Periphery And Brain, Innate And Adaptive Immunity in Parkinson's Disease Part 1

Abstract

Parkinson's disease (PD) yog ib qho kab mob neurodegenerative uas alpha-synuclein ua lub luag haujlwm tseem ceeb hauv kev tuag thiab kev ua haujlwm tsis zoo ntawm cov neurons, ob qho tib si, hauv nruab nrab, nrog rau hauv lub paj hlwb peripheral.

Dhau li ntawm cov xwm txheej neuronal pom hauv cov neeg mob, PD kuj suav nrog cov tshuaj tiv thaiv kab mob tseem ceeb. Nws tau pom zoo tias PD-koom nrog lub cev tiv thaiv kab mob yuav muaj kev cuam tshuam rau kev noj qab haus huv neuronal, yog li qhib kev tiv thaiv kab mob raws li lub peev xwm kho mob hauv PD. Kev tiv thaiv kab mob thaum lub sij hawm tus kab mob tshwm sim nyob rau hauv lub hlwb, nrog rau microglia, tab sis kuj nyob rau hauv periphery nrog kev hloov nyob rau hauv lub hlwb ntawm lub cev tiv thaiv kab mob, tshwj xeeb tshaj yog monocytes, nrog rau cov adaptive tiv thaiv kab mob, xws li T-cells. Qhov kev paub no tshwm sim los ntawm ntau tus neeg mob cov kev tshawb fawb, tab sis kuj los ntawm cov ntaub ntawv hauv cov qauv tsiaj ntawm tus kab mob, muab cov pov thawj muaj zog rau kev tiv thaiv kab mob hauv nruab nrog cev thiab kev sib txuas lus hauv nruab nrab paj hlwb thiab periphery hauv PD.

Ntawm no peb tshuaj xyuas cov ntaub ntawv qhia tias alpha-synuclein ua lub luag haujlwm tseem ceeb hauv kev ua kom lub cev tsis muaj zog thiab hloov pauv lub cev. Peb kuj tseem yuav piav qhia txog cov kev tshawb fawb qhia tias qhov mob hauv PD suav nrog kev hloov pauv thaum ntxov hauv lub cev thiab hloov pauv lub cev tiv thaiv kab mob uas tsim muaj zog los ntawm lub sijhawm thaum muaj kab mob, pab txhawb rau neuronal degeneration thiab symptomatology hauv cov neeg mob. Cov nyiaj tshiab no tau pab txhawb rau lub ntsiab lus ntawm PD raws li kab mob ntau yam uas yuav tsum tau ua kom muaj kev sib koom ua ke ntau dua li lub hlwb tsom mus rau classical mus kom ze.

Kev sib raug zoo ntawm lub cev tiv thaiv kab mob adaptive thiab lub cev tiv thaiv kab mob yog kev sib koom ua ke. Lub cev tiv thaiv kab mob hloov pauv yuav tsum muaj lub cev tiv thaiv kab mob los muab kev tiv thaiv txaus tiv thaiv kab mob tab sis kuj yuav tsum muaj lub cev tiv thaiv kab mob los pab thaum cov tshuaj tiv thaiv tsis txaus. Lub cev tiv thaiv kab mob, ntawm qhov tod tes, xav kom lub cev tiv thaiv kab mob kom paub txog thiab tua cov kab mob nyuaj. Ob qho tib si ntxiv rau ib leeg kom lub cev tiv thaiv kab mob ua haujlwm zoo li qub. Ntxiv rau cov no, peb kuj yuav tsum txhim kho peb txoj kev tiv thaiv kab mob. Cistanche tuaj yeem txhim kho kev tiv thaiv zoo. Nqaij tshauv muaj ntau yam khoom xyaw lom, xws li polysaccharides, ob lub nceb, thiab Huangli, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb nqa ntau yam haujlwm ntawm lub cev. Cell-zoo li cov hlwb, nce lawv cov kev tiv thaiv kab mob los txhim kho kev tiv thaiv.

Nyem cistanche tubulosa cov txiaj ntsig

Ntsiab lus

Alpha-synuclein · Parkinson · Microglia · Monocyte · T-Cell · Neuroinflammation.

Taw qhia

Parkinson tus kab mob (PD) yog tus cwj pwm los ntawm qhov tseem ceeb dopaminergic neuronal poob hauv substantia nigra (SN) thiab intraneuronal aggregation ntawm alpha-synuclein (-syn) hauv Lewy lub cev. Nyob rau hauv kaum xyoo dhau los, kev tshawb fawb txog lub luag haujlwm ntawm kev tiv thaiv kab mob hauv PD tau txais lub zog. Ntau cov ntaub ntawv pov thawj txhawb nqa qhov tshwm sim ntawm qhov mob hnyav tau tshwm sim los ntawm kev tshawb fawb hauv tib neeg lub hlwb thiab biofluids (CSF thiab serum), nrog rau cov tsiaj qauv ntawm PD. Lub zej zog kev tshawb fawb tam sim no tau tshaj tawm tias cov tshuaj tiv thaiv kab mob hauv PD tshwm sim thaum ntxov thiab hloov pauv hloov pauv nrog cov kab mob kev loj hlob, pab txhawb rau neuronal degeneration thiab symptomatology hauv cov neeg mob.

Tsis tas li ntawd, kev tshawb fawb tau pom tias ob lub hlwb, nrog rau cov kab mob peripheral tiv thaiv kab mob, tau koom nrog hauv qhov mob no uas ua rau lub cev tsis muaj zog thiab yoog raws. Qhov kev nkag siab tshiab no tau pab txhawb rau lub ntsiab lus ntawm PD raws li kab mob ntau yam uas yuav tsum tau ua kom muaj kev sib koom ua ke ntau dua li lub hlwb tsom mus rau classical mus kom ze. Hauv qhov kev tshuaj xyuas no, peb yuav tshawb nrhiav cov kev tshawb fawb tseem ceeb tshaj plaws uas tau ua tiav nyob rau xyoo kaum xyoo dhau los hais txog kev tiv thaiv kab mob hauv PD, nrog rau kev tsom tshwj xeeb rau lub luag haujlwm ntawm -syn.

