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Imunologie seminář 1

Immunology. Imunologie seminář 1. J. Ochotná j.ochotna @seznam. cz. http://uia.fnplzen.cz/. Immune system. J. Ochotná. The main functions of the immune system Immune system belongs to the basic homeostatic mechanisms Defense Autotolerance Immune surveillance.

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Imunologie seminář 1

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  1. Immunology Imunologie seminář 1 J. Ochotná j.ochotna@seznam.cz

  2. http://uia.fnplzen.cz/

  3. Immune system J. Ochotná

  4. ThemainfunctionsoftheimmunesystemImmunesystembelongs to the basic homeostaticmechanismsDefenseAutotoleranceImmunesurveillance

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

  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)*antigen-antibodycomplexisreversible

  8. Typesofantigensaccording to antigen presentation1) thymusdependentantigens*more frequent, especiallyprotein Ag*forinductionofhumoralimmuneresponseisnecessarycooperationwith THcells*assistanceimplemented in theformofcytokinesproduced by THcells

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

  10. Superantigens*stimulatelymphocytespolyclonalyandmassively(5-20%)*massiveactivationof T lymphocytes (massivecytokinerelease) cancause 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*Moleculesoftheimmunesystem

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

  15. Secondarylymphoidtissuesandorgans * meeting placeofimmunocompetentcellswithAgspleen lymphnodesandtheirorganizedclusters (tonsils, appendix, Peyerpatches in theintestine MALT(mucousassociatedlymphoidtissue)

  16. Cellsoftheimmunesystem*developmentofredandwhitebloodcellsbeginatyolksack, thenhaematopoiesistravels to fetalliverandspleen (3 to 7 monthgestation), thenbone marrowhasthemainhematopoieticfunction*allbloodcellsarisefrom a pluripotent stem cell (CD 34)*haematopoiesisisregulated by cytokines

  17. Immunemechanisms

  18. Nonspecific (innate) immunemechanisms* non-adaptive, innate*evolutionarilyolder* no immunologicalmemory* in the presence ofpathogensreactquickly, in minutes (based on moleculesandcellswhich are in the body prepared in advance)*componentcellular– granulocytes (neutrophils, eosinophils, basophils), monocytes (macrophages, DC), NK cells, mast cellshumoral- complement, interferons, lectinsandotherserumproteins

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

  20. Phagocytosis

  21. Phagocytosis • = ability to absorbparticlesfromthesurroundingsProfessional phagocytes*protect the body by ingesting harmful foreign particles, bacteria, and dead cells*neutrophilicgranulocytes, monocytes, macrophagesand DC

  22. Professional phagocytes • granulocytes - defense againstextracellularpathogens - able to performeffectorfunctionsimmediatelymacrophages - removalofownapoptoticcells, defense againstcertainintracellularparasites, APC - fullyfunctionalafteractivation by cytokines (IFNg, TNF) Macrophage

  23. Themigrationofphagocytesin damagedandinfectedtissues7% ofperipheralneutrophilsandphagocytes93% neutrophilsandphagocytes in the bone marrow* in placeofdamagephagocytes are capturedon endothelium (due to inflammatorycytokineexpressionofadhesionmoleculesishigher)

  24. Phagocytosis*thefirstinteractionswithadhesionmoleculesslowsthemovementofneutrophils - roling*thenthereis a stronger link betweenendothelialcellsandleukocytesandsubsequentpenetrationbetweenendothelialcells to thetissue - diapedesis(orextravasation)*phagocytesdirecttheirmovementto thesiteofinflammation by chemokines(IL-8, MIP-1aandb, MCP-1, RANTES, C3a, C5a, bacterialproducts...)

