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http://uia.fnplzen.cz/

http://uia.fnplzen.cz/. Immune system. J. Ochotná.

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  1. http://uia.fnplzen.cz/

  2. Immune system J. Ochotná

  3. ThemainfunctionsoftheimmunesystemImmunesystembelongs to the basic homeostaticmechanismsDefense - identificationandprotectionagainstpathogenicmicroorganismsandtheirtoxinsAutotolerance – recognitionofowntissuesandkeeping tolerance to themImmunesurveillance- identifyingandremovingtheold , damagedandotherwisechangedcells

  4. Antigen (immunogen)* substance thatcaninduce a humoral and/or cell-mediated immune response*predominantlyproteinsorpolysaccharides*molecules >5 kDa* optimalsizeof antigen isabout 40 kDa

  5. * autoantigen- antigen derivedfrom his own body *exoantigen - alien substance fromtheexternalenvironment *allergen - exoantigenthat in susceptibleindividualsmay cause pathological (allergic) immune response

  6. Haptens*smallmolecules, that are able to inducespecificimmune response onlyafterthe establishment to themacromolecularcarrier (separatehaptens are not immunogenic) *typicallydrugs (eg penicillinantibiotics, hydralazin)

  7. Interaction antigen – antibody*Bindingsiteofantibody(paratop) form non-covalentcomplexeswiththecorresponding part on antigen molecule(epitope)*participation: thehydrogenbonds, electrostaticandhydrophobicinteractions, van der Waalsforces* antigen-antibodycomplexisreversible

  8. Typesofantigensaccording to antigen presentation1) thymusdependentantigens*more frequent, especiallyprotein Ag*forinductionofhumoralimmune response isnecessarycooperationwith THlymphocytes(or response isn´t enougheffective)*assistanceimplemented in theformofcytokinesproduced by THlymphocytes

  9. Typesofantigensaccording to antigen presentation2) thymus independent antigens*caninduceantibodiesproductiondirectlywithouttheparticipationof T lymphocytes*mainlybacterialpolysaccharides, lipopolysaccharidesand polymer formsofproteins(e.g. Haemophilus, Str.pneumoniae)

  10. Superantigens*stimulatelymphocytespolyclonalyandmassively(5-25%)*massiveactivationof T lymphocytescan cause shock*e.g. bacterialtoxins (Staph.aureus, Str.pyogenes, Pseud.aeruginosa)

  11. Sequesteredantigens*autoantigensthat are normallyhiddenfromtheimmunesystemandthereforeunknow (e.g. thelensoftheeye , testes, brain)*ifthey are "uncovered" by demage, caninducetheimmune response (oneofthetheoriesofautoimmuneprocesses)

  12. Componentsoftheimmunesystem

  13. Componentsoftheimmunesystem*Lymphoidtissuesandorgans*Cellsoftheimmunesystem*MoleculesoftheimmunesystemComponentsoftheimmunesystem*Lymphoidtissuesandorgans*Cellsoftheimmunesystem*Moleculesoftheimmunesystem

  14. Lymphoidtissuesandorgans* are linkedwiththeotherorgansandtissues by network oflymphaticandbloodvesselsPrimarylymphoidtissuesandorgans*bone marrow, thymus*maturationanddifferentiationofimmunocompetentcells*immaturelymphocytesacquireheretheirantigenic specificity

  15. Bone marrow

  16. Thymus

  17. Secondarylymphoidtissuesandorgans* meeting placeofimmunocompetentcellswithAgspleen - in contrast to thelymphnodesfilterthebloodandcapturespresentedantigenslymphnodesandtheirorganizedclusters (tonsils, appendix, Peyerpatches in theintestine) - filterlymphandcapturepresentantigensMALT(mucousassociatedlymphoidtissue) - diffuselymphatictissue, themain role iscaptureofantigensthatpenetratethroughthemucousmembrane

