Interplay Of Immune and Kidney Resident Cells nyob rau hauv Kev Tsim Cov Txheej Txheem Tertiary Lymphoid hauv Lupus Nephritis

Yog xav paub ntxiv:ali.ma@wecistanche.com

Simin Jamaly et al

TSAB NTAWV

Lub raumKev koom tes ua rau muaj kev mob hnyav thiab kev tuag hauv cov neeg mob uas muaj kab mob lupus erythematosus (SLE). Lub pathogenesis ntawm lupus nephritis (LN) cuam tshuam nrog ntau yam txheej txheem instigated los ntawm cov ntsiab lus ntawm autoimmune teb uas hloov cov biology ntawmraumcov nyob hauv hlwb. Cov txheej txheem hauv glomeruli thiab interstitium tuaj yeem ua haujlwm ntawm nws tus kheej txawm hais tias kev sib tham ntawm ob yog qhov kev zam. Podocytes, mesangial hlwb, tubular epithelial hlwb,raumCov neeg nyob hauv macrophages, thiab stromal hlwb nrog cov tswv yim los ntawm cytokines thiab autoantibodies tam sim no nyob rau hauv cov kev ncig hloov pauv kev qhia ntawm enzymes, tsim cytokines thiab chemokines uas ua rau lawv raug mob thiab kev puas tsuaj ntawm lub cev.raum. Ob peb ntawm cov molecules no tuaj yeem tsom nws tus kheej los tiv thaiv thiab thim rov qab raum tsis ua haujlwm. Tertiary lymphoid cov qauv nrog cov chaw muaj kab mob muaj tseeb muaj nyob rau hauv ob lub raum ntawm cov neeg mob nrog lupus nephritis thiab tau txais kev pom zoo kom koom nrog cov neeg pluag.lub raumqhov tshwm sim. Stromal hlwb, tubular epithelial hlwb, siab endothelial hlab ntsha, thiab lymphatic venule hlwb tsim chemokines uas pab tsim cov qauv tsim ntawm T-cell-nplua nuj cheeb tsam nrog paub tab dendritic hlwb nyob ib sab ntawm B-cell follicle nrog cov yam ntxwv ntawm cov kab mob chaw. surrounded los ntawm plasma hlwb. Ua raws li kev txheeb xyuas ntawm kev sib cuam tshuam ntawm lub cev tiv thaiv kab mob nrog rau lub raum cov neeg nyob hauv lub raum, peb tham txog cov xwm txheej ntawm cov cellular thiab molecular uas ua rau tsim cov txheej txheem tertiary lymphoid hauv interstitium.lub raumntawm nas thiab cov neeg mob lupus nephritis. Nyob rau hauv parallel, molecules thiab cov txheej txheem uas tuaj yeem raug tsom kho tau raug nthuav tawm.

Nyem rau Cistanche DHT rau mob raum

Taw qhia

Systemic lupus erythematosus (SLE) yog ib qho kab mob autoimmune nrog cov kev soj ntsuam zoo heterogeneity uas tshwm sim los ntawm ntau lub cev. Ntau cov kab mob pathogenic tau raug txheeb xyuas los ntawm cov noob caj noob ces, epigenetic, hormonal, ib puag ncig, thiab kev tiv thaiv kab mob thiab tag nrho cov converge ntawm ua rau mob ntawm cov ntaub so ntswg thiab lub cev puas tsuaj [1,2]. Txhua yam ntawm lub cev thiab hloov lub cev tiv thaiv kab mob tau raug tshaj tawm tias muaj feem cuam tshuam rau cov neeg mob SLE thiab lawv pab txhawb rau kev nthuav qhia tus kab mob hauv cov neeg mob sib txawv. Lub xub ntiag ntawm plethora ntawm autoantibodies tau typified tus kab mob thaum lub sij hawm zus tau tej cov uas qhia tawm tsam nuclear antigens, me me nuclear ribonucleoproteins, ob-stranded DNA (dsDNA), thiab nucleosomes sawv cev rau lub hom phiaj ntawm tus kab mob [1,3]. autoantibodies los ntawm soluble immune complexes (IC) nrog autoantigens (xws li nucleosomes) tso tawm nyob rau hauv abundance nyob rau hauv cov kev ncig ntawm cov neeg mob nrog SLE, tej zaum yuav tso rau ntawm basal daim nyias nyias ntawm ntau yam kabmob nrog rau cov kab mob.raum, thiab pib o. Autoantibodies tuaj yeem khi ncaj qha raulub raumantigens thiab daim ntawv nyob rau hauv situ IC raws li yog typified los ntawm cationic anti-dsDNA cov tshuaj tiv thaiv uas khi rau glomerular qab daus daim nyias nyias [4-6]. Nyob rau tib lub sijhawm, kev tsim tawm ntau dhau ntawm cytokines suav nrog hom I interferon (IFN), interleukin (IL)-17, thiab IL-23 ntxiv mus ua ntej lub cev tiv thaiv kab mob tsis zoo lossis ua ncaj qha rauraumYuav ua li cas ua kom lub cev muaj zog [7] Thaum kawg, tab sis tsis kawg, autoreactive T hlwb infiltrateraumqhov twg lawv tuaj yeem tsim tertiary lymphoid qauv (TLS) thiab ua rau lub cev puas tsuaj.

