obligateanaerobes近畿大學(xué)醫(yī)學(xué)部

obligateanaerobes近畿大學(xué)醫(yī)學(xué)部第1頁/共66頁MarchtoJuly2009,Emerginginfectiousdiseaseidentifiedastheseverefeverwiththrombocytopeniasyndrome(SFTS)inruralcentralChina.Causewasunknown.Majorclinicalsymptomsincludedfever,thrombocytopenia,gastrointestinalsymptoms,andleukocytopenia;highinitialcasefatalityrateof30%Multi-organfailuredevelopedRAPIDLY—elevatedserumalanineaminotransferase,aspartateaminotransferase,creatinekinase,lactatedehyrogenase;proteinuria,hematuria.FromDr.O’CallaghanVirologyJournalClubApril29,2011第2頁/共66頁Genus

HumandiseaseOrthobunyavirusLaCrosseencephalitis,Californiaencephalitis

Phlebovirus RiftValleyfever(RVF)Nairovirus Crimean-Congohemorrhagicfever(CCHF)Hantavirus Hemorrhagicfeverwithrenalsyndrome(HFRS)

Hantaviruspulmonarysyndrome(HPS)Tospovirus Plantvirus,noknownhumandisease5generaFamilyBunyaviridaeEncephalitisHemorrhagicFeverPneumonia第3頁/共66頁BUNYAVIRIDAE;BunyamwerainUgandaVirion:ENV,120nm;3Helicalcapsids;three1XRNAs5Genera.2generahaveambisenseRNAs;Phelbovirus&TospovirusTospovirusgenus=tomatospottedwiltvirusM&SRNAsareambisense.NSm34Kprotein=movement.Formstubulesthatpenetratethruplasmadesmatasocapsidscanenterneighboringcell.NSs52Kproteinbinds2XRNAthatcangeneratesiRNAs.TransmittedbyTHIRPSInfectstomato,peanuts,watermelon,zucchini,impatiensS+MRNAs=ambiCaliforniaSinNombreCCHFRiftValleyDr.O’CallaghanJournalClub4/20/12第4頁/共66頁Hantavirus(HFRScontactwithrodents)Nairovirus(CCHF-tick)Orthobunyavirus(LACmosquito)Phlebovirus(RiftValleyFever;mosquito)Tospovirus(Tomatospottedwilt;thrips)PHLEBOVIRUS:68serotypes.

TwoGroups:

1.PhlebotomusFeverGroup55(sandflies)2.UukuniemiGroup13(ticks)

EightmemberslinkedtodiseasehumansAlenquer Chaniru ChagresNaples PuntaToro RiftValleyFever Sicilian ToscanaSFTSVirusisnewGROUPofPHLBOVIRUSGenus.9thPhlebovirustocausediseaseinhumansFromDr.O’CallaghanVirologyJournalClubApril29,2011thripsTheseleavesshowsymptomsoftomatospottedleafvirus./KathieRowell/TheTimesMay12,2011第5頁/共66頁109-A38血球貪食癥候群Hemophagocyticsyndrome（HPS)血球貪食性リンパ組織球癥Hemophagocyticlymphohistiocytosis(HLH)EBV関連血球貪食癥候群EBV-associatedhemophacotyticsyndromeEBVに感染したT細(xì)胞が増殖し、大量のサイトカインを分泌、これによって活性化したマクロファージがサイトカインの分泌や血球を貪食して起こす標(biāo)準(zhǔn)微生物學(xué)第12版ｐ423

第6頁/共66頁Familialhemophagocyticlymphohistiocytosis(FHLorFHLH)iscausedbyaninheriteddeficiencyofperforinHemophagocytosis:ingestionofredbloodcellsbymacrophages