Microgliosis hauv Parkinson's Disease thiab cov cim qhia ntxov ntawm Neuroinflamation

Lub xub ntiag ntawm microglia activation (xws li nce tus lej thiab / lossis kev hloov pauv hauv morphology thiab protein qhia) hauv lub hlwb ntawm PD cov neeg mob tau pom los ntawm cov kev tshawb fawb histopathological hauv cov ntaub so ntswg postmortem [74]. Ntau qhov kev tshawb fawb tau tshaj tawm txog qhov nce ntawm cytokines hauv lub hlwb thiab CSF, qhia txog kev ua rau cov kab mob pro-inflammatory thiab mob ntev hauv PD [102]. Thawj qhov kev xav pom tau hais tias microglia teb ib zaug neurons tuag, thiab qhov kev tiv thaiv kab mob tom ntej yog deleterious rau cov neeg muaj sia nyob. Raws li, ntau cov kev tshawb fawb tau txhawb nqa lub peev xwm neurotoxic ntawm lub cev tiv thaiv kab mob ntau dhau thiab cov cytokines pro-inflammatory (saib hauv [149]). Yog li, nws zoo li tias qhov kev tuag neuronal hauv PD yog, tsawg kawg yog ib feem, vim yog kev tiv thaiv kev tiv thaiv kab mob.

Txawm li cas los xij, seb qhov no yog qhov tsis muaj peev xwm tiv thaiv kab mob (tsis ua haujlwm) lossis qhov kev ua haujlwm pro-inflammatory (tau txais kev ua haujlwm) tseem tsis tau paub. Yuav ua li cas thaum ntxov tus kab mob no yog ib qho teeb meem loj heev nyob rau hauv lub xyoo dhau los thiab lub hom phiaj ntawm kev tshawb fawb los ntawm ntau lub labs. Raws li qhov tshwm sim, qhov ntev ntawm tus yam ntxwv ntawm PD qauv thiab kev tshuaj xyuas dav dav ntawm tib neeg PD lub hlwb cov ntaub so ntswg, tau pom tias microgliosis tshwm sim ua ntej ntawm tes tuag lossis txawm tias tsis muaj [149]. Raws li, microgliosis tau pom nyob rau hauv lub hlwb postmortem los ntawm cov neeg mob PD nyob rau hauv cov cheeb tsam uas tsis pom kev tuag neuronal tseem ceeb [90], uas kuj tau lees paub los ntawm vivo PET duab [61, 132] siv PK11195, ib lub ligand ntawm peripheral benzodiazepine receptor / TSPO (upregulated ntawm activated microglia thiab lwm yam kev tiv thaiv kab mob hlwb).

Tsis tas li ntawd, PD cov qauv tsiaj tau pom tias cov lus teb microglia ua ntej lub paj hlwb poob, qhia ntxiv tias kev tiv thaiv kab mob tshwm sim thaum ntxov, raws li cov neurons pib degenerating, qhov twg neurotransmission thiab lwm yam haujlwm cuam tshuam [149]. Qhov no yog ua tau vim hais tias microglia qhia receptors uas paub txog cov proteins ntawm neuronal keeb kwm, xws li neurotransmitters. Ntxiv mus, nws tau paub tias "homeostatic xwm txheej ntawm microglia" yog lub xeev active, ua tiav los ntawm cov neuronal qhia ntawm molecules assertive ntawm ib tug "zoo" mob [11]. Qhov no tuaj yeem hloov pauv thaum cov kev ua haujlwm neuronal raug cuam tshuam hauv PD, yog li ua kom microglia ua ntej neuronal cell tuag. Qhov kev ua kom ntxov ntxov no tau tshwm sim rau ntau lub sijhawm hauv ntau tus qauv PD, ob qho tib si hauv nas thiab hauv cov tsiaj tsis yog tib neeg (saib hauv qab).

Tsis tas li ntawd, cov ntaub ntawv tau txais los ntawm REM pw tsaug zog kev coj cwj pwm tsis zoo (RBD) cov neeg mob- suav tias muaj kev pheej hmoo siab rau kev tsim PD thiab yog li putative prodromal PD [14]- qhia tias microgliosis tshwm sim ntau xyoo ua ntej kev kuaj mob PD [164]. Yog li ntawd, cov lus teb ntawm microglia tshwm sim thaum ntxov hauv PD thiab tuaj yeem ua rau muaj tus kabmob kis mus. Seb lub cev tiv thaiv kab mob yog deleterious nyob rau hauv txhua theem ntawm tus kab mob (prodromal, ntxov, thiab lig) thiab seb nws plays lub luag hauj lwm nyob rau hauv tus kab mob pib thiab etiology tseem tsis tau txhais.

-synuclein ua tus pib ntawm lub cev tiv thaiv kab mob

Microglia activation yog ib qho tshwm sim thaum ntxov hauv PD, raws li lawv paub cov tsos mob ntxov ntawm neuronal tsis ua haujlwm lossis kev ntxhov siab thiab ua raws li. Ntawm cov cim no, microglia tuaj yeem pom cov kev hloov pauv hauv cov qauv ntawm cov proteins endogenous zoo li -syn, qhov twg nws cov fibrillation thiab antigenic txoj kev loj hlob tuaj yeem pib ua kom tsis muaj menyuam los ntawm kev ua raws li kev puas tsuaj cuam tshuam nrog cov qauv (DAMP) (rau kev tshuaj xyuas ntau ntxiv peb xa mus tus nyeem ntawv rau [51]).

Lub peev xwm ntawm -syn tau pom thawj zaug los ntawm kev ua haujlwm hauv lub cev los ntawm Zhang lab [194] thiab Federof-Maguire-Zeiss pab pawg [165]. Cov kev tshawb pom no tau dhau los tshwj xeeb tshaj yog thaum qhov kev tso tawm ntawm -syn los ntawm neurons tau piav qhia [109]. Ntxiv mus, nws yog speculated tias tag nrho cov misfolded -syn tso tawm los ntawm neurons yuav nce zuj zus los ntawm tus kab mob. Qhov no yuav muaj qhov cuam tshuam ncaj qha txog lub cev tiv thaiv kab mob, raws li kev tshawb fawb tau pom tias muaj peev xwm ntawm -syn los pib cov lus teb tiv thaiv kab mob yog ntau dua thaum cov protein raug misfolded (fibrils los yog oligomeric) [84] los yog cuam tshuam los ntawm PD-txuas kev hloov pauv [83 , 144] thiab tuaj yeem muaj zog los ntawm cov hlwv extracellular muab tau los ntawm PD cov neeg mob cov ntshav [68].

Qhov tseem ceeb, lub luag haujlwm ntawm -syn hauv kev ua kom lub cev tiv thaiv kab mob hauv lub cev yog qhov tseeb rau ob qho tib si microglia thiab monocytic hlwb, raws li kev tshawb fawb tau pom tias -syn tuaj yeem qhib cov hlwb myeloid hauv lub hlwb thiab periphery [103, 111].

