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Immuunreaksie op skok

Immuunreaksie op skok


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Ek studeer verpleging en het 'n vraag oor die fisiologiese reaksie op skok (verminderde perfusie). In lesingnotas wat deur die dosent verskaf is, dui hy aan dat daar 'n neurale, hormonale en immuunrespons op skok is wat kompenserend is.

Die neurale komponent is die aktivering van die simpatiese senuweestelsel, en hormonale reaksie is deur RAAS, ens. Dit maak sin, aangesien hierdie meganismes poog om bloeddruk en bloedvolume te verhoog

Ek verstaan ​​egter nie die immuunrespons nie, wat beskryf word as die vrystelling van pro-inflammatoriese mediators, wat lei tot skade aan endoteelsel, wat die vate laat lek, wat tot edeem lei. So hoe is die kompenserende, dit lyk ontwrigtend? En hoekom presies sou pro-inflammatoriese bemiddelaars vrygestel word in reaksie op skok in die eerste plek?


Eerstens: wat is inflammasie. Van wikipedia https://en.wikipedia.org/wiki/Inflammation

Akute inflammasie is die aanvanklike reaksie van die liggaam op skadelike stimuli en word bereik deur die verhoogde beweging van plasma en leukosiete (veral granulosiete) vanaf die bloed na die beseerde weefsels. 'n Reeks biochemiese gebeurtenisse propageer en verouder die inflammatoriese reaksie, wat die plaaslike vaskulêre stelsel, die immuunstelsel en verskeie selle binne die beseerde weefsel betrek.

Tweede re skok: hoekom gebeur dit? As ek in skok gaan van bloedverlies na 'n verskriklike mesjongleerongeluk sal ek waarskynlik nie die inflammatoriese stuk hê nie: Ek sterf van 'n gebrek aan bloed en gevolglike lae bloeddruk.

Wat as ek in septiese skok is? Dit beteken skok wat veroorsaak word deur organismes, gewoonlik bakterieë, in die bloedstroom. Bakterieë is die antieke vyand en ons het lae op laag verdediging wat oor evolusionêre tyd opgehoop is. Die rede waarom ons hulle het, is dat ons voorouers wat hulle gehad het, op een of ander manier 'n fiksheidsvoordeel gehad het - waarskynlik omdat hulle oorleef het met bakterieë in die bloed.

Sommige van die goed wat saam met daardie pakkie kom, lyk nie baie aanpasbaar nie - soos die lekkende vate en longe wat vol vloeistof word. Miskien sien ons die wilde uiterste van hierdie reaksie, maar in 'n mindere mate (minder infeksies?) is daardie inflammatoriese reaksies goed? Miskien het die vrystelling van 'n storm van neutrofiele onvermydelike newe-effekte vir die omgewing - soos die Avengers wat 'n uitheemse leër in NYC veg? Dit was moeilik op NYC. Miskien red daardie uiterste skokreaksies die organisme 1 keer uit 10, wat beter is as die kans anders met 'n oorweldigende bakteriële infeksie.

Bottom line is egter dat bakterieë in die bloed in groot getalle 'n eksistensiële bedreiging vir die organisme is. Desperate tye vra om desperate maatreëls.


7.6: Die immuunrespons teen patogene

Noudat jy die ontwikkeling van volwasse, naïe B-selle en T-selle, en sommige van hul hooffunksies verstaan, hoe kom al hierdie verskillende selle, proteïene en sitokiene bymekaar om werklik 'n infeksie op te los? Ideaal gesproke sal die immuunrespons die liggaam heeltemal van 'n patogeen ontslae raak. Die aanpasbare immuunrespons, met sy vinnige klonale uitbreiding, is goed geskik vir hierdie doel. Dink aan 'n primêre infeksie as 'n wedloop tussen die patogeen en die immuunstelsel. Die patogeen omseil versperring verdediging en begin vermeerder in die gasheer se liggaam. Gedurende die eerste 4 tot 5 dae sal die aangebore immuunrespons gedeeltelik beheer, maar nie stop nie, patogeengroei. Namate die aanpasbare immuunrespons egter aanskakel, sal dit begin om die patogeen uit die liggaam te verwyder, terwyl dit terselfdertyd sterker en sterker word. Wanneer teenliggaampaksies by pasiënte met 'n spesifieke siekte soos 'n virus gevolg word, word hierdie opruiming na verwys as serokonversie (sero&ndash = &ldquoserum&rdquo). Seroomskakeling is die wedersydse verband tussen virusvlakke in die bloed en teenliggaamvlakke. Soos die teenliggaampies styg, neem die virusvlakke af, en dit is 'n teken dat die immuunrespons ten minste gedeeltelik effektief is (gedeeltelik, want in baie siektes beteken serokonversie nie noodwendig dat 'n pasiënt gesond word nie).

'n Uitstekende voorbeeld hiervan is serokonversie tydens MIV-siekte. Let daarop dat teenliggaampies vroeg in hierdie siekte gemaak word, en die toename in anti-MIV-teenliggaampies korreleer met 'n afname in waarneembare virus in die bloed. Alhoewel hierdie teenliggaampies 'n belangrike merker is vir die diagnose van die siekte, is dit nie voldoende om die virus heeltemal skoon te maak nie. Etlike jare later sal die oorgrote meerderheid van hierdie individue, indien onbehandeld, hul hele aanpasbare immuunrespons verloor, insluitend die vermoë om teenliggaampies te maak, tydens die finale stadiums van VIGS.

Figuur 1. Seroomskakeling, die styging van anti-MIV-teenliggaampies en die gepaardgaande afname in meetbare virusvlakke, vind plaas gedurende die eerste paar maande van MIV-siekte. Ongelukkig is hierdie teenliggaampeaksie ondoeltreffend om die siekte te beheer, soos gesien deur die vordering van die siekte na VIGS, waarin alle aanpasbare immuunresponse gekompromitteer word.

Alledaagse verbinding: Ontsmettingsmiddels&mdash Veg die goeie stryd?

&ldquoWas jou hande!&rdquo Ouers vertel dit al vir geslagte vir hul kinders. Vuil hande kan siektes versprei. Maar is dit moontlik om van genoeg patogene ontslae te raak dat kinders nooit siek sal word nie? Is kinders wat blootstelling aan patogene vermy beter daaraan toe? Die antwoorde op beide hierdie vrae blyk nee te wees.

Antibakteriese doekies, seep, gels en selfs speelgoed met antibakteriese stowwe wat in hul plastiek ingebed is, is alomteenwoordig in ons samelewing. Tog ontslae hierdie produkte nie die vel en spysverteringskanaal van bakterieë nie, en dit sal skadelik vir ons gesondheid wees as hulle dit doen. Ons het hierdie nie-patogene bakterieë op en binne ons liggame nodig om te verhoed dat die patogene groei. Die drang om kinders perfek skoon te hou, is dus waarskynlik verkeerd. Kinders sal in elk geval siek word, en die latere voordele van immunologiese geheue oorskry verreweg die geringe ongemak van die meeste kindersiektes. Trouens, om later in die lewe siektes soos waterpokkies of masels te kry, is baie moeiliker vir die volwassene en word geassosieer met simptome wat aansienlik erger is as dié wat in die kindersiektes gesien word. Natuurlik help inentings kinders om sommige siektes te vermy, maar daar is soveel patogene dat ons nooit teen almal immuun sal wees nie.