Pfp-/-miceinfectedwithsometypesofvirusesresultinadiseasesimilartoFHLbecausetheimmunesystemisuncontrolleddemonstratesthatperforinplaysanimportantroleinregulatingtheimmuneresponseHemophagocyticlymphohistiocytosis(HLH)=Hemophagocyticsyndrome(HPS)=MacrophageactivationsyndromeSomedeficienciescanleadtolymphoproliferativediseases(Table4.2)第7頁/共66頁InFHL,mutationspreventNKcellsandcytotoxicTcellsfromreleasingtheircytoplasmicgranules,whichleadstouncontrolledproliferationoflymphocytesandmacrophagesThesecellsphagocytosebloodcellsandreleasehugeamountsofproinflammatorycytokinesCytokineburstexplainstheinflammation,feverandsystemicillnessTcellandmacrophageinfiltrationinliver,spleen,lymphnodes,bonemarrow,andcentralnervoussystemTcellsandmacrophagesrespondstronglytomicrobestocompensatefortheCTLandNKcelldefects?第8頁/共66頁第9頁/共66頁AnemiaThrombocytopeniaHemophagocytosisinbonemarrow,spleen,lymphnodeIncreasedcytokinerelease:interferon-γ,TNF,IL-6,IL-10,macrophagecolony-stimulatingfactor(M-CSF)Treatment:controlthecytokineburstbychemotherapyandimmunotherapywithetoposide,corticosteroidsandcyclosporine,followedbybonemarrowtransplantation第10頁/共66頁Hemophagocyticlymphohistiocytosis(HLH)Hemophagocyticsyndrome(HPS)第11頁/共66頁Familialhemophagocyticlymphohistiocytosis(FHLorFHLH)(Table4.2) FHL1:unidentifiedgeneonchromosome9 FHL2:perforin(PRF1)mutation FHL3:Munc13-4(UNC13D)mutation FHL4:syntaxin11(STX11)mutation FHL5:syntaxinbindingprotein(STXBP)2(Munc18-2)mutation Allfourproteinsareinvolvedinthegranule-mediated cytotoxicpathwayoflymphocytesImmunedeficiencysyndromes(Table4.1) Chediak-Higashisyndrome1:LYST(=CHS1)mutation Griscellisyndrome2:RAB27Amutation LYSTandRAB27A:roleinvesicletraffickinginCTL

X-linkedlymphoproliferativesyndrome:SH2D1Amutation NKcellinhibitionleadstosevereEBvirusinfection andsustainedproliferationofCTL(Table4.3a)

Genetichemophagocyticlymphohistiocytosis=primaryhemophagocyticsyndrome第12頁/共66頁第13頁/共66頁第14頁/共66頁第15頁/共66頁AdefectinLYST(=CHS1),whichisinvolvedinintracelluarvesicleformationandtraffickingReportedbyMoisesChediak(1954)andOtotakaHigashi(1956)AfailureoflysosomesandphagosomestofuseproperlyPhagocyteshaveenlargedgranulesandimpairedintracellularkillingabilityPartialalbinism,abnormalplateletfunction,severeimmunodeficiencyChediak-HigashisyndromeOtotakaHigashi,東音高h(yuǎn)ttp://www.nurs.or.jp/~academy/igaku/t1/t1241.htmhttp://www.jpeds.or.jp/saisin/saisin_100604.html第16頁/共66頁第17頁/共66頁109-A60含み聲muffledvoice,

hotpotatovoiceくぐもったような、手で口を押さえてしゃべったときのような聲のどの奧からうるんだようなような聲がれが出ること

急性喉頭蓋炎、扁桃周囲膿瘍など/watch?v=96n_nrgBV44第18頁/共66頁109-B16原発性免疫不全癥慢性肉芽腫癥Chronicgranulomatousdisease(CGD)

第19頁/共66頁P(yáng)rimaryImmunodeficiencyExpertCommittee/iuis/index.php/primary-immunodeficiency-expert-committee.html第20頁/共66頁MSMD:Mendeliansusceptibilitytomycobacterialdisease5.Congenitaldefectsofphagocytes第21頁/共66頁ImmunodeficienciesofphagocyticcellsMyeloiddeficienciesprimarilyaffecttheinnateimmunesystem Phagocyteimmunodeficienciescanbegroupedinto4types:DeficiencyinPhagocyteproduction:Development–defectingenerequiredformyeloidprogenitorcelldifferentiationPhagocyteadhesionPhagocyteactivation:PhagocytosisKilling第22頁/共66頁Defectsinphagocyticcellsareassociatedwithpersistenceofbacterialinfection5.3:Defectsofrespiratoryburst6.2,6.3:IRAK4,MyD88deficiency5.2:Defectsofmotility5.1:DefectsofneutrophildifferentiationTable4.1:Immunodeficiencywithhypopigmentation第23頁/共66頁ThemostsignificantproblemistheinabilityofcellstoattachtothevascularendotheliumandmigratetositesofinflammationLADtype1(LAD-1):deficientexpressionofβ2integrinsduetoCD18genemutationsLADtype2(LAD-2):absenceofsialylLewisX:ligandonneutrophilsrequiredforbindingtoE-selectinandP-selectinonendothelium Causedbyfucosetransportergenemutation:thefailuretotransportfucose intotheGolgicomplexresultsinfailuretosynthesizesialylLewisXLADtype3,deficiencyofKindlin-3,requiredforfirmadhesionLeukocyteadhesiondeficiency(LAD)(Table5.2)第24頁/共66頁Leukocyteadhesiondeficiency(LAD)resultsfrommutationintheCD18molecule–theb2chainoftheintegrinfamilyTheresultisalossofsurfaceexpressionofkeyintegrinmolecules:Abnormalfunctions:endotheliumadherence,neutrophilchemotaxis,phagocytosis,cytotoxicityLADtype1Mac-1p150:95第25頁/共66頁第26頁/共66頁109-D4解答：d.落葉狀天皰瘡選択肢：e.皰疹狀皮膚炎dermatitisherpetiformisヘルペスウイルスとは無関係グルテン過敏腸癥第27頁/共66頁Celiacdisease(Celiacsprue