Lub luag haujlwm no ntawm -syn raws li DAMP tau ua rau muaj ntau yam ntawm kev ua haujlwm tshawb xyuas kev sib cuam tshuam ntawm ntau hom -syn nrog ntau hom membrane proteins uas qhia txog microglia (thiab lwm cov hlwb myeloid) (Table 1). Ntawm qhov cuam tshuam tshwj xeeb, Tus Hu Xov Tooj Zoo li receptors (TLR) 2 thiab 4, uas tau tswj hwm hauv monocytes thiab microglia hauv PD cov neeg mob [40, 41, 97], tau raug npaj ua tus tseem ceeb hauv kev tiv thaiv kab mob hauv lub cev. Ntau lub chaw kuaj mob tau pom nyob rau hauv vivo thiab hauv vitro tias TLR2 paub txog oligomeric lossis fibrillar cov ntaub ntawv ntawm -syn, ua rau cov teeb meem pro-inflammatory, ntxiv ua rau neuronal degeneration thiab tuag [34, 72, 97].

Txawm li cas los xij, TLR4 zoo li paub txog txhua hom -syn (monomeric thiab fibrillar) thiab thaum nws pib cov lus teb inflammatory, nws kuj txhawb nqa -syn clearance, txhawb kev hloov lossis kev tiv thaiv lub luag haujlwm rau TLR4 [50]. Raws li, thaiv TLR2 tau pom tias yog neuroprotective, thaum ua kom lossis overexpression ntawm TLR4 exerts tiv thaiv hauv nas qauv ntawm -synucleinopathies [98, 176].

-syn kuj tau pom tias muaj kev cuam tshuam nrog kev sib ntxiv receptor (CR) 3 (integrin M 2, lossis CD11b / CD18) thiab CR4 (integrin X 2, lossis CD11c / CD18), uas paub tias kho microglial phagocytosis. Aggregated -syn cuam tshuam nrog CD11b ua rau NOX2 ua kom muaj zog thiab nce oxygen radicals hauv nas [87, 180]. Peb txoj kev tshawb fawb tsis ntev los no qhia tau hais tias, txawm hais tias tib neeg -syn cuam tshuam nrog tib neeg CR3 thiab CR4, CR4 zoo li muaj lub luag haujlwm tshwj xeeb hauv kev lees paub ntawm cov ntaub ntawv fibrillar.

Ntxiv mus, kev hloov pauv ntawm CRs yog qhov tseem ceeb rau kev tshem tawm ntawm cov protein thiab phagolysosome tsim [93], qhia txog cov luag haujlwm ntawm cov membrane receptors. Tsis tas li ntawd, nas integrins CD11b (M 2) thiab 1 tau cuam tshuam nrog chemotaxis thiab microglia tsiv teb tsaws induced los ntawm -syn [96, 180]. -syn kuj cuam tshuam nrog CD36 [165] thiab ua ke nrog fyn kinase (nonreceptor Src tsev neeg tyrosine kinase), mediates -syn uptake thiab tom qab NLRP3 inflammasome activation [133]. NLRP3 inflammasome activation tau pom tias ua lub luag haujlwm tseem ceeb hauv cov txheej txheem neurodegenerative ntawm cov qauv PD sib txawv, raws li kev tsom mus rau nws cov haujlwm yog neuroprotective hauv cov qauv nas [65, 120]. Qhov no kuj tau txais kev txhawb nqa los ntawm kev hloov pauv hauv IL-1 thiab NLRP3 hauv PD cov neeg mob [29].

Yog li -syn kev cuam tshuam nrog lub cev tiv thaiv kab mob yog txhais los ntawm -syn-hom, pab txhawb rau nws qhov kev tshem tawm thiab nyob rau tib lub sijhawm rau kev tiv thaiv kab mob. Yog li, -syn induces activation ntawm intracellular cascades xws li ERK thiab p38 MAPK, stimulation ntawm NFκB nyob ntawm cov noob transcription, thiab NLRP3 inflammasome activation, tag nrho cov ua rau induction ntawm pro-inflammatory signals [38, 65, 72, 83, 97, 133] ib.

Raws li, peb thiab lwm tus 'kev tshawb fawb tau pom tias extracellular -syn ua rau pro-inflammatory cytokine ntau lawm thiab oxidative kev nyuaj siab, thaum kawg ua rau neurodegeneration [65, 77, 78]. Ib daim ntawv ceeb toom hais txog -syn concentrations siv nyob rau hauv feem ntau cov kev tshawb fawb, uas nyob deb ntawm lub physiological -syn theem qhia nyob rau hauv tib neeg kua [26] (rau kev sib tham ntxiv saib [51]). Ntxiv mus, paradoxically, CSF -syn txo qis hauv cov neeg mob PD vs. cov neeg noj qab haus huv [26], txawm tias oligomeric lossis misfolded zoo li nce li no nce antigenicity [76].

Ib yam li ntawd, nyob rau hauv lub hlwb cov ntaub so ntswg, siab molecular hnyav -syn nce nyob rau hauv synucleinopathies, thiab tag nrho cov protein kuj nce nyob rau hauv MSA, txawm hais tias tsis heev nyob rau hauv PD [173]. Yog li, -syn kev tiv thaiv kab mob tuaj yeem cuam tshuam rau hauv zos nce ntxiv ntawm misfolded antigenic -syn hauv synapses, es tsis yog qhov nce ntawm cov protein ntau.

Lub luag haujlwm ntawm microglia ntawm kev sib kis ntawm lub cev ntawm -synuclein pathology

Nws tau npaj siab tias -syn pathology tuaj yeem kis tau anatomically, thiab qhov no yuav tshwm sim los ntawm kev tso tawm ntawm misfolded -syn thiab nws cov tom ntej uptake los ntawm kev sib txuas ntawm tes noj qab haus huv, qhov twg misfolded -syn tuaj yeem ua tus qauv thiab txhawb kev sib sau ua ke. Hauv cov ntsiab lus no, microglia kuj tseem tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev kis tus kab mob los ntawm cov txheej txheem tsis-cell autonomous mechanisms. Raws li tau hais, -syn tso tawm los ntawm neurons activates microglia thiab qhov no nyob rau hauv lem yuav ntxiv txhawb pathological -syn hloov kho.

Piv txwv li, -syn-induced inflammasome activation yuav ua rau caspase-1 qhia, uas ua rau -syn truncation [181].Tsis tas li ntawd, microglial activation txhawb oxidative kev nyuaj siab uas tuaj yeem ua rau oxidation lossis nitration ntawm -syn [55, 160]. Ib txoj kev tshawb fawb tsis ntev los no qhia tias microglia-tsim exosomes kuj koom nrog hauv qhov kev sib kis no, vim tias lawv tuaj yeem yog qhov chaw ntawm oligomeric -syn thiab txhawb nqa ntawm neuronal -syn aggregation [39]. Yog li, -syn per se lossis lwm yam tseem ceeb txhawb kev ua kom microglia (raws li cov xwm txheej tsis muaj kev tiv thaiv kab mob, saib hauv qab no) yuav ua rau -syn pathology, txuas ntxiv txuas ntxiv mus.