Kan oor-skoonheid die rede wees dat allergieë in meer ontwikkelde lande toeneem? Sommige wetenskaplikes dink so. Allergieë is gebaseer op 'n IgE-teenliggaampeaksie. Baie wetenskaplikes dink die stelsel het ontwikkel om die liggaam te help om van wurmparasiete ontslae te raak. Die higiëneteorie is die idee dat die immuunstelsel ingestel is om op antigene te reageer, en as patogene nie teenwoordig is nie, sal dit eerder reageer op onvanpaste antigene soos allergene en self-antigene. Dit is een verduideliking vir die toenemende voorkoms van allergieë in ontwikkelde lande, waar die reaksie op nie-patogene soos stuifmeel, garnale en katdander allergiese reaksies veroorsaak terwyl dit geen beskermende funksie dien nie.


Wat gebeur wanneer die immuunstelsel nie help om indringers uit te hou nie?

'n Werkende immuunstelsel is noodsaaklik vir oorlewing, maar selfs die gesofistikeerde sellulêre en molekulêre verdediging van die soogdier-immuunreaksie kan by feitlik elke stap deur patogene verslaan word. In die kompetisie tussen immuunbeskerming en patogeenontduiking het patogene die voordeel van vinniger evolusie vanweë hul korter generasietyd en ander eienskappe. Byvoorbeeld, Streptococcus longontstekinge (die bakterie wat longontsteking en breinvliesontsteking veroorsaak) omring homself met 'n kapsule wat keer dat fagosiete dit verswelg en antigene vir die aanpasbare immuunstelsel vertoon. Staphylococcus aureus ('n bakterie wat velinfeksies, absesse en meningitis kan veroorsaak) sintetiseer 'n gifstof wat fagosiete doodmaak nadat hulle die bakterie verswelg het. Ander patogene kan ook die aanpasbare immuunstelsel belemmer. MIV infekteer helper-T-selle via hul CD4-oppervlakmolekules, wat die aantal helper-T-selle in die liggaam geleidelik uitput. Die uitputting van helper T-selle inhibeer die aanpasbare immuunstelsel se vermoë om voldoende reaksies op infeksie of gewasse te genereer. Gevolglik ly MIV-geïnfekteerde individue dikwels aan infeksies wat nie siekte by mense met gesonde immuunstelsels sal veroorsaak nie, maar wat verwoestende siektes kan veroorsaak vir individue wat immuun is.


Abstrak

Kenmerke van inflammasie in verskeie kardiovaskulêre siektes, veral aterosklerose, is al lank waargeneem. Bewyse vir 'n (outo)antigeengedrewe proses by hierdie plekke van inflammasie het egter eers onlangs na vore gekom. Hitteskokproteïene (HSP's) is geïdentifiseer as óf immunologies-gemedieerde siektebevorderende óf beskermende rolle. Daar is getoon dat HSP60 aangebore en aanpasbare immuunresponse veroorsaak wat die vroegste nog omkeerbare inflammatoriese stadium van aterosklerose inisieer. HSP60 word struktureel hoogs bewaar en volop uitgedruk deur prokariotiese en eukariotiese selle onder stresvolle toestande. Voordelige beskermende immuniteit teen mikrobiese HSP60 verkry deur infeksie of inenting en bona fide outo-immuniteit teen biochemies veranderde outoloë HSP60 is teenwoordig in alle mense. In vitro en in vivo eksperimente het getoon dat klassieke aterosklerose risikofaktore kan optree as endoteel stressors wat die gelyktydige uitdrukking van adhesiemolekules en van HSP60 in mitochondria, in sitoplasma en op die seloppervlak uitlok, waar dit as 'n "gevaarsein" optree. vir sellulêre en humorale immuunreaksies. Daarom moet beskermende, bestaande anti-HSP60-immuniteit dalk "betaal" word deur skadelike (outo-)immuun kruisreaktiewe aanval op arteriële endoteelselle wat deur aterosklerose risikofaktore mishandel word. Hierdie eksperimenteel en klinies bewese bevindings is die basis vir die outo-immuun konsep van aterosklerose.

Tipiese sellulêre kenmerke van chroniese inflammasie en infeksies, veral infiltrasie deur mononukleêre selle, is ook teenwoordig in die kardiovaskulêre stelsel, soos dit al vir meer as 150 jaar bekend is. Dit was egter tot redelik onlangs nie duidelik of hierdie inflammatoriese immunologiese prosesse primêr of sekondêr van aard is nie. 1 Een van die redes vir hierdie onsekerheid was moontlik die feit dat die meeste ondersoeke in mense uitgevoer is op chirurgiese of lykskouingsmonsters wat baie gevorderde stadiums van kardiovaskulêre siekte (KVS) verteenwoordig en dus nie inligting verskaf het oor die aanvanklike meganismes wat hierdie prosesse veroorsaak het nie. In komplekse situasies, soos in aterosklerose, was dit ook moeilik om te besef dat verskillende, klinies goed bewese risikofaktore 'n soortgelyke, of selfs identiese, patofisiologiese uitkoms kan veroorsaak. Die hoofdoel om hierdie dilemma op te los was om die reeks nie-spesifieke en spesifieke humorale en sellulêre inflammatoriese reaksies wat binne die geteisterde vaskulêre gebiede plaasvind, af te baken. Die beskikbaarheid van diermodelle wat, ten minste gedeeltelik, menslike CVS naboots, was van uiterste belang vir hierdie vordering. In onlangse dekades was die doel om eksogene of outoloë antigene te identifiseer wat die plaaslike kardiovaskulêre immuunreaksies kan veroorsaak. Onder die kandidate vir sulke antigene is aansteeklike middels, soos Chlamydia pneumoniae, sowel as outo-antigene, soos biochemies veranderde (bv. geoksideerde lae-digtheid lipoproteïen [oxLDL], fosfolipiede en hitteskokproteïene [HSPs]). In hierdie oorsig sal ons fokus op die rol van HSP's in aterosklerose.

Onder fisiologiese toestande vervul HSP's belangrike intrasellulêre take met betrekking tot proteïenvou en vervoer. Onder stres kan HSP's as chaperone optree wat proteïendenaturering en funksieverlies voorkom. Soos die naam aandui, is die uitdrukking van HSP's eers gedemonstreer as 'n reaksie op verhoogde temperatuur. 2 Onlangs is 'n eerste poging vir 'n konsekwente en duidelike nomenklatuur vir die HSP's en verwante chaperone-gene in die menslike databasis bereik. 3 HSP's word volgens hul molekulêre massa geklassifiseer in families wat wissel van minder as 5 kDa tot meer as 100 kDa. 4 HSP's is struktureel hoogs behoue ​​​​van prokariotiese tot eukariotiese selle. HSP60 van verskillende bakteriese spesies vertoon meer as 95% volgorde homologie op beide DNA en proteïen vlakke. 'n Algehele 55% homologie bestaan ​​tussen menslike en bakteriese HSP60 wat selfs 72% kan bereik by sekere domeine van die 573-aminosuur-lange molekule. Alle diere en mense toon beskermende aangebore en aanpasbare immuniteit teen HSP60. As gevolg van die antigeniese ooreenkoms tussen prokariotiese en eukariotiese HSP's, word die liggaam gekonfronteer met die dilemma dat HSP60 herken moet word en daarteen gereageer moet word om infeksie te beveg, maar outoloë HSP60 moet steeds geduld word om outo-immuniteit te vermy. 5

Onder fisiologiese toestande blyk diere en mense verdraagsaam te wees teen outoloë HSP60. Hoe hierdie toestand van verdraagsaamheid geaktiveer en in stand gehou word en onder watter omstandighede dit verbreek kan word (bv. deur 'n opbouende lewenslange aansteeklike lading of deur immunisering saam met byvoegmiddels) is nog 'n kwessie van debat. Met betrekking tot sentrale verdraagsaamheid is dit getoon dat HSP's onder die molekules is wat promisku uitgedruk word deur timiese epiteelselle. 6 Daarbenewens kan ekstrasellulêre monsterneming deur sirkulerende dendritiese selle wat in die timus migreer oorweeg word. 7 Ook, posttimiese perifere faalveilige meganismes moet werksaam wees om die aanvang van openlike outo-immuniteit teen HSP60 te voorkom. 8