  25. Receptors on phagocytesPAMPs(pathogenassociatedmolecularpatterns) PRR (pathogenrecognitionreceptors) * TLR receptors (bindsbacteriallipoproteins, lipopolysaccharides, bacterialDNA…) * mannose receptor* galactose receptor* CD14 (bindsbacterial LPS)* scavengerreceptors (bindphospholipids on thesurfaceofapoptoticcells)

  26. Opsonisation*enhancesphagocytosisofan antigen * antigen ismarkedwith opsonin*Opsonins- IgG, IgA, C3b, MBL, fibronectin, fibrinogen, CRP, SAP* Fcreceptorson phagocytes (recognizeantibodieslinked to surfaceofmicro-organism)* complementreceptors(forbinding C3b)

  27. Phagocytosis

  28. Degradationofingestedmaterial*fagosomefusionwithlysosomes - oxygen independent(lysozyme, defensines, serine proteases, myeloperoxidase, acidic pH…)*activationofmembrane NADPH oxidase- oxygen dependent(superoxide, hydrogen peroxide, hypochlorousacid)*productionofnitric oxide (NO) by macophages

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

  30. Neutrophils Neutrophils have three ways of attacking pathogen: phagocytosis, degranulation and the formation of NETs

  31. Complement

  32. Complement • * systemofabout30 serumandmembraneproteins* complementcomponentsare present in theserum 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…

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

  34. Complementactivation • * Alternativepathway* Clasialpathway* Lektinpathway

  35. Regulationofcomplementandprotectionofowncells • Activation of complement cascade is controlled by the plasma and membrane inhibitors. Anaphylatoxin inactivator DAF Protectin MCP

  36. Complementregulation • C1 inhibitor(C1-INH) – inhibits C1; if missing→ HAE • factor Iwith cofactors: MCP (membrane cofactor protein), CR1,factor H – C3b, C4b cleavage • DAF (decay-accelerating protein)-degradation of C3 and C5 convertase

  37. Complementregulation • factor S (vitronectin) – inhibitscomplex C5bC6 • CD 59(protectin) - preventsthepolymerizationof C9 • anaphylatoxininactivator(CPN)- inactivatesanafylatoxins (C3a, C4a, C5a)

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

  39. Basophilsand mast cellsandtheirimportance in immuneresponses

  40. Mast cells • Mucosal mast cells- in themucousmembranesofrespiratoryandgastrointestinaltract, participate in parasitosisandallergy • Connectivetissue mast cells- theconnectivetissue, in parasitosisandallergy are not participating

  41. Mast cell functions • Defense againstparasiticinfections • Responsiblefortheearly type ofhypersensitivity(allergicreaction) • Applyduringinflammation, in angiogenesis, in tissueremodeling • Regulationofimmune response

  42. Mast cell activation Mast cellsdegranulationcanbestimulated by: • Antigen orallergenthroughcross-linkingofIgEFcreceptors • anafylatoxins (C3a, C4a, C5a) • TLR

  43. Mast cell activation by cross-linkingofIgEFcreceptors • Establishingof multivalent antigen (multicellular parasite) to IgElinked to highaffinnityFc receptor forIgE(FcRI) • AggregationofseveralmoleculesFcRI • Initiate mast cell degranulation (cytoplasmicgranulesmergerswiththesurfacemembraneandreleasetheircontents) • Activationofarachidonicacidmetabolism (leukotriene C4, prostaglandin D2) • Productionofcytokines (TNF, TGF, IL-4, 5,6 ...)

  44. Activationschemaof mast cell

  45. Secretoryproductsof mast cells • Cytoplasmaticgranules: hydrolyticenzymes, heparin, chondroitin sulphate, histamine, serotonin • Arachidonicacidmetabolites(leukotriene C4, prostaglandin D2) • Cytokines(TNF, TGF , IL-4, 5,6 ...)

  46. Histamine • vasodilation • increasedvascular permeability • bronchoconstriction • increasesintestinalperistalsis • increasedmucussecretion

  47. Basophils • Differentiatefrommyeloidprecursor • Are verysimilar to mast cells by the receptor equipment, contentofgranules, themechanismsofstimulationandfunctions • Play role in inflammation, regulation of immune responses, in allergic reactions, they are responsible for the emergence of anaphylactic shock • In highnumbersatthesitesofectoparasiteinfection

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