Qhov tseem ceeb, microglia yog cov hlwb uas zoo tshaj plaws ntshiab extracellular -syn nyob rau hauv lub hlwb, thiab qhov no yuav tsum tiv thaiv kom txhob kis tau tus kab mob / noob [110]. Txawm li cas los xij, thaum txhim kho thiab tswj tsis tau, lub peev xwm microglial tshem tawm tuaj yeem ua rau muaj kuab lom los yog ua tsis taus thiab ua rau cov synaptic degeneration. Tseeb tiag, LPS-induced microglia activation txhawb tus tswv tsev -syn hloov mus rau grafted neurons, corroborating cov nyhuv deleterious ntawm overt pro-inflammatory activation.

Txawm li cas los xij, qhov depletion ntawm microglia nce kev hloov pauv ntawm -syn ntawm grafted neurons, txhawb microglia qhov tseeb hauv -syn clearance [60]. Controversially, lwm txoj kev tshawb fawb qhia qhov opposite, txij li thaum nyob rau hauv lawv cov kev sim tsim, microglia depletion txo -syn neuronal pathology tom qab intracerebral txhaj ntawm -syn fibrils [39]. Cov kev tsis sib xws no yuav tshwm sim vim yog cov qauv sib txawv siv thiab xav tau kev tshawb fawb ntxiv kom nkag siab txog lub luag haujlwm ntawm microglia hauv -syn pathology thiab nws qhov kev sib kis.

-syn degradation nyob rau hauv microglia cuam tshuam nrog autophagy thiab lysosomal clearance, uas zoo nkaus li nyob ntawm qhov ua kom cov profile ntawm microglia, hom -syn (misfolded, mutated ...), nrog rau muaj lwm yam molecules. Raws li tau hais, kev hloov pauv ntawm CR yuav tsum muaj rau -syn ntsig txog phagolysosome tsim [93]. Qee cov kev tshawb fawb qhia tias muaj zog phagocytosis thaum ua kom muaj monomeric -syn [135] thaum txo qis yog tias raug mob fibrillar -syn [32, 190]. -syn zoo li induce lysosomal puas thiab oxidative kev nyuaj siab [53].

Raws li, kev ua haujlwm tsis ntev los no qhia tias fibrillar tab sis tsis yog monomeric -syn ua rau lysosomal puas thiab, yog li ntawd, tsis ua hauj lwm hauv autophagy hauv microglia, uas ua rau mitochondria puas thiab microglia cell tuag [21]. Txawm hais tias qhov kawg no, qhov degeneration thiab tuag ntawm microglia tau kawm tsis zoo hauv PD.

Fig. 1 Kev tiv thaiv kab mob rau alpha-synuclein-induced neurodegeneration. Thaum lub sij hawm Parkinson tus kab mob, -Synuclein (-syn) raug hloov pauv tom qab kev hloov pauv (phosphorylation, nitration, truncation ...), tsim cov hom oligomeric, thiab thaum kawg cov fibrils insoluble uas sib sau ua ke hauv cov neurons hauv Lewy Bodies. Cov txheej txheem no ua rau kev ua haujlwm tsis zoo neuronal thiab thaum kawg ntawm tes tuag. Neurons tuaj yeem tso tawm monomeric lossis hloov kho -syn mus rau qhov chaw extracellular.

Nyob ntawd, lawv yuav tsum raug tshem tawm los ntawm microglia thiab / lossis infiltrating macrophages (CD163 ntxiv / CCR2 ntxiv), tab sis kuj los ntawm astrocytes. Yog tias cov txheej txheem no ua tsis tiav, qhov hloov kho -syn tuaj yeem raug coj los ntawm cov neeg nyob sib ze noj qab haus huv neurons, qhov chaw uas nws yuav cog cov aggregation ntawm endogenous -syn. Kev hloov kho -syn yuav ua ke ua ke raws li kev puas tsuaj ntawm cov qauv molecular (DAMP) thiab ntawm ntau lub cev tiv thaiv kab mob pom muaj nyob hauv microglia thiab macrophages, ua rau muaj kev cuam tshuam rau cov lus teb. Cov pro-inflammatory cytokines yuav ntxiv txhawb neurodegeneration los ntawm kev ncaj qha nyob rau hauv neurons los yog indirectly los ntawm kev txhawb A1 astrocyte sib txawv. Qhov kev tiv thaiv kab mob hauv lub cev no kuj tseem yuav nrog los ntawm kev hloov lub cev tiv thaiv kab mob. Lub intracellular degradation ntawm pathological -syn yuav coj peptides ntawm cov protein mus rau MHC system uas yuav tig mus qhib CD8 (T-cytotoxic cells, Tc), ntawm MHCI, thiab CD4 (T-helper hlwb, Th), ntawm MHCII. Cov txheej txheem zoo li no yuav tshwm sim ob qho tib si hauv lub hlwb, tab sis kuj nyob rau hauv qhov chaw. Nyob ntawm cov cytokines tsim, CD4-Th hlwb yuav raug kev sib txawv / kev loj hlob mus rau Th1 lossis Th17 T-cells, uas feem ntau muaj peev xwm ua rau muaj kev mob tshwm sim; los yog rau hauv Th2 lossis Treg T-cells uas yuav daws tau qhov mob.

Tsis tas li ntawd, B-cell activation yuav ua rau tsim cov tshuaj tiv thaiv uas yuav pab tshem tawm -syn thiab NK ua kom, uas tuaj yeem pab kom meej -syn. Tsis tas li ntawd, cov txheej txheem no yuav cuam tshuam los ntawm cov xwm txheej tiv thaiv kab mob xws li kab mob, kab mob hauv plab, thiab kev hloov pauv hauv microbiota hauv plab, uas tuaj yeem ua rau lub plab permeability thiab ua rau lub plab phab ntsa. Qhov no yuav hloov lub cev tsis muaj zog milieu, tejzaum nws yooj yim -syn pathology thiab ntxiv txhawb o. (Daim duab tsim siv BioRender.com)

Fc Rs kuj tau hais kom ua lub luag haujlwm hauv kev tsim kho thiab tshem tawm ntawm -syn [23]. Nyob rau hauv tas li ntawd, lub humoral teb yuav yog lwm yam cuam tshuam rau lub clearance ntawm -syn, txij li thaum lub xub ntiag ntawm cov tshuaj tiv thaiv tsub kom lub efficiency ntawm Fc R-mediated clearance [8]. Nws yog ib qho tseem ceeb kom nco ntsoov tias kev laus, qhov tseem ceeb ntawm kev pheej hmoo rau PD, nce zuj zus tuaj yeem txo qhov peev xwm ntawm microglia (thiab macrophages) rau phagocytose -syn [12].

