Innate Immunity

Innate Immunity

1. 1st line defence

   • present @ birth
   • induces+ amplifies adaptive response
     • no memory of prior exposure
   • rapid

2. Innate immunity=0-4 hours

3. Early induced innate response=4-96 hours

4. properties + contrast with adaptive system

   • See slide 4-5

5. Anatomical Physical Barriers

   • see slide 7
   • Skin: Physical barrier- prevent pathogens /dehydration, surface- lactic acid + antimicrobial fatty acids- pH3-6, deeper layer- keratinocytes - produce IL-8 + TNF if damaged> inflammation
     • Epithelial cells - Slide 11
       • Tears/ Saliva -lysozyme- digests peptidoglycan components of bacterial cell walls. Phospholipase A- highly basic enzyme, hydrolyses phospholipids in cell membranes
         • Mucosal Surface-Internal epithelial (mucosal epithelial) secretes mucus contains mucins, protective layer of mucus over epithelia- pathogens coated in mucus prevented from adhering to surface. AIRWAY- mucociliary escalator- moves mucus + trapped particles 2 throat 2 swallow. STOMACH - mucus protects gastric mucosa from stomach acid Commensal bacteria + fungi inhabit mucosal surface- compete with pathogens 4 sites of attachment, some produce antimicrobial mols- e.g. lactic acid by vaginal lactobacili, but if allowed to over-grow can cause disease
       • Temperature/pH-bacteria optimum growth 20-25 degree C, 37 degree C=bacteriostatic 4 sum bacteria. Similarly 37-40 d C in fever also inhibits bacterial + viral infection

6. Soluble innate immune molecules

   • Enzymes e.g. Lysozyme + secretory phospholipase A2-disrupts bacterial cell walls,
   • Antimicrobial peptides- disrupt microbial membranes, secreted by mucosal epithelia + macrophages, 3 main types: defenins, cathelicidins, histatins
     • Lectins- bactericidal proteins, bind carbohydrates groups on pathogens + damage cell membrane
   • Complement components- lyse bacteria, opsonise bacteria, induce inflammation
     • Cytokines + chemokines- diverse collection of soluble proteins + peptides that modulate behaviour of cells at nM to pM concs (cansee S21)
     • Acute phase protein (APP) - ill defined set of proteins, increase in conc rapidly upon infection
       • C-reactive protein (CRP) binds to some bacteria via surface phospholipids and stimulates both phagocytosis + complement activation. /is a good marker of inflammation

7. Innate antigen recognition (PRRs and PAMPs

   • Pathogen associated molecular pattern 'PAMPs' - 'danger signals' . We possess molecules which have evolved 2 recognise + bind 2 such molecules (Pattern recognition receptors- PRRs) . 2 major groups 1) Toll-like receptors - often found on cell surfaces (in membranes) and 2) NOD- like receotirs- found often within the cell's cytoplasm
     • NOD- like receptors (NLRs) Large fam of cytosolic PRRs , activated by intracellular PAMPs, can sense changes in intracellular enviro . In contrast to TLRs , NLRs are located in cytoplasm of epithelial, macrophages, DCs. Recognise intracellular PAMP (more info S29)
   • see slide 27