  18. Secondarylymphoidtissuesandorgans

  19. Lymphoidtissuesandorgans

  20. Cellsoftheimmunesystem*developmentofredandwhitebloodcellsbeginatyolksack, thenhaematopoiesistravels to fetal liver andspleen (3 to 7 monthgestation), bone marrow has themainhematopoieticfunction*allbloodcellsarisefrom a pluripotent stem cell (CD 34)* stem cellsself-renewandmaintainthroughoutlife*haematopoiesisisregulated by cytokinesthat are secreted by bone marrowstromalcells, activated THcellsandmacrophages

  21. Immunemechanisms

  22. Nonspecificimmunemechanisms* non-adaptive, innate*evolutionarilyolder* no immunologicalmemory* in the presence ofpathogensreactquickly, in minutes (based on moleculesandcellswhich are in the body prepared in advance)*componentcellular - phagocytes (some are APC), NK cellshumoral- complement, interferons, lectinsandotherserumproteins

  23. Specificimmunemechanisms*adaptive, antigen-specific*evolutionarilyyounger*haveimmunologicalmemory*developmentof a full-specificimmune response takesseveraldaysevenweeks*componentcellular- T lymphocytes (TCR)humoral- antibodies

  24. Phagocytosis

  25. Phagocytosis= ability to absorbparticlesfromthesurroundingsProfessional phagocytes*cells, whichprovidedefenses by mechanismofphagocytosis*neutrophilicandeosinophilicgranulocytes, monocytesandmacrophagesgranulocytes - defense againstextracellularpathogens - able to performeffectorfunctionsimmediately - neutrophils don´t express MHCgpII (not APC)macrophages - removalofownapoptoticcells, defense againstcertainintracellularparasites - fullyfunctionalafteractivation by cytokines (IFNg, TNF)

  26. Themigrationofphagocytesin damagedandinfectedtissues7% ofperipheralneutrophilsandphagocytes93% neutrophilsandphagocytes in the bone marrow*this ratio changesdue to inflammatorycytokinesandbacterialproducts* in placeofdamage are capturedphagocytesto endothelium (due to inflammatorycytokineexpressionofadhesionmoleculesishigher)

  27. *thefirstisinteractionsslowsthemovementofneutrophils - calledroling*thenthereis a stronger link betweenendothelialcellsandleukocytesandsubsequentpenetrationbetweenendothelialcells to thetissue - diapedesis , extravasation*phagocytes are directed to thesiteofinflammation by chemokines(IL-8, MIP-1aandb, MCP-1, RANTES, C3a, C5a, bacterialproducts...)

  28. Receptors on phagocytesPAMPs- "pathogenassociatedmolecularpatterns„ - structuresthat are located on thesurfaceofmicroorganisms, but not on theirownintactcells* mannose receptor* galactose receptor* CD14 (bindsbacterial LPS)* TLR receptors(bindsbacteriallipoproteins, lipopolysaccharides, bacterialDNA)* scavengerreceptors (bindphospholipids on thesurfaceofapoptoticcells)

  29. Opsonisation*is the process by which a pathogen is marked for ingestion and destruction by phagocyte *Opsonins- IgG, IgA, C3b, MBL, fibronectin, fibrinogen, CRP, SAP* Fcreceptors on phagocytes (recognizeantibodieslinked to surfaceofmicro-organism)* complementreceptors (forbinding C3b)

  30. Phagocytosis

  31. Liquidationofabsorbedorganism*fagosomefusionwithlysosomes*activationofmembrane NADPH oxidase*productionofnitric oxide (NO)

  32. Fagosomefusionwithlysosomes * bactericidalsubstances (defensins) * hydrolyticenzymes (cathepsin, lysozyme) * liquidwith a pH of 4-5

  33. activationofmembrane NADPH oxidase * activationofFcreceptorsandcomplementreceptorsleads torespiratory (oxidative) flash * oxygen intermediates (superoxidradical O2-, singlet oxygen, hydrogen peroxide, hydroxyl radical) → damageofthepathogen

  34. productionofnitric oxide (NO) * macrophagesproduce NO afteractivationwithcytokines (IFNg, TNF) that are produced by TH1 lymphocytes * NO liquidateintracellularparasitesofmacrophages