Raws li ib txwm muaj nyob rau hauv CNS, microglia yuav tsum muaj peev xwm tshem tawm -syn thaum txhawb kev noj qab haus huv neuronal los ntawm synaptic pruning thiab tso tawm ntawm cytokines thiab kev loj hlob. Tshwj xeeb tshaj yog nyob rau hauv cov kab mob, phagocytosis ntawm pathological -syn yuav coj cov protein mus rau qhov loj histocompatibility complex (MHC) system thiab yog li, kev nthuav qhia ntawm -syn peptides los ntawm microglia (los yog lwm lub hlwb) rau lub adaptive system [77, 150]. Raws li peb yuav tham txog hauv kev nthuav dav ua ntej, qhov no ua rau kev nrhiav neeg ua haujlwm ntawm lub cev tiv thaiv kab mob thiab T-cell thiab B-cell activation (Fig. 1).

Kev tiv thaiv kab mob hauv cov tsiaj qauv ntawm -synuclein pathology

Thaum nws tab tom tham txog seb puas yog neuroinflammation yog tus pib, tus neeg tsav tsheb, lossis qhov tshwm sim ntawm tib neeg PD, cov qauv tsiaj tau pom tias qhov mob ua ntej dhau los ntawm neurodegeneration, qhia tias nws yuav yog tus tsav tsheb ntawm cov kab mob pathogenesis raws li kev tshawb fawb txog kev tiv thaiv kab mob feem ntau yog neuroprotective.

Kev tiv thaiv kab mob hauv qhov tsis muaj kev tuag neuronal hauv -synuclein transgenic qauv

Txog niaj hnub no, ntau tus qauv tsiaj tau tsim uas overexpress full-length human-syn, genetic mutations, los yog gene duplication txheej xwm txuas mus rau tsev neeg PD (saib saib [104]). Cov qauv no tau siv los piav txog -syn tsav neuroinflammation thiab correlating synuclein lub nra nrog lub hnub nyoog thiab lub cev tsis muaj zog (saib hauv [91]). Koj-1- -syn transgenic nas (kab 61) tau ua rau muaj kev cuam tshuam ntau rau cov kab mob neuroinflamation raws li lawv qhia txog kev nthuav qhia ntawm TLRs 1,2,4, thiab 8 hauv SN, nrog rau nce TNF mRNA ntawm 6 lub hlis, MHCII qhia ntawm IBA-1 ntxiv rau cov hlwb ntawm 14 lub hlis thiab nce CD4 thiab CD8 T hlwb hauv cov ntshav thaum muaj hnub nyoog 22 lub hlis [182], qhia tias -syn lub nra cuam tshuam nrog kev tiv thaiv kab mob.

Txawm li cas los xij, nws yuav tsum raug sau tseg tias transgene yog tsav los ntawm Thy -1 tus txhawb nqa kuj tau hais tawm hauv lub cev tiv thaiv kab mob yog li cuam tshuam kev txhais lus. Qhov nyuam qhuav tsim BAC- -syn nas pom kev nce qib -syn aggregation thiab neurodegeneration, nrog rau kev ua kom microglia thaum ntxov thiab tseem ceeb tiv thaiv kab mob [107]; uas thaum immunomodulation siv resolvin D1, ua rau neuroprotection. Autosomal dominant PD kev hloov pauv hauv -syn kuj tau muab tso rau hauv cov qauv nas transgenic. Txawm hais tias feem ntau ntawm cov qauv no tsis tau muaj qhov tshwj xeeb rau cov kab mob neuroinflammation lossis infiltration ntawm peripheral lub cev tiv thaiv kab mob, microgliosis (IBA-1 ntxiv cov hlwb) tau tshaj tawm nyob rau hauv koom nrog -syn pathology thiab neurodegeneration [48, 62, 64].

Innate thiab adaptive tiv thaiv yog qhib rau hauv -synuclein kab mob qauv

Viral-vector lossis overexpression qauv, tshwj xeeb tshaj yog adenoassociated virus (AAV) qauv tau ntev tau nrov thiab txhim khu kev qha rau lub sij hawm ntev, txwv tsis pub -syn qhia hauv neurons hauv CNS. Cov vectors no tau ua tib zoo tsim los rau overexpress tib neeg tag nrho-ntev lossis tsev neeg hloov pauv ntawm -syn hauv subsets ntawm neurons hauv CNS nyob ntawm serotype nrog qis lossis tsis muaj qhov hloov pauv ntawm glial txhawb hlwb [177]. Nws yuav tsum tau hais tias, thaum cov qauv no yog qhov zoo rau kev kawm hauv zos cov teebmeem ntawm -syn overexpression nyob rau hauv spatial txwv cov pejxeem ntawm neurons, thaum cov neurons raug transduced, tsis muaj overt kis los yog templateing thoob plaws hauv CNS raws li pom nyob rau hauv tib neeg kab mob, ua rau lawv. pluag qauv ntawm -syn kis tau tus mob. Tsis tas li ntawd, kev siv cov qauv kab mob viral yuav tsum tau ua tib zoo saib xyuas thiab tswj xyuas vim tias muaj cov kab mob kis tau tuaj yeem muaj cov teebmeem neuroinflammatory ntawm neurons thiab glia hauv CNS.

Ntau cov serotypes tau siv los hloov cov neurons hauv basal ganglia los qhia txog tib neeg -syn, cov uas muaj kev tiv thaiv kab mob ntau tshaj plaws yog AAV2/1 [77, 171] thiab AAV2/5 [150]. Ua ke, overexpression ntawm -syn nyob rau hauv neurons nyob rau hauv lub SN nyob rau hauv nas ua rau muaj zog qhia ntawm MHCII [77, 150] thiab CD68 [150, 171] ntawm microglia thiab infiltration ntawm CD4 thiab CD8 T hlwb [150].

Ib yam li ntawd, AAV2/5 kev kho kom haum xeeb ntawm tib neeg WT -syn lossis A53T -syn hauv cov tsiaj tsis yog tib neeg primates kuj ua rau microglia proliferation, ua kom muaj zog, thiab nce MHCII qhia, ntawm nws tus kheej ntawm qhov muaj lossis tsis muaj dopaminergic cell tuag; ntxiv kev lees paub kev tiv thaiv kab mob microgliosis raws li qhov tshwm sim thaum ntxov thaum -syn pathology [9]. Ntxiv mus, nyob rau hauv tus qauv primate no, peb pom infiltration ntawm B-hlwb (CD19 ntxiv rau HLA-DR-). Xws li B-cell infiltration kuj tau pom raws li AAV2/1 mediated -syn qhia hauv nigral neurons, uas ua rau zoo li thaum ntxov pro-inflammatory cytokine qhia (TNF, IL-6, iNOS), deposition ntawm IgG nyob rau hauv lub ipsilateral midbrain [24, 171] thiab infiltration ntawm CCR2 ntxiv rau monocytes ua ntej cell poob [80].