Autoantibody los yog IC deposition nyob rau hauv lubraum, nrog rau kev ua ntawm cytokines thiab infiltration ntawm lub cev tiv thaiv kab mob ua rau muaj kev loj hlob ntawm lub raum o hauv cov neeg mob SLE uas tshwm sim li lupus nephritis (LN) nrog kev mob hnyav thiab kev tuag [8,9]. Tom qab kev hloov kho tshiab ntawm kev sib cuam tshuam ntawm cov neeg nyob hauv thiab lub raum lub cev tiv thaiv kab mob, peb yuav tham txog kev nthuav dav ntawm kev tsim TLS hauvlub rauminterstitium thiab nws cov nyhuv ntawm lub raum ua haujlwm.

Lub raum nyob hauv cov hlwb

2.1. Podocytes

Podocytes yog cov hlwb tshwj xeeb ntawm sab visceral ntawm Bowman's capsule uas nyob ib puag ncig glomerular capillaries. Lawv yog ib feem ntawm glomerular filtration machinery thiab tseem ceeb heev rau kev tswj xyuaslub raumua haujlwm [10]. Lawv qhia cov protein tshwj xeeb xws li synaptopodin, nephrin [11], podocin [12], thiab Wilms 'cov qog protein [13], txhua yam yog qhov tseem ceeb hauv kev saib xyuas lawv cov qauv thiab kev ua haujlwm [14]. Cov noob caj noob ces los yog tau txais tsis xws luag nyob rau hauv qhov kev qhia ntawm lub ntsiab podocyte molecules ua rau invariably rau lawv detachment thiab kev loj hlob ntawmlub raumkev tsis ncaj ncees [15]. Kev raug mob Podocyte yog qhov tseem ceeb hauv cov neeg uas muaj LN thiab suav nrog kev tsim cov proteinuria thiab glomerular puas [16,17].

Podocytes paub tias tsim thiab nthuav qhia cov khoom ntawm txoj hauv kev ntxiv uas nrog rau kev tso tawm thiab ua kom muaj kev sib ntxiv los ntawm kev ncig ua rau kev raug mob podocyte. Inhibition ntawm txoj hauv kev ntxiv tau lom zem hauv kev sim tshuaj kho cov neeg nrog LN [18]. Tsis tas li ntawd, podocytes qhia tag nrho cov Toll-like receptors (TLR) thiab Nod-like receptor protein-3 (NLRP3) thiab caspase 1 [19]. Homocysteine ​​activates NLRP3 inflammasomes nyob rau hauv lub podocytes ntawm lupus-nrhiav nas thiab cov neeg mob nrog LN [20] thiab nws suppression txo proteinuria, histologiclub raumCov kab mob, thiab cov txheej txheem podocyte ko taw effacement [16] qhia tias NLRP3 tuaj yeem raug tsom rau kev kho mob.

Podocytes los ntawm lupus-nrhiav nas thiab cov neeg uas muaj LN nthuav qhia nce qib ntawm cov histocompatibility loj molecules nrog rau cov costimulatory molecules CD80 thiab CD86 uas yog suav hais tias yog cov cim ntawm kev raug mob ntawm tes tab sis tib lub sij hawm lawv tuaj yeem ua rau cov neeg mob ntshav qab zib lymphocytes thiab pab txhawb rau lawv cov tsub zuj zuj hauv. tuslub raumparenchyma. Rov qab, ua txhaum cai hauv Bowman's capsule, hauv tib neeg crescentic glomerulonephritis tuaj yeem tso CD8 ntxiv rau T hlwb kom ncav cuag glomerular tuft thiab podocytes thiab ua rau lawv puas tsuaj [21].