Onder die CVD's is die rol van HSP60 hoofsaaklik vir aterosklerose bestudeer. HSP60 is 'n mitochondriese uitgedrukte stresproteïen wat na die sitosol getranslokeer kan word en later na die seloppervlak vervoer kan word en na die omgewing gestort kan word. 9 Dus, die plasmakonsentrasie van oplosbare HSP60 (sHSP60) toon 'n wye reeks wat verband hou met genetiese, biologiese en sielkundige faktore in CVD, en pasiënte met grenslyn hipertensie 10 en pasiënte met vroeë CVD toon verhoogde vlakke van sHSP60. 11 Translokasie van HSP60 na die seloppervlak is 'n beduidende stresreaksie wat korreleer met apoptose en verergering van die siektetoestand. 12,13 HSP60 kan beide die aangebore immuunstelsel (via tolagtige reseptor 4) en die aanpasbare immuunstelsel aktiveer. 14

HSP in aterosklerose

Vroeë menslike aterosklerotiese letsels

Die oorwegend inflammatoriese aard van aanvanklike aterosklerotiese letsels word ondersteun deur beide kliniese en eksperimentele feite wat egter steeds dikwels verwaarloos word. Alhoewel hipercholesterolemie 'n bewese risikofaktor vir aterosklerose is, is meer as 60% van pasiënte normocholesterolemies. Verder is geaktiveerde T-selle (hoofsaaklik CD4+) die eerste indringers van die arteriële intima in vroeg menslike aterosklerotiese letsels, 15-17 eers later gevolg deur makrofage en gladdespierselle (SMC's), laasgenoemde 2 het dikwels omskep in skuimselle wat oorheers in laat, ingewikkelde gedenkplate en in vroeë xanthoma. Toe gesonde babas, kinders en jong volwassenes (van 8 maande tot 16 jaar oud) bestudeer is, het mononukleêre sel-infiltrasie by voorliefdeplekke weer begin met T-selle, gevolg deur makrofage, SMC's en 'n paar verstrooide maselle. In 'n groep baie jong kinders (8 maande tot 8 jaar) het makrofage nie die eienskappe van skuimselle getoon nie, en ekstrasellulêre lipiedneerslae was nog nie in die intima waarneembaar nie. 18 In 'n ander studie oor jong proefpersone (15 tot 34 jaar oud) wat uit die Amerikaanse Pathobiological Determinants of Atherosclerose in Youth-studie versamel is, 19 kon dieselfde fenotipiese waarnemings wat hierbo opgesom is weer bevestig word met die bykomende kenmerk van 'n ingewikkelde netwerk van dendritiese selle teenwoordig in die arteriële intima verskaf die voorvereistes vir 'n plaaslike immuunreaksie. 16

Die outo-immuun konsep van aterosklerose

Eksperimentele en kliniese feite wat hieronder opgesom word, het die basis verskaf vir die ontwikkeling van die outo-immuun konsep van aterosklerose 20 wat skematies in Figure 1 en 2 uitgebeeld word.

Figuur 1. Skematiese oorsig van die outo-immuun konsep van aterosklerose. Onder fisiologiese toestande druk menslike vaskulêre EC's nie HSP60 (groen sterre) op hul oppervlak uit nie. Wanneer ECs egter gestres word deur klassieke aterosklerose risikofaktore, lei dit tot die gelyktydige uitdrukking van HSP60 en adhesiemolekules. HSP60-uitdrukking op die EC-oppervlak kan dien as 'n teiken vir voorafbestaande kruisreaktiewe antimikrobiese menslike (kruis)reaktiewe HSP60-immuniteit of bona fide outo-immuunreaksies wat deur biochemies veranderde outoloë HSP60 geïnduseer word. Deurlopende stres deur aanhoudende risikofaktore lei tot ernstige aterosklerose. Gedeeltelik aangepas uit Wick et al 20 en Servier Medical Art.

Figuur 2. Skematiese oorsig van HSP60 uitdrukking/funksie in vroeë en laat aterosklerose. Stres-geïnduseerde EC-oppervlakuitdrukking van adhesiemolekules en HSP60 stel T-selle, monosiete en dendritiese selle in staat om aan die EC's te heg en na die intima te transmigreer. Die T-selle (meestal CD4+) is die eerste selle wat die intima binnegaan tydens vroeë aterosklerose. Antigeenherkenning kan uitgevoer word deur beide professionele antigeen-presenterende selle (dendritiese selle en makrofage) en deur EC's en SMC's wat MHC klas I en klas II uitdruk (geïnduseer deur interferon-γ). Daarbenewens is sirkulerende anti-HSP60-teenliggaampies teenwoordig. Tydens progressie van 'n vroeë letsel na 'n ernstige plaak, kan EC-skade via anti-HSP60-teenliggaampies, 'n verhoogde aantal makrofage en SMC's wat dikwels met lipiede (skuimselle) gelaai is, en neovaskularisasie gedemonstreer word. Die skuimselle kan skeur en hul inhoud in die letselarea vrystel, wat lei tot die kenmerkende vorming van cholesterolkristalle. Die konsentrasie van sHSP60- en anti-HSP60-teenliggaampies is ook verhoog in die serum van proefpersone met ernstige aterosklerose. Anti-HSP60-teenliggaampies kan die EC's op 'n komplement-gemedieerde wyse of via teenliggaamafhanklike sellulêre sitotoksisiteit (ADCC) lyseer. By mense is die patogenetiese rol van onderskeidelik HSP60-spesifieke T-selle en teenliggaampies nog nie heeltemal uitgeklaar nie. Studies in proefdiere het egter bewyse gelewer vir beide meganismes om by te dra tot aterogenese. IL dui op interleukien IFN, interferon ADCC, teenliggaamafhanklike sellulêre sitotoksisiteit. Gedeeltelik aangepas uit Servier Medical Art.

Alle mense ontwikkel beskermende, voordelige aanpasbare immuniteit teen die filogeneties hoogs bewaarde mikrobiese HSP60-antigeen via infeksie of inenting bykomend tot die immuniteit teen organisme-spesifieke epitope. Onder fisiologiese toestande druk vaskulêre endoteelselle (EC's) nie HSP60 uit nie. Wanneer dit egter deur klassieke risikofaktore vir aterosklerose beklemtoon word, lei die gelyktydige uitdrukking van adhesiemolekules en HSP60 deur ECs tot 'n (kruis)reaksie teen en vernietiging van hierdie teikenselle deur voorafbestaande sellulêre en humorale immuniteit teen HSP60, wat intimale infiltrasie deur mononukleêre selle meebring. As aterosklerose risikofaktore voortduur, gaan hierdie vroeë, steeds omkeerbare inflammatoriese stadium van aterosklerose voort tot gedenkplaatvorming met nadelige gevolge. Aanvullende Tabel I (aanlyn beskikbaar by ) lys die belangrikste bydraes van verskeie laboratoriums oor die assosiasie van CVD met anti-HSP-teenliggaampies, sHSP's en HSP-spesifieke T-selle wat verskyn het sedert ons laaste uitgebreide oorsig oor hierdie onderwerp in 2004. 20

Self-HSP-reaktiewe T-selle en B-selle

Omdat opregulering van HSP60 deel is van 'n inflammatoriese respons, behoort self-HSP60-reaktiewe T-selle met 'n regulatoriese fenotipe deel te wees van die fisiologiese beëindiging van die inflammatoriese respons. T-selle wat reageer op self-HSP epitope is gevind in beide menslike en dier studies. 'n Belangrike voorvereiste vir stimulasie van HSP-reaktiewe T-selle is die aanbieding van die ooreenstemmende peptiede deur groot histoversoenbaarheidskompleks (MHC) molekules. Self-HSP peptiede het toegang tot beide MHC klas I en klas II molekules.