Qhov tseem ceeb, qhia txog qhov cuam tshuam ntawm MHCII-T cell kev sib cuam tshuam thiab lub luag haujlwm ntawm kev hloov kho, genetic deletion ntawm MHCII [77], lossis CIITA (transcriptional co-activator of MHCII) [186] attenuated -syn mediated neuroinflammation thiab neurodegeneration (saib hauv qab no rau kev sib tham ntxiv). Ib yam li ntawd, kev tshem tawm ntawm CCR2, qhov tseem ceeb rau kev nrhiav neeg ua haujlwm ntawm cov hlwb monocytic los ntawm qhov chaw ib puag ncig, kuj ua rau muaj kev tiv thaiv neuroprotection [80], uas qhia tau hais tias cov khoom siv peripheral yog qhov tseem ceeb hauv kev tsav tsheb neurodegeneration pom hauv AAV2/1 qauv.

Tus tshiab-synuclein preformed fibril qauv: ib qho tseem tsis tau txhais lub cev tiv thaiv kab mob

Mirroring txoj kev vam meej ntawm cov qauv kab mob thiab tsim kom kov yeej cov teeb meem ntawm kev ua hauj lwm nrog spatial txwv -syn qhia nyob rau hauv neuronal subpopulations, ntau labs tau hloov mus rau kev siv -syn preformed fibrils (PFF) [116, 178] los yog tib neeg Lewy lub cev rho tawm los ua qauv templates thiab prion zoo li cov khoom ntawm -syn hauv PD. Thaum txhaj rau hauv striatum ntawm A53T -syn transgenic nas (M83 kab) [117], expansive propagation thiab templating ntawm -syn tshwm sim thoob plaws hauv CNS, ua qauv "prion hypothesis" (saib hauv [118]). Nyob rau hauv nas, -syn propagation tshwm sim raws li ib tug connectome raws li lub cheeb tsam nrog lub siab tshaj plaws ntawm endogenous -syn. Nyob rau hauv cov nas uas tsis yog-transgenic, kev nthuav tawm ntau dua txwv rau thaj chaw sib txuas ntawm lub hlwb ua rau me me neurodegeneration nyob rau lub sijhawm, zoo ib yam li qhov tau pom nyob rau hauv lwm cov kab mob thiab cov qauv transgenic nrog qee qhov kev kuaj mob me me [117].

Tus cwj pwm ntawm kev tiv thaiv kab mob thaum ntxov nyob rau hauv cov qauv no tab tom pib thiab rau hnub tim, cov kev tshawb fawb tsom rau neuroinflamation yog txwv. Hauv cov nas, striatal txhaj ntawm murine -syn PFF tau qhib NLRP3 inflammasome hauv microglia, thaum NLRP3-inhibitor MCC950 attenuated -syn pathology, lub cev tsis muaj zog, thiab neurodegeneration [65]. Ntxiv rau kev tawm tswv yim txog lub luag haujlwm microglial depletion, qhov depletion ntawm microglia hauv PFF tus qauv nas ua rau muaj qhov txo qis ntawm cov neuronal -syn pathology [70]. Ib txoj kev tshawb fawb tsis ntev los no tau pom tias tus qauv nas ua rau microgliosis, T-cell, natural killer (NK)-cell, thiab B-cell infiltration, uas tau sib npaug los ntawm kev hloov pauv ntawm cov kab mob peripheral hauv cov poov xab thiab cov qog ntshav [44] . Hauv kev tshawb nrhiav tom qab, pab pawg tau pom lub luag haujlwm tiv thaiv kev nkag mus rau NK hlwb los ntawm kev khawb -syn thiab txo cov kab mob [45]. Tus qauv kuj tau cuam tshuam nrog microglia ua kom ua rau muaj kev txhawb nqa astrocyte hloov dua siab tshiab rau A1 neurotoxic phenotype, cov txheej txheem uas, yog tias zam, ua rau neuroprotection [192].

Intranigral [78] los yog striatal txhaj [42] ntawm nas PFF -syn fibrils rau hauv Sprague Dawley nas coj mus rau upregulation ntawm MHCII thiab IBA -1 qhia nyob rau hauv midbrain, nrog rau infiltration ntawm peripheral myeloid hlwb (CD163 ntxiv) thiab T hlwb ua ntej ntsuas tau neurodegeneration, qhia tias innate thiab yoog raws lub cev tiv thaiv kab mob zoo li ua si ua ntej overt neurodegeneration hauv PFF qauv. Interestingly, MHCII cov lus teb tsis tshua muaj zog nyob rau hauv tus qauv nas (peb kev soj ntsuam), uas tej zaum yuav yog vim muaj kev sib txawv ntawm cov nas thaum siv murine (thiab tsis yog nas) PFF -syn los ua rau pathology. Txawm li cas los xij, kev tshawb fawb ntxiv yuav tsum tau ua kom paub meej qhov no. Hais txog qhov ntawd, qee yam yuav tsum tau txiav txim siab rau kev tshawb fawb yav tom ntej hauv PFF-based qauv.

Ua ntej, PFF concentrations siv nyob rau hauv tus qauv (5-10 µg) nyob deb ntawm -syn physiological theem, yog li cov tshuaj tiv thaiv kab mob pom nyob rau hauv qhov chaw txhaj tshuaj tej zaum yuav yog ib qho khoom cuav. Txhawm rau kov yeej qhov no, tshawb xyuas cov kev hloov pauv hauv cov neeg mob neuronal thiab glia ntawm thaj chaw deb anatomically txuas nrog rau qhov chaw txhaj tshuaj thiab nrog -syn pathology tuaj yeem cuam tshuam txog kev tiv thaiv kab mob vim yog neuronal -syn mishandling raws li nws yuav tshwm sim hauv cov neeg mob. Thaum kawg, kev xaiv tswj; yog siv monomeric -syn, qhov no yuav cuam tshuam txog "cov lus teb zoo rau -syn" piv rau lwm txoj kev tswj hwm ntawm PBS / saline sib raug rau qhov tsis muaj kev tiv thaiv kab mob.