Podocytes nthuav qhia cov me nyuam mos Fc receptor (FcRn) uas ua rau kev hloov ntawm IgG los ntawm capillary mus rau qhov chaw tso zis. IgG los ntawm cov neeg mob nrog LN nkag mus rau hauv podocytes siv FcRn thiab ua rau muaj kev tswj hwm ntawm calcium / calmodulin-dependent protein kinase IV (CaMK4) uas phosphorylates 14–{3}}, scaffold protein ntawm synaptopodin, uas thaum nws tso tawm yog degraded. Synaptopodin yog ib qho tseem ceeb hauv kev saib xyuas ntawm cov qauv podocyte [22]. Nyob rau hauv parallel, CaMK4 activates NFkB uas suppresses cov kev qhia ntawm nephrin, ib qho tseem ceeb proteins ntawm lub phua diaphragm, los ntawm kev txhawb lub functionality ntawm transcriptional repressor SNAIL [23]. IgG los ntawm cov neeg mob uas muaj LN nquag ua rau kev txhim kho ntawm CaMK4 nyob rau hauv qis-galactosylated [23]. Kev tshem tawm thoob ntiaj teb ntawm Camk4 hauv MRLlpr lupus-nruab nas nas tau zoo suppresses LN [24]. Qhov tseem ceeb tshaj, podocyte-targeted xa ntawm CaMK4 inhibitor suppresses tag nrho cov ntsiab lus ntawm LN thiab obviates cov deposition ntawm IC [22], tawm tswv yim tias kev saib xyuas ntawm cov qauv thiab kev ua haujlwm ntawm podocytes los ntawm suppressing cov haujlwm ntawm CaMK4 IC tsis tso. Cov kab lus no qhia txog qhov tseem ceeb ntawm cov xwm txheej hauv zos hauv kev txhim kho kev puas tsuaj ntawm lub cev thiab tus nqi ntawm cov xov tooj ntawm tes / cov khoom siv tshwj xeeb xa cov tshuaj los txwv cov kab mob hauv nruab nrog cev hauv autoimmunity.

Cistanche yog qhov zoo rauraum

2.2. Mesangial hlwb

Mesangial hlwb thiab mesangial matrix ua raulub raumcorpuscle lub vascular ncej thiab yog qhov tseem ceeb hauv kev tshem tawm cov protein ntau thiab cov IC me me los ntawm cov ntaub ntawv hauv qab daus [19]. Lawv koom nrog hauv pathogenesis ntawm LN raws li mesangial cell proliferation thiab mesangial matrix yog tam sim no invariably nyob rau hauv lub LN.lub raum[25]. Mesangial hlwb nthuav qhia Tus Hu-zoo li receptors (TLRs) [25,26], thiab thaum txhawb nqa nrog TLR3 ligand (dsRNA) lawv tsim hom I IFN [25] - cytokine uas tau lees tias yog ib qho tseem ceeb hauv pathogenesis ntawm SLE [25] , 27] ib.

Cov tshuaj tiv thaiv kab mob rau dsDNA khi rau cov hlwb mesangial thiab ua rau cov kab mob inflammatory thiab fibrotic, tshwj xeeb tshaj yog cov uas koom nrog cov mitogen-activated protein kinase (MAPK) thiab protein kinase C (PKC) qhia txoj hauv kev, ua rau kev tsim cov proinflammatory cytokines [27,28]. Mesangial hlwb secrete interleukin (IL)-6, uas ntawm nws tus kheej tuaj yeem tsav kev txhim kho ntawm glomerulonephritis [29]. CaMK4 yog qhov tsim nyog rau kev loj hlob ntawm cov hlwb mesangial thiab tsim cov cytokines. Tshwj xeeb, mesangial hlwb los ntawm lupus-prone MRLlpr nas uas tsis muaj caj ces CaMK4, tsis proliferate nyob rau hauv teb rau platelet-derived kev loj hlob yam thiab tsis tsim IL-6 [30].