Soos reeds genoem, het ons getoon dat CD4 + T-selle die eerste T-selpopulasie in is vroeg menslike letsels. Baie van die CD4+-selle is HLA-DR- en CD25-positief, en 'n meerderheid van intima-infiltrerende T-selle dra die T-selreseptor α/β, maar 'n onverwagse hoë proporsie van hierdie T-selle is T-selreseptor γ/δ positief . Beide SMC's en EC's is HLA-DR-positief wanneer geaktiveer, interferon-γ-produserende T-selle is teenwoordig in die omgewing, 15-17 wat daarop dui dat SMC's en EC's as antigeenpresenterende selle kan deelneem aan die voortsetting van die outo-immuunreaksie. Interessant genoeg is die T-selreaksie teen menslike HSP60 (hHSP60) aansienlik verhoog in intralesionale T-selle (wat hoofsaaklik 'n oligoklonaal beperkte T-selreseptor α/β-repertorium vertoon) in vergelyking met perifere T-selle (poliklonale repertorium) van dieselfde individu. 21 Verder, karotis gedenkplate van aterosklerose pasiënte huisves in vivo-geaktiveerde CD4 + T-selle wat spesifiek reageer op self-HSP60 peptiede. 22 Benewens kruisreaktiewe T-selle, is daar ook getoon dat kruisreaktiewe B-selle-epitope as outo-immuun teikens in beginnende aterosklerose dien. 23

MHC klas II antigeen uitdrukking op ECs wat oorliggende aterosklerotiese letsels is gevind in lae-digtheid lipoproteïen-reseptor (LDLr)/interferon-γ dubbele uitklop muise. 24 In muise wat geïmmuniseer is met hitte-gedood Mycobacterium tuberculosis, was ongeveer 20% van alle mycobacterium-reaktiewe CD4 + α/β T-selle spesifiek vir HSP60, 25 en immunisering met mycobacterial HSP60 (mHSP65 as 'n paradigmatiese voorbeeld van bakteriese HSP60) geïnduseerde kruising reaktiewe CD8 + α/β T-selle. 26 Beide α/β- en γ/δ-positiewe HSP60-reaktiewe T-selle kan 'n rol speel in die patogenese van menslike outo-immuun siektes (bv. rumatoïede artritis, veelvuldige sklerose, Behcet-siekte en aterosklerose). 27 Byvoorbeeld, CD8 + α/β T-selle herken HSP60-peptiede op MHC-klas I in vitro, en na oordrag na α/β T-sel-tekorte muise, kan hierdie T-selle outo-immuun siekte met ernstige skade van die derm-epiteel veroorsaak. 27 Na stimulasie met mHSP65-peptiede in vitro, herken en lyseer HSP60-spesifieke CD8+ T-selle gasheerselle wat aan eksterne stresfaktore blootgestel is. Herkenning en lise word egter voorkom wanneer HSP60-uitdrukking in teikenselle geblokkeer word met antisense-nukleotiede. 28

Baie minder is bekend oor die patogeniese rol van B-selle en anti-HSP60-teenliggaampies in aterogenese as oor die rol van T-selle. Immunohistologiese ontledings van vroeë en meer gevorderde menslike aterosklerotiese letsels het slegs lae getalle B-selle in vergelyking met T-selle aan die lig gebring. Verder kan B-selle meestal net in die media en in die adventitia van aterosklerotiese gedenkplate gevind word, maar nie binne vroeë letsel nie. 16,17,29 Studies oor aterosklerotiese aneurismes het egter die teenwoordigheid van plasmaselle en af ​​en toe limfoïede follikels getoon. 30 Bejaarde apolipoproteïen E-nul (ApoE −/− ) muise het ook adventitiele vorming van inflammatoriese follikelagtige strukture getoon wat prolifererende B-selle en plasmaselle bevat, 31 wat aandui dat die adventitia 'n plek van plaaslike adaptiewe immuunreaksies tydens aterogenese kan wees. Nietemin het onlangse studies van die effek van B-sel-uitputting op die ontwikkeling van aterosklerose teenstrydige resultate gelewer. In die meeste gevalle het B-sel-uitputting 'n verergering van die siekte behels, 32-34, terwyl verskeie ander verslae 'n verbetering van aterosklerose beskryf het. 33,35 Hierdie verskil kan verklaar word deur 'n verhoogde vorming van aterobeskermende (outo)teenliggaampies (bv. anti-oxLDL) 32 in eersgenoemde of van aterogeniese (outo)teenliggaampies (bv. anti-HSP60) in laasgenoemde geval.

hHSP60 kan naïewe muis B-selle veroorsaak om te prolifereer en interleukien-10 en interleukien-6 af te skei. hHSP60-behandelde B-selle kan die uitdrukking van MHC klas II en bykomstige molekules CD69, CD40 en B7-2 opreguleer. Daarbenewens kan sHSP60 B-selle aktiveer via tolagtige reseptor 4-MyD88-sein. 36 Verder kan hHSP60 muis B-sel apoptose inhibeer, spontaan of geïnduseer, via MyD88 sein (tolagtige reseptor 4 word nie in hierdie geval vereis nie). Inhibisie van apoptose deur hHSP60 word geassosieer met opregulering van die antiapoptotiese molekules Bcl-2, Bcl-xL, en oorleef. Dit is belangrik dat B-selle wat met hHSP60 geïnkubeer is, langdurige oorlewing gemanifesteer het na oordrag na ontvangermuise. 37 Ten slotte, hierdie bevindinge toon dat beide T- en B-selle HSP60-immuunreaksies kan reguleer en dus outoreaktiewe T- en B-selle kan induseer wat self-HSP60-peptiede herken, maar met betrekking tot primêre aterogeniese meganismes lyk dit of die balans na T-selle gekantel is.

Eksperimentele waarnemings

Tot dusver is 'n patogene rol in aterogenese slegs vir HSP60 bewys, en die induksie van aterosklerose in proefdiere is tot dusver slegs bereik deur immunisering met prokariotiese en eukariotiese HSP60. In die huidige konteks word mHSP65 altyd gebruik as 'n paradigmatiese en kragtige verteenwoordiger van bakteriële HSP60. 'n Induksie van aterosklerose is suksesvol gedemonstreer in normocholesterolemiese konyne na immunisasies met mHSP65. 38 T-sel uitputting in mHSP65 geïmmuniseerde konyne lei tot 'n beduidende afname van aterosklerotiese letsels. 39 Dit is ook die geval vir nie-geïmmuniseerde hipercholesterolemiese aterosklerose-geneigde (LDLr −/− ) muise gekruis met limfosiet-tekort (RAG-1 −/−) muise. By die nageslag van hierdie dubbele uitklopmuise is vroeë letselontwikkeling met 54% verminder, wat aandui dat limfosiete 'n belangrike rol speel in vroeë aterosklerose. 40 Immunisering van konyne met mHSP65 het 'n selfs meer uitgesproke effek gehad toe hulle gelyktydig 'n cholesterolryke (Westerse) dieet gevoer is. 41 Alhoewel die vroeë inflammatoriese stadium van aterosklerose in normocholesterolemiese mHSP65-geïmmuniseerde konyne steeds omkeerbaar was gedurende 'n 32-week waarnemingsperiode, het die letsels in 'n soortgelyke geïmmuniseerde hipercholesterolemiese groep voortgeduur. 41 Dit is later bevestig in aterosklerose-weerstandige wilde-tipe C57BL/6J muise wat 'n Westerse dieet gekombineer met mHSP65 immunisering en in LDLr −/− muise gevoer met normale chow dieet saam met mHSP65 immunisasies (Figuur 3). 42,43