glutensensitiveenteropathy)Chronicsmallintestinalimmune-mediatedenteropathyprecipitatedtodietaryglutenAcommoncauseofmalabsorptioninCaucasiansIntheUS,estimatedincidence:1:113Onset;fromthefirstyearthroughtheeightdecadeDiarrhea,steatorrhea,weightloss,consequenceofnutrientdepletion(anemiaandmetabolicbonedisease)Gliadin,acomponentofgluten(wheat,barley,rye)Serumantibodies:antigliadinIgA,anti-transglutaminaseIgAHLA-DQ2allelepresentin80-95%ofpatients;HLA-DQ8Associatedwithdermatitisherpetiformis(IgAdepositionintheskin),diabetesmellitustypeI,thyroiditis,IgAdeficiencyEnteropathy-associatedT-celllymphoma第28頁/共66頁Aftergluten-freedietDermatitisherpetiformisSkinIgAdeposition第29頁/共66頁AmultisystemdiseaseresultingfromanautoimmunereactiontoinfectionwithgroupAstreptococciAlmostallofthemanifestationsinmanypartsofthebodyresolvecompletelyExceptioniscardiacvalvulardamage:rheumaticheartdisease(RHD)Diseaseofpoverty:lesscrowdedhousingandbetterhygieneresultedinreducedtransmissionofgroupAstreptococci+antibioticsandimprovedmedicalcare109-D14急性リウマチ熱Acuterheumaticfever(ARF)/content.aspx?aID=2881862Harrison’sOnline第30頁/共66頁Molecularmimicryinrheumaticfever第31頁/共66頁RHD:rheumaticheartdisease第32頁/共66頁StreptococcalMproteinareimmunologicallysimilartomyosin,tropomyosin,keratin,actin,laminin,vimentin,andN-acetylflucosamineAntibodiesthatrecognizecardiacmyosininthemyocardiumalsorecognizethevalveendotheliumandlamininOncediseasehasbecomechronicinthevalve,otherproteinsinthevalvesuchaslaminin,vimentin,collagenandothersmaybepresentedtotheimmunesystemandepitopespreadingwouldbepredictedtooccur第33頁/共66頁12-4Epitope(determinant)spreadingInanimals,autoimmunediseasecanbegeneratedbyimmunizingautoantigen(proteinX)inadjuvantFirstresponseisdominatedbyTcellresponsetoonepeptidederivedfromproteinXLater,tissuedamagereleaseproteinXandotherselfproteins(proteinY)FurtheractivateTcellresponsestoproteinsXandYExample:12-7Experimentalallergicencephalomyelitis(EAE),animalmodelformultiplesclerosis第34頁/共66頁Self-antigenisreleasedfromdamagedtissuecanbetakenupbyantigenpresentingcells(APCs),processedandpresentedtoautoreactiveTcellsFurthertissuedestructionbyactivatedTcellscausesthereleaseofmoreself-antigenfromtissuesTheresponsecanthenspreadtoinvolveTcells(orantibodies)specificforotherself-antigensinaprocessknownasepitopespreadingEpitopespreading第35頁/共66頁109-D44Mumps急性耳下腺炎第36頁/共66頁MumpsChildwithparotitis(CDCwebsite:/mumps/about/photos.html)Mumpscausessalivaryglandswelling,particularlytheparotidglandMumps;“Otafuku”inJapaneseOtafuku,Japanesemask(“fuku”=swelling)第37頁/共66頁109-D49項(xiàng)部硬直髄膜炎第38頁/共66頁ViralMeningitisvs.EncephalitisViralMeningitis(Enteroviruses,HIV,HSVtype2,Arboviruses)