2.3. Lub raum tubular epithelial hlwb

Lub raumTubular epithelial hlwb koom nrog hauv pathophysiology ntawm LN. Lawv tso cov kab mob cytokines, suav nrog hom I IFN [31] thiab B cell-activating factor (BAFF) [32], ob qho tib si muaj lub luag haujlwm tseem ceeb hauv kev txhim kho SLE (Fig. 1). Tsis tas li ntawd,lub raumtubular epithelial hlwb los ntawm LN cov neeg mob qhia cov costimulatory molecule B7-H4, qhia tias lawv tuaj yeem qhib T hlwb. Qhov sib ntxiv ntawm anti-dsDNA cov tshuaj tiv thaiv rau lub raum tubular epithelial hlwb hauv kab lis kev cai ua rau cov kab mob sib kis ntawm cov qog necrosis factor (TNF), IL-1 , thiab IL-6 [33], uas qhia cov hlwb pab txhawb. rau cov txheej txheem inflammatory hauv tubulointerstitium hauv LN [34].Lub raumtubular epithelial hlwb qhia apoptotic endonucleases [35] uas pom tau tias thaum qhib los ntawm cov txheej txheem tseem tsis tau paub, tuaj yeem ua rau cell tuag [36]. Tsis ntev los no, nws tau pom tias tubular epithelial hlwb tuaj yeem tsim CXCL12 hauv cov lus teb rau IL-23 los txhawb kev cuam tshuam thiab nws cov caj ces tshem tawm tsuas yog hauv cov hlwb txwv glomerulonephritis hauv lupus-prone nas [7].

BAFF, yog qhov tsim tau zoo B cell loj hlob thiab qhov sib txawv uas yuav pab tau nws pib-reactive B hlwb kom ciaj sia thiab dim peripheral kam rau ua [37,38]. BAFF blockade nrog cov tshuaj tiv thaiv kab mob (Benlysta) tau pom zoo los kho nrog SLE [39] thiab LN [40]. BAFF kuj tau nthuav tawm los ntawm tubular epithelial hlwb ntawm cov neeg uas muaj LN proliferative thiab cov theem ntawm kev qhia cuam tshuam nrog cov histopathology-txhais kev ua index [32]. BAFF tuaj yeem txhawb kev sib txawv ntxiv ntawm B hlwb uas muaj nyob rau hauv qhov chaw nruab nrab ntawmlub raumlos ntawm cov neeg mob nrog LN [41]. Tsis tas li ntawd, BAFF tau raug lees paub los txhawb kev tsim TLS hauvraumlos ntawm kev nce tus naj npawb ntawm T hlwb nyob rau hauv lub glomeruli thiab nce o hauv nas [42] uas yuav piav qhia txog kev kho mob ntawm Benlysta hauv cov neeg mob LN [40]. Benlysta lub hom phiaj B hlwb kom loj hlob thiab kev taw qhia los ntawm inhibiting B hlwb ciaj sia, thiab txo qhov sib txawv rau Ig-tsim plasma hlwb hauv cov neeg mob LN [43].

2.4. Mesenchymal qia cell

Mesenchymal stem cells (MSCs) yog cov kab mob uas muaj zog tiv thaiv kab mob ntau yam uas muaj nyob hauv txhua cov ntaub so ntswg [44]. Lawv zoo li muaj lub luag haujlwm hauv dendritic thiab T-cell suppression [45]. Cov kev tshawb fawb yav dhau los tau pom tias thaum cov concentrations ntawm proinflammatory cytokines tsawg, MSCs yuav muaj peev xwm immunostimulatory [45,46]. MSCs tuaj yeem ntes tau nyob rau hauv phab ntsa pelvis thiab TLS hauvlub raumCov nas uas muaj kab mob lupus [47] Kev txhawb nqa ntawm MSCs nrog inflammatory cytokines ua rau kev qhia ntawm TNF- , IL-1 , CCL19, thiab ICAM [47]. Txawm hais tias tsis meej, MSCs zoo li muaj lub luag haujlwm zoo ib yam li cov qog nqaij hlav qog nqaij hlav (LTo) cov hlwb thiab cov ntaub so ntswg tshwj xeeb hauv MSCs ua haujlwm zoo li cov qog nqaij hlav lymphoid inducer (LTi) hlwb. Lawv muaj peev xwm reprogram thiab pib ib tug thaum ntxov inflammatory cascade los ntawm interacting nrog T hlwb [47]. MSC sib txawv thiab kev tiv thaiv kab mob hauv lub cev ua rau muaj kev nthuav dav ntawm cov hlab ntsha lymphatic thiab yog li tsim TLS [48].