8. Innate immune effector response

   • These are defenses the body uses no matter what the invader may be
     • phagocytosis
     • inflammation- caused by HISTAMINE release from LEUKOCYTES
       • Impinges on both innate + adaaptive systems, a local response to injury, important in recruitment of cells o immunity + repair to site of injury/infection. Largely cordinated by lymphocyte + lymphocyte traffic , gross characteristics= swelling, redness, heat & pain , see S39
       • Control of movement of white blood c (espesh neutrophils + lymphocytes across endothelium blood vessels = v important 4 process of inlammation , controlled by intracellular adhesion molecs (CAMS)
       • Mediators of inflammation, some small complement fragments act as inflammatory mediators. These fragments enhance blood supply 2 area in which they are released, by binding 2 receptors on endothelial cells inducing the small blood vessels and inducing an increase in capillary diameter. They also attract other cells to the site of tissue damage. THE CHEMOKINES- group of peptides responsible 4 coordination+ regulation of leukocyte adhesion, activation + attraction to areas of inflammation (CHEMOTAXIS), upregulated by no. chemokines involved in infection+ inflamamtion importantly g-interferon & TNF-a. Are TWO TYPES of chemokine:1) CC type 2) CXC type. These are produced by no. cell types + affect mostly leukocytes-espesh lymphocytes-via chemokine receptors
     • margination
     • diapedesis- (S39)
     • complement
       • refers 2 set of serum proteins that cooperates wiv innate + adaptive immune syst 2 eliminate blood + tissue pathogens . Complement proteins interact with 1anuva in catalyti cascades. Various complement components bind + opsonise bacteria, rendering them suceptible 2 receptor-mediated phagocytosis by macrophages, which express membrane receptors 4 complement proteins
         • series of ova 30 proteins that constantly circulate in blood + fluids that bathe the tissues
         • most made by liver also produced by monocytes + macrophages
         • Secreted as inactive enzymes known as zymogens (enzymes that must b modified in order 2b active)
         • Most of these r inactive until theyr cleaved by protease which in turn converts them in2 a protease by splitting the protein in2 small + large fragments. This pattern of sequential info produces expanding cascade of activity, when activated cooperate wiv other host defense systems 2 generate inflammation + rapidly remove patbogen (S57-58)
       • Complement inhibitors (S59)
       • complement deficiency (S60)
     • phagocyte migration
       • phagocytosis (S31-33)
         • What stimulates phagocytosis?1) -ve charged particulates-latex microspheres will b phagocytosed by macrophages 2) Opsonisation- coating of targets with antibody/ complement which is detected by phagocytes via receptors3) Pattern recognition molecules- recognise specific molecular patterns on bacterial membranes (e.g. toll-like receptors)
           • Intracellular killing pathways : O2 dependent, NO dependent, OTher indepdent- S37
     • fever

9. Cells of the Innate Immune System

   • Macrophages - derived from hematopoietic stem cells in bone marrow (S63), MONOCYTES migrates into the tissues and differentiate into macrophages. Monocytes: phagocytose microbes, differentiate into macrophages, present antgens to T-cells (bot of S64)
   • DENDRITIC CELLS- most POTENT antigen presenting cells, Interstitial Dc in most organs, Interdigitating DC in lymphoid tissue, circulating DC
     • Major type of Ag presenting cell (professional), presents antigen to T-cell receptor, different types depdent on body, location +origin e.g. Langerhans (skin), myeloid, lymphoid, Patrol major portals of pathogen entry – skin, GI tract, respiratory tract, GU tract, patrol blood + tissues, constantly saple enviro by pinocytosis + phagocytosis in search of Ag for T cells “immune survelliance”, express receptors (PRRs) for PAMPs, express receptors for chemokines released @ sites of acute inflammation L3 S57
     • L3 S54
   • Neutrophils- 50-50% of circulating white cells. Infection activates Cytokines that stimulate bone marrow 2 make 20million neutrophils per ml of blood. Neutrophils= active phagocytic cells, circulate in peripheral blood and migrate by EXTRAVASATION into tissues where have life span of few days. Neutrophils= attracted to tissues by CHEMOTACTIC FACTORS
   • Basophils/ Mast Cells
     • Basophils = in circulation, mast cells= in tissue, primary granules in these cells contain histamine + leukotrienes – released when stimulated wiv allergen, products of granules enhance inflammation, mast cells – fond in skin, connective + mucosal tissue, important role in devel of allergies.
       • mast cells in inflammatory response: Vasoactive amines released by MAST cells cause RELAXATION of smooth muscle in blood vessel walls, dilating blood veseels&increase bloodflow. Also promote loosening of connections b2wen blood vessel endothelial cells- producing leakage of serum in2 tissues- local oedema,
   • Eosinophils- granulocytes able 2 kill Ab-coated parasites through degranulation, involved in allergic reactions

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