Figuur 3. Plaakvorming in 'n aterosklerose-geneigde diermodel, die ApoE −/− muis. A, Die aortaboog van 'n 22-week-oue vroulike ApoE -/− muis wat normale chow dieet gevoer word. B, 'n 22-week-oue vroulike ApoE -/− muis wat vir 14 weke 'n cholesterolryke Westerse dieet gevoer is en boonop 4 keer met mHSP65 (50 μg/100 ml) ingespuit is. Swart pyle dui op sigbare plaakvorming. C, 'n Hoër vergroting van die aortaboog en vertakkingsare (van B). D, 'n Dwarssnit van die aortaboog (van A). E, 'n Dwarssnit van die aortaboog (van B).

Letsel-afgeleide T-selle van normocholesterolemiese mHSP65-geïmmuniseerde konyne toon 'n aansienlik verhoogde reaktiwiteit teen mHSP65 in vergelyking met outoloë perifere bloed T-selle. 44 Passiewe oordrag van T-selle vanaf mHSP65 geïmmuniseerde aterosklerotiese LDLr -/− muise na nie-geïmmuniseerde sinergene LDLr -/− ontvangers lei tot die ontwikkeling van siekte by laasgenoemde. 45 Interessant genoeg, passiewe oordrag van 'n muis monoklonale teenliggaampie (II-13) wat 'n epitoop herken wat bestaan ​​uit aminosuurreste 288 tot 366 van HSP60, of van affiniteit poliklonale anti-hHSP60 teenliggaampies wat gesuiwer is uit die serum van aterosklerotiese pasiënte kan ook by Apoherosclerosis induseer −/− ontvangermuise. 46 Dit is belangrik dat immunisering van hipercholesterolemiese ApoE -/− muise met homoloë malondialdehied-lae-digtheid lipoproteïen die teenoorgestelde effek gehad het, dit wil sê, 'n siekte-verbeterende effek. 47

Uitoefening van endoteelstres by rotte of konyne, bv. deur binneaarse inspuiting van bakteriële lipopolisakkaried, lei tot die gelyktydige uitdrukking van adhesiemolekules en HSP60 by bekende voorkeurplekke vir die latere ontwikkeling van aterosklerotiese letsels in EC's by arteriële vertakkingspunte wat aan turbulente bloedvloeitoestande onderwerp is. . 48 Hierdie proses kan in vitro en in vivo gevisualiseer word deur molekulêre beeldingstegnieke (Aanvullende Figuur I). 49

In vitro waarnemings

HSP60 word in die kern geënkodeer, maar word in mitochondria uitgedruk. Onder stresvolle toestande word HSP60 in die sitosol vervoer en verskyn dan op die seloppervlak, waar dit as 'n "gevaarsein" dien vir aangebore en aanpasbare immuniteit. Laasgenoemde is bewys met immunofluoressensie, 50 atoomkragmikroskopie, 9 en metaboliese etikettering. 51 In ons hande lei alle klassieke aterosklerose-risikofaktore wat tot dusver bestudeer is eers tot die gelyktydige endoteeluitdrukking van adhesiemolekules en HSP60, wat 'n interaksie van HSP60-spesifieke T-selle en (outo)teenliggaampies met die teikenselle moontlik maak, in hierdie geval die beklemtoonde EC's. Interessant genoeg is die drempel vir adhesiemolekule en HSP60-uitdrukking by konfrontasie met sulke stresfaktore laer in arteriële in vergelyking met veneuse EC's omdat eersgenoemdes aan lewenslange "voorspanning" onderwerp is deur die hoër arteriële bloeddruk. Dit is gedemonstreer in 'n arterio-veneuse karotis-omleidingsmodel. Hierdie veneuse buise wat aan die nuwe arteriële bloedvloei en druktoestande onderwerp is, het binne 1 tot 2 weke na die operasie neointimale letsels ontwikkel, wat uiteindelik tot volledige restenose gelei het. 52 Die eerste gebeurtenis in hierdie patologiese prosesse is die ECs-uitdrukking van HSP60 en adhesiemolekules en T-selle wat die intima infiltreer. 20 Gestresde EC's, maar nie onbeklemtoondes nie, word gelys deur anti-HSP60 monoklonale of affiniteit-gesuiwerde poliklonale menslike anti-HSP60 teenliggaampies op 'n komplement-gemedieerde wyse of via teenliggaam-afhanklike sellulêre sitotoksisiteit. 53 Verder kan HSP60 ook funksioneer as 'n induseerder van anti-EC-teenliggaampies wat sitotoksiese en apoptotiese reaksies kan aktiveer wanneer dit deur die verwante outo-teenliggaampies herken word. Afhangende van die HSP60 epitoop spesifisiteit, blyk dit dat anti-EC teenliggaampies met HSP60 reaktiwiteit kan verskil in hul funksionele effekte. 54

EC Stressors

Die rol van klassieke aterosklerose risikofaktore is bewys in oorvloedige getalle kliniese, eksperimentele en in vitro studies. Omdat die outo-immuun konsep van aterosklerose in wese staatmaak op 2 aannames—(1) voorafbestaande immuniteit teen HSP60 en (2) patologiese stres-geïnduseerde transformasie van ECs na HSP60-uitdrukkende teikens vir hierdie immuniteit—is dit van belang geag om die rol van verskillende risikofaktore met betrekking tot laasgenoemde verskynsel. Hierdie stressor effek is die eerste keer waargeneem vir hoë (bloed) druk in vivo en in vitro in rotte, 55 sowel as vir lipopolisakkaried in vivo in konyne 48 en in vitro op menslike ECs. 56 Hierdie laasgenoemde data stem ook ooreen met die korrelasie van die lewenslange aansteeklike lading met anti-HSP60 immuniteit en die voorkoms van aterosklerose. 20

Recently, we have obtained in vitro evidence that oxLDL, ie, an inducer of foam cell formation, and advanced glycation end products as a surrogate for diabetic metabolic conditions, also act as endothelial stressors. oxLDL showed a more pronounced HSP60-inducing capacity compared with advanced glycation end products (Figure 4). For a considerable period of time, cigarette smoke extract appeared to be our most potent endothelial stressor. Using cigarette smoke extract in vitro and calibrating its concentration via the nicotine content mimicking blood levels in mild, intermediate, or heavy smokers, we were able to achieve abundant expression of HSP60, adhesion molecules, proinflammatory cytokines, and at higher concentrations autophagy and necrosis. 57 As a final step in this series of experiments on the mode of action of endothelial stressors, we have just recently finished a study on the potential stressor effect of an infection with C. pneumoniae and found this to be the most potent EC stressor that we have observed so far, even exceeding the effect of cigarette smoke extract. C. pneumoniae also induces excessive expression of adhesion molecules and proinflammatory cytokines. Furthermore, ongoing experiments in our laboratory have also revealed a downregulation of the expression of antioxidant molecules and, most importantly, of autophagy-associated molecules, notably ATG 2, ATG 5, and ATG 12. Thus, for a certain period of time, this intercellular endothelial stressing organism seems to be able to create a subtle equilibrium of the host cell metabolism, providing appropriate conditions for its own survival.