  35. Secretoryproductsofphagocytes* IL-1, 6, TNF (systemic response to inflammation)* IL-8 (chemokine)* IL-3, GM-CSF (controlhaematopoiesis)* TGFa, TGFb(tissueregeneration)* metabolicproductsofarachidonicacid (prostaglandins, prostacyclin, leukotrienesandthromboxanes)

  36. Complement

  37. Complement* systemofabout 30 serumandmembraneproteins (humoralcomponentofnonspecificimmunity)* complementcomponents in serum are present in inactiveform* complementactivation has cascadecharacter* complementproteins are synthesized in the liver, less by tissuemacrophagesandfibroblasts* themaincomplementcomponents: C1-C9 (C3 isthecentralcomponent)* othercomplementcomponents: factor B, factor D, factor P* regulatoryproteins: C1 - inhibitor, factor I, factor H, DAF, MCP, CR1, CD59 (protektin) inactivatorofanafylatoxin

  38. Complementfunctions* Opsonization (C3b)* Chemotaxis (C3a, C5a)* Osmoticlysis (MAC C5b-C9)* Anafylatoxins (C3a, C4a, C5a)

  39. Complementactivation* Alternativepathway* Clasialpathway* Lektinpathway

  40. Alternativepathway* C3 componentofcomplementspontaneouslybreaksinto C3b and C3a* C3b cancovalentlybind on thesurfaceofmicroorganism* to bound C3b join a factor B, whichiscleaved by factor D to Ba andBb, resultingcomplex C3bBb isstabilized by factor P andfunctions as analternative C3 convertase* C3 convertasecleaves C3 to C3a (chemotacticforphagocytes) and C3b, whichbinds to thesurfaceofthemicroorganism (opsonization), orgivesrise to other C3 convertases* fromsome C3 convertasesform C3bBbC3b thatact asanalternative C5 convertase, whichcleaves C5 to C5a (chemotaxis) and C5b (startsterminallyticphase)

  41. Classicalpathway* Canbeinitiated by antibodies (IgG, not by IgG4; IgM)orso-calledpentraxins (CRP, SAP - acutephaseproteins)* afterbindingofantibodies to thebacteriasurface, thereis a change in itsconformationand C1 protein canbind* C1 have to bind to the 2 moleculesofantibodies, changetheirconformationandgetproteolyticactivity - willcleaveproteins C4 and C2* fragments C4b and C2a bind to thesurfaceoforganismandcreatetheclassic C3 convertase(C4bC2a), whichcleaves C3 to C3a and C3b* thencreates a classic C5 convertase(C4bC2aC3b) thatcleaves C5 to C5a and C5b

  42. Lectinpathway* isinitiated by serummannosebindinglectin (MBL)* MBLbinds to manose, glucoseorothersugars on thesurfaceofsomemicrobes, afterthebindinsstartscleave C4 andC2* thiswayissimilar to theclassicalpathway

  43. Terminal (lytic) phaseofthecomplementcascadeC5b fragmentscreates a complexwith C6, C7 and C8, thecomplex dive intothe lipid membraneofthe cell andattached to itinto a circle 13-18 moleculesof C9, thuscreateporesin themembraneandcell canlysis (G-bacteria, protozoans, someviruses). Most microorganismsisresistant to thislyticeffectofcomplement(protection by cell wall).

  44. ComplementregulationandprotectionofowncellsActivationofcomplementcascadeiscontrolled by serumandmembraneinhibitors.* C1 inhibitor* DAF (decay-accelerating protein)-degradationof C3 convertase* factor I, MCP (membranecofactor protein), CR1, factor H – C3b cleavage* CD 59 (protectin) - preventsthepolymerizationof C9 * anafylatoxininactivator- inactivatesanafylatoxins (C3a, C4a, C5a)

  45. Complementreceptors* BindfragmentsofcomplementcomponentsCR1 - on variouscells - removingofimmunecomplexesCR2 - on B lymphocytesand FDC- activationof B cellsCR3, CR4 - on phagocytes- participation in opsonization, adhesion

  46. NK cellsInterferons

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