Peripheral tiv thaiv kab mob Parkinson: pov thawj rau kev koom tes ntawm monocyte thiab infiltration

Lub xub ntiag ntawm -syn pathology nyob rau hauv lub periphery thiab peripheral neuropathy nyob rau hauv PD txhawb ib tug ntau holistic kev hlub ntawm lub paj hlwb nyob rau hauv PD [31]. Qhov no peripheral -syn pathology tshwm sim thaum ntxov raws li nws kuj pom nyob rau hauv cov neeg mob RBD, thiab prodromal PD [4]. Txij li thaum cov antigenicity ntawm -syn muaj tseeb rau ob qho tib si microglia thiab monocytes [103, 111] ib qho kev tiv thaiv kab mob hauv lub cev yuav tsum tshwm sim ob qho tib si hauv lub hlwb thiab sab hauv, thiab lawv cov lus sib tham yuav ua rau lub cev tiv thaiv kab mob sib koom ua ke hauv PD (Daim duab 1. ).

Raws li, peb tau pom tias, hauv cov neeg mob RBD, TLR4 qhia hauv cov ntshav monocytes ncaj qha cuam tshuam rau lub cev tsis muaj zog lub hlwb ua haujlwm thiab tsis ncaj qha rau dopaminergic neurotransmission raws li qhia los ntawm PET (Farmen, Romero-Ramos, et al., unpublished), yog li txhawb nqa ib qho thaum ntxov hauv nruab nrab thiab peripheral tiv thaiv kab mob, thiab kev sib tham ntawm lub hlwb thiab periphery uas koom nrog cov xwm txheej neurodegenerative. Txawm li cas los xij, nws tsis paub meej npaum li cas ntawm qhov no tau tawm los ntawm qhov chaw ib puag ncig lossis los ntawm kev nrhiav neeg ua haujlwm thiab infiltration.

Infiltration ntawm monocytes / macrophages hauv PD tau pom zoo raws li kev nthuav qhia ntau ntxiv hauv lub hlwb ntawm cov protein uas cuam tshuam nrog cov hlwb tsis-microglia myeloid, xws li CD163 thiab CCR2 (Fig. 1). Peb tau pom tias muaj kev nce ntxiv hauv cov hlwb uas qhia txog qhov scavenger receptor CD163 hauv lub hlwb ntawm nas PD qauv [78, 170], uas yog pom zoo nrog kev tshawb pom hauv lub hlwb postmortem los ntawm cov neeg mob PD [139]. Pharmacological anti-inflammatory modification ntawm CD163 ntxiv rau cov pej xeem nyob rau hauv periphery ua rau ib feem ntawm neuroprotection nyob rau hauv SN ntawm tus nas PD qauv [170]. CCL2-CCR2 axis tau raug qhia kom ua lub luag haujlwm tseem ceeb hauv kev nkag mus ntawm monocytes rau hauv lub hlwb mob [63]. Peb tau pom tias CCR2 ntxiv rau monocytes infiltrate lub hlwb hauv tus qauv -syn-raws li PD nas thiab cov noob caj noob ces deletion ntawm CCR2 yog neuroprotective, qhia txog lub luag haujlwm tsis zoo rau infiltrating monocytes hauv PD [80].

Ntxiv rau kev txhawb nqa lub luag haujlwm rau CCR2, cov receptor tau pom muaj kev tswj hwm hauv PD tus neeg mob cov monocytes classical, txawm tias tag nrho cov naj npawb ntawm CCR2 ntxiv rau monocytes raug txo qis [54], thaum lwm txoj kev tshawb fawb pom tias ua kom CCR2-CCL2 axis [142 ] thiab CCL2 enrichment hauv cov neeg mob cov ntshav [67]. Qhov tseem ceeb, qhov sib txawv ntawm qib CCL2 hauv cov ntshav los yog CSF zoo li muaj feem cuam tshuam nrog cov chaw kho mob sib txawv ntawm PD [17, 73]. Yog li ntawd, CD163 ntxiv lossis CCR2 ntxiv rau monocytes zoo li ua lub luag haujlwm hauv neurodegeneration hauv PD tsis yog los ntawm lawv qhov kev ua nyob rau hauv lub periphery tab sis kuj los ntawm inflating lub hlwb.

Kev hloov pauv hauv monocyte subpopulations hauv Parkinson tus kab mob

Genetic profileing ntawm monocytes tuaj yeem paub qhov txawv ntawm PD los ntawm kev tswj hwm kev noj qab haus huv, txhawb nqa cov kab mob cuam tshuam rau cov neeg no [67]. Txoj hauv kev no tau txheeb xyuas qhov sib txawv ntawm kev kos npe rau hauv monocytes los ntawm cov neeg mob PD thaum ntxov, nrog cov kev qhia sib txawv xws li HLADQB1 (MHCII system), MYD88 (koom nrog TLR2 & 4), REL (tus tswv cuab ntawm NFκB transcription yam tseem ceeb) thiab TNF [156], yog li lees paub. qhov tseem ceeb ntawm kev tiv thaiv kab mob hauv PD. Gene qhia kuj txawv nyob rau hauv ceev piv rau qeeb PD kev loj hlob phenotypes [140]. Txawm hais tias cov ntaub ntawv tau txais hauv cov kev tshawb fawb no yog qhov kev tshawb nrhiav thiab qee zaum nyuaj, lawv lees paub qhov kev koom tes ntawm monocytes thaum ntxov ntawm tus kab mob thiab lawv qhov cuam tshuam hauv kev kho mob tshwm sim hauv cov neeg mob.

Cov ntshav monocytes feem ntau yog cais raws li CD14 thiab CD16 qhia [95]. Classical monocytes (CD14 ntxiv / CD16-) qhia qhov siab tshaj plaws ntawm chemokine receptors thiab thaum qhib, lawv tso IL-10, CCL2, IL-6, thiab RANTES [189]. Lawv tuaj yeem sib txawv rau hauv monocyte-derived macrophages thiab dendritic cells (DCs) thiab ua ib feem tseem ceeb hauv kev kho mob thiab nws cov kev daws teeb meem hauv cov ntaub so ntswg, txuas lub cev thiab kev hloov pauv. Intermediate monocytes (CD14 ntxiv / CD16 ntxiv) qhia cov qib siab tshaj plaws ntawm cov tshuaj tiv thaiv kab mob ntsig txog kev nthuav qhia (HLADR=MHCII) thiab lawv zais TNF, IL-1 , IL-6, thiab IL{ {16}} [189].