Figuur 4. hHSP60 surface expression of human umbilical vein endothelial cells (HUVECs) treated with metabolic stressors. (A) Comparison of the effect of 2 different concentrations of advanced glycation end product (AGE) (200 mg/mL and 400 mg/mL) to native bovine serum albumin (BSA) (400 mg/mL). (B) oxLDL (moderate or high) was compared with native low-density lipoprotein (LDL) (60 μg/mL). Measurements were performed after 6, 16, and 24 hours of stimulation.

Damage of ECs and their sloughing off into the bloodstream has been demonstrated for several atherosclerotic risk factors (eg, cigarette smoking and hyperlipidemia), especially in areas of turbulent blood flow conditions. This results in increased endothelial turnover with increased EC apoptosis or necrosis. Interestingly, this damage seems to be continuously repaired. This reendothelialization can occur both by outgrowing neighboring ECs and by circulating endothelial progenitor cells. 58,59 We hypothesize—but have no experimental proof—that ECs at atherosclerosis predilection sites are especially prone to this sequence of events.

Clinical Observations

All healthy humans display innate and adaptive anti-HSP60 immunity, the latter induced by infection, by vaccination, or as bona fide autoimmunity against biochemically altered autologous HSP60, probably derived from damaged or necrotic ECs. 20,60 For example, it has been speculated that in genetically predisposed individuals the same antigen(s), especially mycobacterial antigen(s), eg, HSP60 (Mtb-HSP60), may induce different immune responses, leading to the development of sarcoidosis and tuberculosis, respectively. 61

The use of circulating sHSP60 concentrations or anti-hHSP60 antibody titers as prognostic biomarkers for the risk of developing CVD has been discussed during the last decade. In a prospective follow-up study of 195 healthy subjects, significantly higher anti-hHSP60 antibody titers were found in individuals with future CVD compared with individuals without cardiovascular events. 62 Similarly, a large population-based study with 826 subjects showed elevated sHSP60 levels in individuals with prevalent/incident carotid atherosclerosis, with serum levels that correlated with common carotid artery intima-media thickness (IMT). 63 These data were later confirmed in a prospective follow-up study. 11 Furthermore, patients with borderline hypertension and coronary heart disease present with elevated levels of sHSP60 64,65 and increased titers of anti-hHSP65 and anti-hHSP70 antibodies are associated with established hypertension. 10 Increased serum levels of sHSP60, sHSP72, and inflammatory markers can be correlated with the extent of cardiac and microvascular dysfunction in patients with angiographically normal coronary arteries. 66

A significant correlation between the titers of anti-hHSP65 antibodies and sHSP60 with carotid atherosclerosis lesion size has been found in a large prospective longitudinal atherosclerosis prevention study originally comprising 1000 volunteers of both sexes, aged 40 to 79 years (the BRUNECK study). 67,68 In follow-up studies on this cohort, it was then shown that anti-HSP60 reactivity of peripheral blood T cells correlates with increased IMT in clinically healthy male youngsters but not in men aged 50 to 69 from this cohort, 69 indicating a more prominent role of specific cellular immunity to HSP60 in the early stages of atherosclerosis. Furthermore, the anti-hHSP60 antibody titer was not only identified as a new early biomarker for morbidity but also for mortality from atherosclerosis. 70 In Western blots, these anti-hHSP60 antibodies not only react with recombinant bacterial HSP60 but also cross-react with recombinant hHSP60. Interestingly, anti-HSP60 antibody titers drop after myocardial infarction, a phenomenon that is probably due to immune complex formation with hHSP60 released from the damaged myocardial tissue. 71 This possible sequence of events has been suggested and proven later in experiments in rats on induction of cardiac hypoxia, as mentioned above. 72

A cross-sectional study involving 17 to 18 year-old clinically healthy men (the Atherosclerosis Risk Factors in Male Youngsters study), 73 revealed an unexpected and alarmingly high incidence of increased arterial IMT as a hallmark of the first inflammatory stage of the disease already afflicting 28% of these young men. This parameter showed a significant correlation with cigarette smoking, followed by a significant correlation with HSP60-specific reactivity of peripheral T cells, surprisingly only then followed by a correlation with the diastolic blood pressure and finally, least significantly, with anti-hHSP60 antibody titers. 73 Furthermore, T-cell reactivity against hHSP60 correlates with increased IMT in these youngsters. 69 This indicates a prominent role of specific cellular immunity to HSP60 in very early stages of atherosclerosis. In a study investigating 19- to 21-year-old young healthy female volunteers (the Atherosclerosis Risk Factors in Female Youngsters study), 74 19% had an increased arterial IMT that correlated significantly with passive smoking and, again similar to the Atherosclerosis Risk Factors in Male Youngsters study, anti-HSP60 reactivity of peripheral T cells. In this group, no correlation between increased IMT and anti-HSP60 antibodies emerged. 74

Lifelong infectious load has been discussed as correlated with antimicrobal HSP60 antibody titers and with atherosclerosis. More detailed studies on anti-HSP60 antibody reactivity have revealed a linear correlation of the antibody titer to non-HSP60 antigens of C. pneumoniae and Helicobacter pylori with the antibacterial HSP60 titer and atherosclerosis. 75,76 Cross-reactivity of plasma anti-GroEL and anti- Porphyromonas gingivalis antibodies with hHSP60 have also been demonstrated in atherosclerosis patients. 77 It therefore seems that anti-HSP60 immunity is a common denominator for the association of infectious load with atherosclerosis. In contrast, no association with ECs dysfunction and the presence and severity of coronary artery disease and antibody response to C. pneumoniae IgG or human or Chlamydia HSP60 has been documented, arguing against the suggestion that infection contributes to disease progression. 78 In our hands, anti-cytomegalovirus antibody titers do not correlate with anti-HSP60 antibody titers. 76 However, this is not surprising, taking into account the fact that viruses do not encode their own HSP60 but that the HSP60 found in viral envelopes originate from the surface of the host cells.

In summary, the results point to a possible primary pathogenetic role of HSP60-specific T cells in the earliest stages of the disease, whereas HSP60 antibodies seem to lead to later aggravation and perpetuation. Our laboratory has recently confirmed this assumption in mice showing that T cells from draining lymph nodes and spleens in ApoE −/− animals immunized with mHSP65 harbor mHSP65 peptide–specific T cells. In humans, we have isolated intralesional T cells both from late and, more importantly, vroeg, clinically still inapparent lesions (Figure 5). The reactivity of intralesional T cells against HSP60 significantly exceeded that obtained with T cells from the peripheral blood from the same donors.

Figuur 5. Immunohistochemical staining of early, clinically inapparent human atherosclerotic lesion. A, Under stress conditions, ECs (green: von Willebrand factor) express hHSP60 (red). Yellow represents colocalization between vWF and HSP60. Blue indicates DNA. B, Adhesion molecules (green: vascular cell adhesion molecule-1) and hHSP60 (red) simultaneously expressed on the EC surface. Blue indicates DNA. The intima of the early lesion contain a higher number of T cells (C) (red: CD3) compared with macrophages (D) (brown: CD68). Original magnification: ×250 (A), ×600 (B), and ×400 (C and D). *Lumen.

