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Fish- Cytokines.pdf

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Department
Immunology
Course
IMM250H1
Professor
Julius
Semester
Winter

Description
Fish-Cytokines Cytokine Structural Classes • 4α-helicalbundles • ○ Stable-loopsdeterminereceptorcontact ○ Shortchain  IL-2,IL-3,IL-5, GM-CSF, IFN-γ ○ LongChain  IL-6,IL-11, OSM, LIF,CNTF, G-CSF,IFN-α/γ,IL019,EPO • Longchain β-sheet ○ TNFfamilyofcytokines(TNF-α,CD40L,FASL,OPGL) ○ IL-1,FGF family ○ PDGFs,NGFs  Cysteineknots-3disulphidebridges • Shortchain α/β ○ EGF,insulin-related,IL-8 ○ ChemokineswithC-termαsegmentandβsheets ○ Insulin-relatedhaveconserved3disulphidebondslinking3short α-helices • Mosaicstructures ○ Mixture ○ IL-12heterodimer IL-12heterodimer  1subunitwithlong4α-helicalbundle  1subunitwithhaemopoietindomainreceptor ○ Hepatocytegrowthfactorheterodimer  1subunit"kringle"domain  1Subunitsharesidentitywithserineproteases Cytokine Signalling • 4differentJAKs ○ Kinasesinvolvedwithtyrosinephosphorylation • STATS ○ SignalTranduserandActivatorsofTranscription  Bindsasdimer  SH2serinephosphorylated SH2serinephosphorylated ○ OnceJAKsareactivethetyrosinephosporylatedsitesbecomedocksforSTATS ○ PhosphorylatedSTATSenternucleusfortranscriptionalactivation • CytokineReceptors ○ ClassI ○ ClassII  IFNs  IL-10related  FVIIa ○ Sharedreceptorsubunitsusuallymeansimilarsignallingevents ○ Receptorshavespecificalphareceptor ○ Betacommonsubunitmeanssimilaroverlappingfunctions Tcell activation Th1 Th2 Treg Th17 Th9 Th22 IFN-γ IL-4,IL-5 Suppression IL-17A/F,IL-6 IL-9 IL-22,IL-13, TNF Intracellular Parasitic Autoimmunity Inflammation& Skinpathology pathogens Allergy allergy • Tolerance-promoting ○ TGFβ ○ IL-2  IL-2.Ig,IL-2/anti-IL-2complex ○ Retinoicacid ○ IL-10 ○ AAT,anti-IL-6,anti-TNFα • Rejectionpromoting ○ Ischemia-reperfusion ○ Infection ○ IL-6 ○ TNFα ○ IL-1β ○ IL-12 • EffectorThelpercell(CD4) ○ Th1: cellularimmunity ○ Th2: Humoralimmunity ○ Th17: IL-17and proinflammation 1. APCactivatedbypathogen • ImmunogenicvsRegulatoryDC 2. TCRrecognizespathogen-activation • IL-12production • IL-12Rβ2expressiononTcells 3. APCIL-12initatesTh1development • IL-12acts viaSTAT4 □ UpregulatesIFN-γ 4. IFN-γrequired-activatesSTAT1 • TranscriptionofT-bet □ MajorTh1 commitmentfactor □ TransactivatesIFN-γandchromatinremodellingthere 5. IL-12inducesIL-18Rexpression • IL-18synergizewithIL-12increaseIFN-γ • IFN-γnegativelyregulatesTh2linage ○ RequiresabundantpathogenonMHCClassII withhighaffinity ○ LowaffinityorextracellularresultsinTh2 • IL-4 • IL-10 • HellminthsandallergenspromotesTh2lineage ○ TGF-βpolarizetowardsregulatory • InabsenceofinfectionDCsecretionthis ○ Proinflammaotry(IL-6IL-23)forTh17 (FromearlyinfectionDC) • IL-17 • Solublereceptorscanactas decoy ○ NaïveTcellsdonotrespondtoIL-12 becauseitisonlyexpressedaftersignallingevent IL-1 • Macrophages-CofactorforT/B cellactivation • Centralmediatorofinflammation ○ Hematopoiesis ○ Fever ○ Bonbreakdown ○ Neutrophils,vascularendothelial,proteinrelease,muscleproteolysis,cytokins • IL-1α,IL-1β,IL-1ra ○ IL-1αandIL-1ß are agonists ○ IL-1rais an antagonist • IL-1Receptors ○ TypeIR(IL-1RI) • MediatesallIL-1responses • Cytoplasmicdomainforsignalling • NFkBandMAP kinase • IL1ra >IL1α > IL-β ○ TypeIIR(IL-1RII) • Differenttransmembraneandcytoplasmicdomains • Notsignallingreceptor • Notsignallingreceptor • NegativeregulatorofIL-1β • SolubleveryeffectivenegregulatorofIL-1β • SecretionofsIL01RIIleadstoselectiveresponsetoIL-1α • L-1β> IL-1ra= IL-1α IL-2 • 4αhelicalbundle • ClonalexpansionofTcells • Tcelldifferentiationfactor-inductionofIFN-γandIL-4 • SomeBcellsandNKcellsalsorespond • IL-2R ○ X-linkedSCIDmappedtoIL-2Rγ ○ α,β,γ subunits ○ RestingTcellsdon'tproduceIL-2 ○ βand γ alwaysexpressed ○ α(CD25) inducible ○ RestingNKonlylymphocytethatreliesononly β+γ IL-2Rs forproliferation ○ BcellsrespondtoIL-2mediatedbyhighaffinityreceptors • Threesubunitsmustcontactforhighaffinity □ N-termαhelix:IL-2Rβ(Intermediateaffinity) □ InterloopofA-Bhelices:IL-2Rα(Lowaffinity) □ C-termDhelix:IL-2Rγ • EachIL-2R must haveγ receptor Interferons (IFN) Dendritic Cells (DC) and Pathogen Clearance Interferons • TypeI ○ IFNA-R1/2c ○ Dimer ○ IFN-α,β,etc. • TypeII ○ IFN-γR1/2 ○ Tetramer • Dimericbinding-JAK2STAT1 ○ OnlybindsIFN-γ • TypeIII ○ IFNλ-R1,IL-10R2 ○ Dimer ○ IFN-λ(IL-28A/B,IL-29) TypeI TypeII TypeIII TypeI TypeII TypeIII IFN-α IFN-β IFN-γ IFN-λ PlasmicDC PlasmicDC Macrophages PlasmicDC Epithelial Epiethlial Tlymphocytes Epithlial Firboblasts Fibroblasts Leukocytes Leukocytes Macrophages Macrophages dsDNA dsDNA Antigens Viruses Viruses Viruses Mitogens TLR TLR TLR IL-2,IL-12 Inhibitviral Inhibitviral Inhibitviral Antiviralprotection IncreaseMHCI/II IncreaseMHCI Enhancemacrophage NK,Th1,APC,apoptosis NK MHC I/II IncreaseTh1 DelayedNKactivation IFNAR1/2 IFNAR1/2 IFN-γ1/2 IFN-λR1,IL-10R2 ○ Bothαand β forantibacterialresponses ○ STAT1 through5allcan berecruited ○ ISGF:Interferonsensitivegenefactor3 ○ ISRE:Interferonsensitiveresponseelement ○ FirstlineofcytokinesproducedinresponsetoanyviralrecognitionistypeIIFN VirusenterscellandactivatesTLRtocreateIFN-β ○ VirusenterscellandactivatesTLRtocreateIFN-β ○ IFN-βbindstoitsreceptoronneighboursandturnsonIFN-α ○ Bothactivateimmunecells Protein ActivatingReceptor Genedisruption Stat1 IFN-α/β,IFN-γ,IL-10 Lackof Antimicrobialdefenses IL-6,IL-11, OSM, LIF,CNTF IL-2,IL-7,IL-9 GH,PRL, G-CSF EGF,PDGF, CSF-1 RANTES,MIP-1α Stat2 IFN-α/α Lackof Antimicrobialdefenses Stat3 IFN-α,IL-10 Embryoniclethality IL-6,IL-11OSM, LIF, CNTF,leptin IL-12 IL-2,IL-7,IL-9 GH,G-CSF EGF,PDGF RANTES,MIP-1α Stat4 IL-12 LackTh1 differentiation Stat5a/b IFN-α,IL-10 a:Lack ofmammaryglanddevelopmentandlactogenesis IL-2,IL-7,IL-9, IL-15 b:Lack of GHfunction IL-3,IL-5,GM-CSF a/b:Lack ofproliferationresponsestoIL-2inTcells EPO,GH, PRL,G-CSF Leptin Stat6 IL-4,IL-13 Lackof Th2differentiation Tyk2 IFN-α/β,IL10 IFN-αresponsiveonlyathighlevels IL-6 IL-12inducedTcellfunctiondefective IL-12 NodefectsinIL-6orIL-10 Jak1 IFN-α/ß,IFN-γ Perinatallethal IL-6,IL-11, OSM, LIF,CNTF G-CSF IL-2,IL-4,IL-7, IL-9, IL-13, IL-15 EGF,PDGF, CSF-1 Jak2 IFN-γ embryoniclethal IL-6,OSM, LIF,CNTF,leptin IL-12 IL-3,IL-5,GM-CSF EPO,GH, PRL,G-CSF EGF,PDGF, CSF-1 Jak3 IL-2,IL-4,IL-7, IL-9, IL-15 autosomalSCID
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