HeadacheStiffneckPhotophobiaLittlealterationinconsciousnessNofocalsignsViralEncephalitis(HSV,Arboviruses,Rabies,Nipahvirus)AlteredconsciousnessFocalneurologicalsignsSeizuresMeningealsignsDr.JohnE.Greenlee,MD,UniversityofUtah/watch?v=bj2CNkjvY4o第39頁/共66頁109-E50慢性炎癥性脫髄性多発根神経炎第40頁/共66頁第41頁/共66頁109-E52クループ第42頁/共66頁P(yáng)aramyxoviridaeHumanDiseasesFamilyincludesnumeroushumandisease-causingmembers:PaRaMyxovirus:Parainfluenza,Respiratorysyncytialvirus,Rubeola(Measles),MumpsSubfamilyParamyxovirinaeMorbillivirus(measles)–fever,cough,conjunctivitisleadingtomacropapularrash;canbefatal;Subacutesclerosingpanencephalitis(SSPE)Rubulavirus(mumps)–feverleadingtosalivary(parotid)glandswelling;canbetesticularandcentralnervoussystem(CNS)involvement;occasionallyfatalRubulavirus(humanparainfluenzavirus2/4a/4b)–acuterespiratorytractdisease;feverleadingtobronchitisandpossiblypneumoniaRespirovirus(humanparainfluenzavirus1/3)–acuterespiratorytractdisease;feverleadingtobronchitisandpossiblypneumonia;“croup”ininfants<6mos.

第43頁/共66頁Croup/patient/videoplayer/7xDM8vuVEPo第44頁/共66頁109-E52急性喉頭蓋炎：選択肢正常2016年近畿大學(xué)６年寺田徹さんクリクラ第45頁/共66頁109-F13選択肢：手足口病第46頁/共66頁Hand,footandmouthdisease(HFMD)Vesicularlesionsonthehands,feet,mouth,andtongueOccursinchildrenCausedbyenteroviruses,includingcoxsackievirusA16,10,andenterovirus71Mildlyfebrile,andtheillnesssubsidesinafewdays/virol/picorna.htm第47頁/共66頁CoxsackievirusThefirststrainswereisolatedfromtwoparalyzedboysinthevillageofCoxsackie,NewYorkMeningitisandencephalitisMyocarditis第48頁/共66頁Aphtho:fromGreekaphtha,"vesiclesinthemouth";English:aphtho,"thrush”Entero:fromGreekenteron,"intestine”Hepato:fromGreekhepatos,"liver“Kobu:fromJapaneseKobu"humporknob“Rhino:fromGreekrhis,rhinos,"nose"

ThetwooriginalhumanrhinovirusspecieshavebeenmovedtothegenusEnterovirus;thegenusRhinovirusnolongerexists.Whittonetal.,NatureReviewsMicrobiology2005v.3p.765第49頁/共66頁GenusAphthovirus

Typespecies:Foot-and-mouthdiseasevirus(FMDV)Infectcloven-hoofedanimals(cattle,goats,pigs,sheep)Rarelyinfecthumans7serotypes,eachwithsubtypesLoseinfectivityatlowpHvaluesoflessthan6.8The“typespecies”:thevirusinitiallynecessitatedthecreationofthegenusandbestdefinesoridentifiesthegenus第50頁/共66頁

PicornaviruspathogenesisThetargettissueinfectedbythevirusdeterminesthepredominantdiseasecausedbythevirus.Coxsackie;coxsackievirusecho;echovirus;HAV;hepatitisAviruspolio;poliovirusrhino;rhinovirus.第51頁/共66頁109-I67SSPE亜急性硬化性全脳炎第52頁/共66頁ADEM,acutedisseminatedencephalomyelitisMIBE;measlesinclusionbodyencephalitisADEM,demyelination;MIBE;inclusionbodyandviralantigenSubacuteChronicAcute第53頁/共66頁SSPE,subacutesclerosingpanencephalitisOccursyearsordecadesafteraninitialmeaslesinfection0.4to9.7permillionpatientswithmeaslesMutationsintheMproteinClonalexpansionofthemutatedviruswithinthebrainMproteinisnotproduced,nobuddingCellfusionbytheFandHproteinsismaintained,allowingthevirustospreadwithinthebrainbylocalcellfusion;virusevadestheimmunesystem,anti-virusantibodiesotherthanMproteinBrainatrophy,gliosisandmononuclearcellinfiltration,andrarefiedandglioticwhitemattergliosis

[′′+osis,condition]:proliferationofastrocytes=scarintheCNS.第54頁/共66頁ArarediseaseintheUS,withfewerthan10casesperyear,sincetheintroductionofmeaslesvaccine(0.4to9.7permillionpatientswithmeasles)Mostpatientshadtheirmeaslesinfectionpriortotheageof2yearstheonsetofdiseaseoccursbetweentheagesof5to15yearsin85%ofpatientsThediseaseusuallybeginswithpoorschoolperformance,personalitychangesandthendementia(stageI).Myoclonus,seizures,andmovementdisordersoccurinstageII.Eventuallythecomatosean