HSP Vaccination

In the last few years, several studies have provoked an increased interest in mucosal tolerization against HSP60 aiming to suppress atherogenesis. 79,80 Both of these studies could successfully demonstrate a reduction in aortic plaques by this approach. However, only full-length mHSP65 (not defined proatherogenic peptides) was applied, therefore not taking into account the importance of bacterial-human cross-reactive epitopes. Full-length HSP60 and a HSP60 peptide (253 to 268) have also been orally administrated to LDLr −/− mice before the induction of atherosclerosis, which resulted in a 80% reduction in plaque size in the carotid arteries and in a 27% reduction in plaque size at the aortic root. 81 The reduction in plaque size correlated with an increase in the number of T-regulatory cells, 81 which are known to be protective in atherosclerosis. 82,83 Nasal treatment with mHSP65 can effectively attenuate atherosclerosis in rabbits fed a Western diet. 84 Moreover, a promising cross-reactive B-cell epitope on both mHSP60 and hHSP60 involved in early atherogenesis has recently been demonstrated. 23 However, whether immune reactions against this epitope are involved in the pathogenesis of atherosclerosis remains to be elucidated. oxLDL is another example in which modulation of autoimmunity against atherosclerotic-associated autoantigens represents a novel and promising target for prevention and treatment of CVDs. Similar to HSP60, oxLDL is targeted by both antibody mediated and cellular immune responses. The immune activation is primarily of the proinflammatory Th1-type and inhibition of Th1 immunity reduces atherosclerosis in experimental animals. Atherosclerosis vaccines based on different antigens derived from oxLDL have been developed to modulate these processes. 85

In conclusion, these studies suggest that vaccination with HSP60, or more preferably with atheroprotective HSP60 peptides, is a promising idea for the prevention and treatment of atherosclerosis. We are now in the process of delineating atherogenic HSP60 peptides in the murine system to use these for the development of an antiatherosclerosis vaccine via the induction of mucosal tolerance. Although the tolerizing approach in mice may form the basis for the subsequent development of such a vaccine in humans, it is rather improbable that the same HSP60 peptide candidates will emerge as atherogenic in both species. Here, our own data obtained with T cells from early human atherosclerotic lesions will be of crucial importance.

Open Issues

There are still many other open questions to be answered with respect to the role of adaptive and innate immunity to HSP60 in atherogenesis: (1) Why are healthy people tolerant to autologous HSP60? (2) Does sensitization of HSP60-specific T cells take place in situ or in regional lymph nodes? (3) How can bona fide beneficial anti-HSP60 immunity, ie, for elimination of damaged and dead cells, be distinguished from pathogenetically relevant immune reactions? (4) Which atherogenic HSP60 epitopes are recognized by T cells isolated from early, clinically still inapparent human atherosclerotic lesions? (5) What is the exact sequence of gene expression in early versus late atherosclerotic lesion as assessed by microarray techniques? (6) With respect to the endothelial stressor-effect of classical atherosclerotic risk factors, what is the role of infection with C. pneumoniae ? (7) Although binding of HSPs to toll-like receptors and trigging of the MyD88 signal-transduction pathway has now been unequivocally demonstrated, what is the possible pathogenic significance of this fact? (8) Finally, because data from clinical studies showed an increasing statistical significance of the reactivity of HSP60-specific T cells in the peripheral blood with decreasing age of the cohorts, we deem it important to perform similar studies in children, ie, revealing the very earliest stages of atherosclerotic disease.


The COVID-19 pandemic poses an unprecedented public health crisis. At present, our narrow understanding of the immune system’s response to the infection limits our capacity to prevent and treat severe disease. As part of the efforts outlined in the NIAID Strategic Plan for COVID-19 Research, NIAID researchers are spearheading a large, international collaboration to unveil the innate and adaptive immune responses during acute COVID-19 infection and convalescence. Each researcher will contribute their unique expertise to collectively elucidate the innate and adaptive immune response to COVID-19 infection. This synergistic coalition of researchers will work closely and share data to maximize the impact of patient samples. The overall goal is to identify immunological and virological correlates and predictors of clinical outcomes.

The research projects will examine the following:

  • Genetic markers of susceptibility to severe COVID-19 infection
  • Composition of T- and B-cell repertoire and mapping of virus-specific T-cell receptor (TCR) sequences
  • Cytokine and chemokine profiling, including interferon (IFN) signature and soluble markers of inflammation
  • Antibody responses to COVID-19 infection
  • Anti-cytokine autoantibodies
  • Levels of plasma gelsolin
  • Humoral immunological signature of the human virome
  • Anti-commensal antibody repertoire
  • Systems biology approach to understand changes in the immune system
  • Intrapatient SARS-CoV-2 genetic variation
  • Role of neutrophil extracellular traps (NETs)

How To Contribute

This website is designed to inform physicians of the research occurring at NIAID. If interested in contributing to any or all of these research projects, please reach out to the contact person on the respective project page.


Antigen-antibody reaction

Cause of

…effects are the result of antibody-antigen responses (i.e., they are the products of B-cell stimulation). These can be divided into three basic types.

…anaphylaxis is mediated primarily by antibodies—specifically those of the immunoglobulin E (IgE) class. These antibodies recognize the offending antigen and bind to it. The IgE antibodies also bind to specialized receptor molecules on mast cells and basophils, causing these cells to release their stores of inflammatory chemicals such as histamine,

…the result of an aberrant immune system.

…carry the Rh factor (an antigen in this context) cross the placental barrier and enter the mother’s bloodstream. They stimulate the production of antibodies, some of which pass across the placenta into fetal circulation and lyse, or break apart, the red blood cells of the fetus (hemolysis).

…of complement in response to antigen-antibody (immune) complexes that are deposited in tissues. The classes of antibody involved are the same ones that participate in type II reactions—IgG and IgM—but the mechanism by which tissue damage is brought about is different. The antigen to which the antibody binds is not…

Antigen-antibody complexes form only after the nuclear contents of a cell are released into the bloodstream during the normal course of cell death or as a result of inflammation. The resultant immune complexes are deposited in tissues, causing injury. Certain organs are more commonly involved…

…components of the streptococci (antigens) whose structure resembles that of molecules found in human tissue (“self antigens”). Because of this resemblance, the antibodies that recognize streptococcal antigens may mistakenly react with similarly shaped antigens of certain cells of the body—such as those of the heart. By binding to these…

…would any foreign invader, forming antigen-antibody complexes that lodge in the blood vessel walls. Complement, a series of blood proteins, is then activated, causing inflammation. Serum sickness develops within two weeks of serum injection and usually lasts only a few days. Its severity depends on both the amount of serum…

Response to

An antigen that induces an immune response—i.e., stimulates the lymphocytes to produce antibody or to attack the antigen directly—is called an immunogen.

A significant feature of antigen-antibody reactions is specificity the antibodies formed as a result of inoculating an animal with one microbe will not react with the antibodies formed by inoculation with a different microbe. Antibodies appear in the blood serum of animals, and laboratory tests of antigen-antibody reactions are…

To be antigenic, a substance is usually both relatively large and foreign to the body. Large proteins are often strong antigens. Smaller chemicals can become antigenic by combining with proteins in chemicals called haptens.

…animals mount two kinds of immune response, humoral and cellular. In humoral immunity, B lymphocytes, usually triggered by helper T lymphocytes, make antibodies (proteins that recognize and bind foreign molecules) to the viral protein. The antibody synthesized as a result of the immune response against a specific viral antigen

Work of

…to be his investigations into antigen-antibody interactions, which he carried out primarily at Rockefeller Institute (now called Rockefeller University) in New York City (1922–43). In this research Landsteiner used small organic molecules called haptens—which stimulate antibody production only when combined with a larger molecule, such as protein—to demonstrate how small…

…many important discoveries about the immune response. Perhaps his most notable achievement was his recognition that the phagocyte is the first line of defense against acute infection in most animals, including humans, whose phagocytes are one type of leukocyte, or white blood cell. This work formed the basis of Metchnikoff’s…

…term allergy to describe these antibody-antigen reactions.