Cov cytokines no kuj tau tso tawm los ntawm cov non-classical monocytes (CD14-/CD16 ntxiv), tab sis lawv tsis qhia MHCII [189], thiab lawv tsis ntev los no tau thov los ua tus saib xyuas ntawm vasculature los ntawm kev saib xyuas cov kab mob endothelial kev ncaj ncees. [7]. Classical monocytes tuaj yeem dhau los ua cov monocytes nruab nrab ua ntej thaum kawg sib txawv rau cov monocytes uas tsis yog classical hauv vivo [136]. Kev soj ntsuam ntawm cov ntshav monocyte subpopulations hauv PD tau ua rau qee qhov tsis sib xws, nrog qee pawg qhia tsis muaj kev hloov pauv [156, 157] thaum lwm tus tau tshaj tawm cov monocytes classical nrog qhov sib npaug ntawm cov neeg tsis yog classic [67, 185]. Cov txiaj ntsig tsis sib xws no yuav yog vim muaj qhov sib txawv ntawm pawg, tshwj xeeb, PD subtype lossis kab mob ntev yuav yog qhov tseem ceeb. Raws li, peb cov ntaub ntawv qhia tau hais tias muaj ntau dua classical monocytes hauv RBD prodromal PD (Farmen, Romero-Ramos, et al., unpublished), thiab thaum ntxov PD (<5y), to decrease later in the disease (Nissen, Romero-Ramos, et al., unpublished). This suggests a response aiming to resolve inflammation early in the disease that later fails as the disease advances.

Kev hloov pauv hauv monocytes hauv Parkinson tus kab mob: kev ua kom tsis zoo, phagocytosis, thiab kev loj hlob

Kev koom tes ntawm monocytes nyob rau hauv PD yog ntxiv corroborated los ntawm kev pom zoo tsis muaj peev xwm ntawm cov hlwb myeloid los ntawm PD cov neeg mob los txhim kho kev noj qab haus huv thiab sib npaug teb rau cov stimuli sib txawv, tshwj xeeb tshaj yog -syn. Peb tau pom tias PD tus neeg mob PBMCs tau pom qhov txo qis rau LPS thiab fibrillar -syn stimulation thiab lawv tsis tuaj yeem hloov kho cov kev qhia ntawm cov proteins xws li CD163, thiab tsis muaj txiaj ntsig induce cytokine tso tawm piv rau kev tswj PBMCs [128].

Txawm li cas los xij, cov kev tshawb fawb los ntawm Danzer pawg tau tshaj tawm tias CD14 ntxiv rau monocytes los ntawm cov neeg mob PD yog cov neeg mob hyperactive thiab dysregulated nyob rau hauv teb rau txawv stimulations xws li pathologic -syn [67, 68]; Txawm li cas los xij, Williams-Gray pawg pom tsis muaj kev hloov pauv nrog CD14 cov hlwb xaiv [184] lossis nrog PBMCs [183]. Ntxiv dua thiab, cov kev tsis sib xws no feem ntau yog vim qhov sib txawv ntawm cov pawg, txheej txheem, thiab biomarkers siv. Qhov tseem ceeb, qee pawg sib txawv monocytes rau macrophages los yog xaiv CD14 ntxiv rau cov hlwb rau lawv cov kev soj ntsuam, thaum lwm tus siv PBMCs, uas yuav ua rau muaj kev cuam tshuam ntawm tes hauv kab lis kev cai uas yuav cuam tshuam rau qhov tshwm sim (piv txwv li T-cells). Kev pom zoo zoo dua yog xav tau nyob rau hauv kev ua haujlwm ntawm yuav ua li cas mus cuag cov kev tshawb fawb ua haujlwm thiab yuav ua li cas cov hlwb no teb rau -syn tshwj xeeb stimulation.

Hais txog lub peev xwm phagocytic ntawm monocytes, ob lub chaw kuaj mob tau qhia txog kev ua haujlwm tsis zoo hauv PD cov neeg mob hlwb [57,67]. Qhov kev txo qis hauv phagocytosis zoo li yog vim -syn nws tus kheej, uas tau pom tias nce intracellularly [57]. Txawm li cas los xij, lwm txoj kev tshawb fawb tau tshaj tawm tias muaj peev xwm phagocytic ntau dua hauv monocytes los ntawm cov neeg mob PD thaum ntxov tom qab kuaj pom (<5y, H and Y 2), suggesting again disease duration is a crucial factor. Notably, the authors report changes only while using autologous serum, vs. the standard animal serum, thus highlighting the relevance of the complex disease environment found in vivo, vs. the simplification of in vitro assays [184]. 

Txawm li cas los xij, tib pab pawg tau pom tsis ntev los no tias qhov muaj peev xwm phagocytic siab dua no tsis muaj tseeb thaum -syn uptake / clearance tau soj ntsuam tshwj xeeb (txawm tias siv autologous serum), yog li qhia txog qee yam kev xaiv tsis ua haujlwm lossis kev txo qis hauv -syn uptake txheej txheem hauv PD [185] . Qhov zoo tshaj plaws, qhov no tau tshwm sim txawm tias muaj kev nthuav qhia TLR4 ntau ntxiv hauv PD monocytes, uas tsis ua rau cov lus teb siab dua rau LPS (tus TLR4 activator) lossis siab dua -syn uptake (raws li xav tau raws li kev pom zoo TLR4 mediated -syn clearance [50] ). Qhov no ntxiv qhia txog kev ua haujlwm tsis zoo ntawm cov monocytes hauv PD cov neeg mob, uas, nrog rau lub hnub nyoog txog kev txo qis ntawm macrophages rau uptake -syn, tuaj yeem ua lub luag haujlwm tseem ceeb hauv PD kev loj hlob [12].

Qhia txog kev mob hlwb hauv lub cev tiv thaiv kab mob thaum lub sijhawm PD, peb tau tshaj tawm txog qhov txo qis kev muaj sia nyob hauv vitro ntawm PD-derived PBMCs nrog qhov sib npaug ntawm qhov muaj peev xwm monocytic proliferative, tshwj xeeb tshaj yog nyob rau hauv cov neeg mob uas muaj hnub nyoog lig thaum pib thiab luv kab mob ntev [128]. Raws li, monocyte precursor enrichment yog ib qho kev tshwm sim ntxov hauv PD cov neeg mob [54] uas yuav cuam tshuam nrog kev nthuav dav ntawm cov neeg monocyte classical hauv cov kab mob thaum ntxov raws li tau hais ua ntej. Nyob rau hauv tas li ntawd, qhov no yuav qhia tau hais tias thawj zaug them nyiaj teb uas lub hom phiaj los daws qhov tshwm sim inflammatory, thaum kawg poob nrog lub sij hawm, qhia hais tias lub chav kawm ntawm tus kab mob yog ib qho tseem ceeb yuav tsum tau xav txog thaum kawm txog kev tiv thaiv kab mob hauv PD. Kev ua haujlwm hauv vitro ua kom deb li deb tau txhawb nqa nrog rau cov pej xeem monocytic uas ua haujlwm txawv ntawm cov kev noj qab haus huv. Txawm li cas los xij, cov ntsiab lus zoo dua los ntawm kev faib cov xwm txheej raws li lawv cov kab mob ntev, subtype, lossis prognosis, yog qhov xav tau los txheeb xyuas lub luag haujlwm ntawm lub cev tiv thaiv kab mob.

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