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Define parenchyma/stroma
- Parenchyma: Main functional cell type within a tissue eg hepatoctes in liver
- Stroma: connective tissue/nerve/adipose
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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
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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
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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
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2 death pathways and caspases involved
- mitochondrial: BCL2
- death receptor: Fas, TNF
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Which antibacterial peptides are present in the lung?
Defensins: present in surfactant, but inactivated in high salt conditions of CF
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Name 7+ initial barriers to infection
Skin (with keratin, squamous epithelium), mucous, cilia, flow of air/fluid, peptides, enzymes (pepsin, defensin, lysozyme), commensals
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Inflammation a response to what 2 things?
- Microbial infection
- Tissue injury (can be sterile)
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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]
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What process generates leukocytes in bone marrow in adults?
Haematopoesis
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Lymphoid lineage gives rise to:
B, T, NK cells
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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
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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
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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
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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
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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
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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
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How do host cells escape complement activation?
Regulatory proteins DAF (decay accelerating factor) and MCP (membrane cofactor protein)
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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
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2 ways of pathogen destruction once inside phagolysosome
- O2 dependent: ROS production
- O2 independent: enzymes eg lactoferrin, antimicrobial peptides
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Innate immune cells with Fc receptors
- Neutrophils
- Macrophages
- Eosinophils
- NK cells
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2 features of cytokine system
- Pleiotropism (1 cytokine can have many effects)
- Redundancy (functions of 1 cytokine can be performed by many others)
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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
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2 Lipid inflammatory mediators
- Arachidonic acid: metabolism to prostaglandins and leukotrienes
- Platelet activating factor: recruits and activates cells inc neutrophils and eosinophils
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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)
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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)
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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
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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)
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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
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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
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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
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2 APPs. Which cytokine induces them?
- MBL and CRP (both involved in complement activation)
- Induced by IL-6, produced by macrophages
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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
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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
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NK cells activated by
Type 1 IFN (alpha and beta) from virally infected cells
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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
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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
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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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