…the first evidence that an immune response could cause damage as well as provide protection against disease. During his career Richet helped to elucidate problems of hay fever, asthma, and other allergic reactions to foreign substances and explained some cases of toxicity and sudden death not previously understood.


Delayed (Type IV) Hypersensitivity

Delayed hypersensitivity, or type IV hypersensitivity, is basically a standard cellular immune response. In delayed hypersensitivity, the first exposure to an antigen is called sensitization, such that on re-exposure, a secondary cellular response results, secreting cytokines that recruit macrophages and other phagocytes to the site. These sensitized T cells, of the Th1 class, will also activate cytotoxic T cells. The time it takes for this reaction to occur accounts for the 24- to 72-hour delay in development.

The classical test for delayed hypersensitivity is the tuberculin test for tuberculosis, where bacterial proteins from M. tuberculosis are injected into the skin. A couple of days later, a positive test is indicated by a raised red area that is hard to the touch, called an induration, which is a consequence of the cellular infiltrate, an accumulation of activated macrophages. A positive tuberculin test means that the patient has been exposed to the bacteria and exhibits a cellular immune response to it.

Another type of delayed hypersensitivity is contact sensitivity, where substances such as the metal nickel cause a red and swollen area upon contact with the skin. The individual must have been previously sensitized to the metal. A much more severe case of contact sensitivity is poison ivy, but many of the harshest symptoms of the reaction are associated with the toxicity of its oils and are not T cell mediated.


Cytokine “storm”

In some cases, the immune system overreacts during an infection, releasing more cytokines than necessary, and progressively recruiting new hordes of activated “angry” white blood cells, which produce even more cytokines. This means a “cytokine storm” is emerging.

Like other signalling molecules (including hormones and neurotransmitters), cytokines can enter the bloodstream. These powerful regulators of inflammation can affect the whole body as seen in sepsis or as a side-effect of some anti-cancer therapies. Large quantities of cytokines can cause widespread (systemic) inflammation that can damage multiple organs.

Some cytokines can also affect the blood vessels, causing a dramatic drop in blood pressure. This limits blood supply and starves the vital tissues and organs – including the heart, lungs, brain and kidneys – of oxygen and nutrients.


Verwysings

1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, and Pinsky MR. (2001). Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Critical Care Medicine, 29(7), 1303–10. Find this resource:

2. van der Poll T, and Opal SM. (2008). Host-pathogen interactions in sepsis. Lancet Infectious Diseases, 8(1), 32–43. Find this resource:

3. Denk S, Perl M, and Huber-Lang M. (2012). Damage- and pathogen-associated molecular patterns and alarmins: keys to sepsis? European Surgery Research, 48(4), 171–9. Find this resource:

4. Hotchkiss RS, and Karl IE. (2003). The pathophysiology and treatment of sepsis. New England Journal of Medicine, 348(2), 138–50. Find this resource:

5. Opal SM. (2004). The nexus between systemic inflammation and disordered coagulation in sepsis. Journal of Endotoxin Research, 10(2), 125–9. Find this resource:

6. Fourrier F. (2012). Severe sepsis, coagulation, and fibrinolysis. Critical Care Medicine, 40(9), 2704–8. Find this resource:

7. Ince C. (2005). The microcirculation is the motor of sepsis. Critical Care, BioMed Central, 9(4), S13. Find this resource:

8. Garrabou G, Moren C, Lopez S, et al. (2012). The effects of sepsis on mitochondria. Journal of Infectious Diseases, 205(3), 392–400. Find this resource:

9. Zarjou A and Agarwal A. (2011). Sepsis and Acute Kidney Injury. Journal of the American Society of Nephrology, 22(6), 999–1006. Find this resource:

10. Wan L, Bagshaw SM, Langenberg C, Saotome T, May C, and Bellomo R. (2008). Pathophysiology of septic acute kidney injury: What do we really know? Critical Care Medicine, 36, S198–203. Find this resource:

11. Bhatia M and Moochhala S. (2004). Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. Journal of Pathology, 202(2), 145–56. Find this resource:

12. Honore PM, Jacobs R, Joannes-Boyau O, et al. (2011). Septic AKI in ICU patients. Diagnosis, pathophysiology, and treatment type, dosing, and timing: a comprehensive review of recent and future developments. Annals of Intensive Care, 1(1), 32. Find this resource:

13. Flynn A, Chokkalingam Mani B, and Mather PJ. (2010). Sepsis-induced cardiomyopathy: a review of pathophysiologic mechanisms. Heart Failure Review, 15(6), 605–11. Find this resource:

14. Tsujimoto H, Ono S, and Mochizuki H. (2009). Role of Translocation of Pathogen-Associated Molecular Patterns in Sepsis. Digestive Surgery, 26(2), 100–9. Find this resource:

15. Scalfani MT, and Diringer MN. (2011). Year in review 2010: critical care—neurocritical care. Critical Care, 15(6), 237. Find this resource:

16. Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe E, and Boudou P. (2006). Diagnosis of adrenal insufficiency in severe sepsis and septic shock. American Journal of Respiratory Critical Care Medicine, 174(12), 1319–26. Find this resource:

17. Marik PE. (2009). Critical illness-related corticosteroid insufficiency. Chest, 135(1), 181–93. Find this resource:

18. Ling Y, Li X, and Gao X. (2012). Intensive versus conventional glucose control in critically ill patients: a meta-analysis of randomized controlled trials. European Journal of Internal Medicine, 23(6), 564–74. Find this resource:


Sources & Further Reading

Edwards, K.M., Burns V.E., Reynolds, T., Carroll, D., Drayson, M., & Ring, C. (2006). Acute stress exposure prior to influenza vaccination enhances antibody response in women. Brain, Behavior, and Immunity, 20:159-68.

Glaser, R., Sheridan, J. F., Malarkey, W. B., MacCallum, R. C., & Kiecolt-Glaser, J. K. (2000). Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosomatic Medicine, 62, 804-807.

Glaser, R., Robles, T. F., Malarkey, W. B., Sheridan, J. F., & Kiecolt-Glaser, J. K. (2003). Mild depressive symptoms are associated with amplified and prolonged inflammatory responses following influenza vaccination in older adults. Archives of General Psychiatry, 60, 1009-1014.

Kiecolt-Glaser, J. K., Glaser, R. (1993). Mind and immunity. In: D. Goleman & J. Gurin, (Eds.) Mind/Body Medicine (pp. 39-59). New York: Consumer Reports.

Kiecolt-Glaser, J. K., & Glaser, R. (2002). Depression and immune function: Central pathways to morbidity and mortality. Journal of Psychosomatic Research, 53, 873-876.

Kiecolt-Glaser, J. K., McGuire, L., Robles, T., & Glaser, R. (2002). Psychoneuroimmunology: Psychological influences on immune function and health. Journal of Consulting and Clinical Psychology, 70, 537-547.

Kiecolt-Glaser, J. K., McGuire, L., Robles, T., & Glaser, R. (2002). Psychoneuroimmunology and psychosomatic medicine: Back to the future. Psychosomatic Medicine, 64, 15-28.

Pressman, S. D., Cohen, S., Miller, G.E., Barkin, A., Rabin, B. S., Treanor, J. J. (2005). Loneliness, Social Network Size and Immune Response to Influenza Vaccination in College Freshmen, Health Psychology, 24, pages.

Robinson-Whelen, S., Tada, Y., MacCallum, R. C., McGuire, L., & Kiecolt-Glaser, J. K. (2001). Long-term caregiving: What happens when it ends? Journal of Abnormal Psychology, 110, 573-584.

Segerstrom, S. C. and Miller, G. E. (2004). Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry. Psychological Bulletin, Vol. 130, No. 4.



Kommentaar:

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