lysis
    • CD59: binds to assembling MAC, prevents recruitment of C9 to form pore
  17. diseases associated with MAC (or lack of)
    • Lack of MAC: gonorrhoea, meningitis caused by Neissera
    • Lack of CD59: RBCs lysed by complement: paroxysmal nocturnal haemoglobinuria
  18. How do host cells escape complement activation?
    Regulatory proteins DAF (decay accelerating factor) and MCP (membrane cofactor protein)
  19. Anaphylotoxin mechanisms of complement
    • C3a and C5a
    • Vascular: increase permeability, upregulate endothelial cell adhesion molecules, increase smooth muscle contraction
    • Degranulation of mast cells: histamine release
  20. 2 ways of pathogen destruction once inside phagolysosome
    • O2 dependent: ROS production
    • O2 independent: enzymes eg lactoferrin, antimicrobial peptides
  21. Innate immune cells with Fc receptors
    • Neutrophils
    • Macrophages
    • Eosinophils
    • NK cells
  22. 2 features of cytokine system
    • Pleiotropism (1 cytokine can have many effects)
    • Redundancy (functions of 1 cytokine can be performed by many others)
  23. 3 Inter-related soluble protein systems
    • Kinin: bradykinin is an inflammatory mediator � vasoactive basic peptide
    • Clotting: makes thrombin: produces insoluble strands of fibrin to produce a clot
    • Fibrinolytic: breaks down clot
  24. 2 Lipid inflammatory mediators
    • Arachidonic acid: metabolism to prostaglandins and leukotrienes
    • Platelet activating factor: recruits and activates cells inc neutrophils and eosinophils
  25. Effects of TLR activation
    • Dendritic cell activation
    • adaptor molecules recruited eg MyD88 (in mice) � activates transcription factor NK-kB (involved in immunity eg upregulates genes involved in T cell development, maturation and proliferation
    • Acute inflammatory exudate (via inflammatory cytokine release, Type 1 IFN, chemokines, antimicrobial peptides)
  26. Examples of TLRs
    • TLR4: expressed on macrophages, specific for bacterial LPS on Gram-negative bacteria
    • TLR3: ds viral RNA (deficiency � susceptibilty to Herpes encephalitis)
    • TLR7: ss viral RNA (HIV)
    • TLR8: ss viral RNA (influenza)
  27. 2 PRRs other than TLRs
    • cytosolic NLR (NOD-like receptors): some sense stress and form inflammasomes: activate caspase 1 and release mature IL-1beta (induces E-selectin) from its proprotein
    • CLR (C-type lectin receptors): important in fungal infection
  28. 4 Endogenous ligands for PRR
    • Self RNA/DNA in endosome (TLR7 and TLR9): auto-immunity
    • HSPs (heat shock proteins) and matrix components released from dying cells
    • Oxidised LDL: TLR4/6 (atherosclerosis)
    • Gout associated uric acid crystals (activate the inflammasome)
  29. 3 features of recruitment of AIE
    • dilation of blood vessels: increased blood flow, heat
    • increased vascular permeability: proteins � osmotic pull, fibrin � web to contain infection
    • leukocyte emigration
  30. Outline leukocyte recruitment
    • P selectin induced by histamine and thrombin
    • E selectin induced by TNFalpha and IL-1 (from macrophages)
    • Sialyl Lewis X glycoprotein on Neutrophils weakly binds to E selectin
    • Chemokines from macrophages activate LFA-1 on Neutrophils
    • Cytokines from macrophages induce high affinity state of ICAM-1 on endothelial cells
    • Activated LFA-1 binds to ICAM-1
    • Diapedesis occurs
    • Neutrophils migrate to infection site via chemokines eg CXCL8 (aka IL8)
    • Over time, cytokines induce V-CAM on endothelial cells, which binds to VLA-4 on monocytes
  31. Pro-inflammatory cytokines secreted by macrophages
    • IL-6: fever, induces APP activation
    • TNFalpha: increases vascular permeability, fever
    • IL-1B: activates vascular endothelium and lymphocytes, local tissue destruction, increases access of effector cells, fever
    • IL-12: activates NK cells
  32. 2 APPs. Which cytokine induces them?
    • MBL and CRP (both involved in complement activation)
    • Induced by IL-6, produced by macrophages
  33. 3 components of granulation tissue
    • macrophages: phagocytosis (debris, apoptotic cells, RBCs, dead organisms etc) and secretion
    • fibroblasts: recruited by FGF from macrophages; induced to increase collagen and ECM protein formation
    • angiogenesis: stimulated by VEGF from macrophages
  34. Factors secreted by macrophage in granulation tissue
    • ROS and NO: killing microbes
    • VEGF: angiogenesis
    • FGF: recruits fibroblasts � scar
    • Cytokines inc IL-12, TNFalpha: inflammation, enhanced adaptive immunity
    • Increased MHC: enhanced antigen presentation, induction of adaptive immune response
  35. NK cells activated by
    Type 1 IFN (alpha and beta) from virally infected cells
  36. 3 NK cell functions
    • Release perforin: form pores: granzymes can enter cell: lysis
    • Bind Fc: ADCC
    • Produce cytokines eg IFNgamma: activate macrophages, help to initiate adaptive immune responses
  37. NK cell activation/inhibition at cells
    • Usually inhibited by self MHC Class 1 (all nucleated cells)
    • Missing self � downregulated by viruses
    • Induced self: stress due to infection/DNA damage causes upregulation of activating factors
  38. What are KIR?
    • Killer Immunoglobulin-Like Receptors (family of genes of NK receptors)
    • Inhibitory and Activating forms
    • Polymorphic (as with HLA): genotypes associated with susceptibilty to HIV, Hep C, auto-immune diseases
    • KIR on uterine NK cells can bind to paternal HLA molecules on placental cells of foetus

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