Cistanche yog qhov zoo rauraum

2.5. Macrophages

Cov neeg nyob hauv macrophages nyob hauvraumfeem ntau pom nyob rau hauv lub interstitium nyob ib ncig ntawm lub glomeruli [49]. Peripheral monocytes tom qab nkag mus rauraumcov ntaub so ntswg thiab kev sib txawv rau macrophages ua raws li cov players tseem ceeb hauv kev mob, raug mob, thiab fibrosis hauv mob raum tsis zoo [50]. CD16 ntxiv lossis CD14 ntxiv rau macrophages raug xaiv los raug moblub raumnyob rau hauv lub xub ntiag ntawm cytokines thiab chemokines [50] Ob peb subtypes ntawm macrophages (M1, M2a-c) [51] tau raug kaw tam sim no hauv LN cov ntaub so ntswg uas tsis paub keeb kwm thiab kev ua haujlwm [49,50,52]. Feem ntau, nws zoo li yog tias cov neeg nyob hauv macrophages raug rau endosomal TLR ligands thiab kev puas tsuaj-txuas nrog cov qauv molecular molecules (DAMPs) [53], lawv dhau los ntawm qhov kev daws teeb meem mus rau theem inflammatory. Thaum lub sijhawm mob, macrophages hloov lawv cov phenotype rau M1 thiab nthuav qhia Ly6C / Gr1 thiab zais cia pro-inflammatory cytokines [54,55]. Hauv qhov sib piv, thaum lub sijhawm kho lossis daws teeb meem, lawv polarize rau hauv M2 phenotype [56,57]. Yog li ntawd, nws zoo nkaus li tias macrophages muaj ob txoj haujlwm ua haujlwm thiab tso saib cov yas siab thaum lub sijhawm mob raum.

3. Tertiary lymphoid qauv

Lo lus 'tertiary lymphoid' tau qhia los ntawm Picker thiab Butcher [58] los piav qhia qhov chaw ntxiv-lymphoid nyob rau hauv cov ntaub so ntswg tsis-lymphoid. TLS tau raug xa mus rau ntau txoj hauv kev, suav nrog tertiary lymphoid organs, tertiary lymphoid cov ntaub so ntswg, thiab ectopic lymphoid qauv. Kev sib sau ntawm lymphocytes nyob rau hauv peripheral non-lymphoid cov ntaub so ntswg, thiab cov degree uas lawv tau koom, nws txawv raws li hom thiab lub sij hawm ntawm antigenic inflammatory stimuli [59]. Raws li qhov tshwm sim, lymphoid aggregates ntau los ntawm cov khoom xoob xoob, suav nrog ob peb lub hlwb T lossis B, mus rau cov ntaub so ntswg uas qhia txog cov cim ntawm TLS [60–63].

TLS yog tsim los ntawm T-cell-nplua nuj cheeb tsam nrog paub tab DCs ntawm ib sab ntawm B cell follicle nrog cov yam ntxwv ntawm cov kab mob chaw nyob ib puag ncig los ntawm cov ntshav plasma. Cov yam ntxwv me me uas xav tau los tsim TLS ua haujlwm tsis tau paub, tab sis TLS txhais tau tias yog cov lymphoid aggregate nrog cov txheej txheem stromal uas muaj cov kab mob follicular dendritic (FDCs) thiab fibroblastic reticular hlwb (FRCs), thiab cov yam ntxwv, nrog siab endothelial venules (HEVs) thiab lymphatic hlab ntsha (LVs) [64,65]. Ib qho kev txhais raws li cov txheej txheem no yuav tsis suav cov sib sau ua ke ntawm B lossis T hlwb hauv kev teb rau qhov mob uas tsis muaj qhov sib txawv stromal compartments (Box 1).

TLS txhim kho ntau yamlub raumpathologies, suav nrog IgA nephropathy [66], theem pib IgG4-txog tubulointerstitial nephritis [67], mob hnyavraumraug mob [68,69], mob qog noj ntshav [70], pyelonephritis [71], hloov pauv thiab LN [41,72,73]. Hauv cov nas uas muaj kab mob lupus, TLS pom nyob ze rau ntawm phab ntsa ntawm lub plab, ib sab ntawm cov hlab ntsha loj thiab cov leeg [74]. Hauv cov kab mob autoimmune xws li mob caj dab rheumatoid, Sjogren's syndrome, ntau yam sclerosis, ntshav qab zib mellitus, Hashimoto's thyroiditis, thawj sclerosing cholangitis thiab thawj cirrhosis biliary, thiab myasthenia gravis, TLS tuaj yeem ua rau muaj ntau tiam neeg ntawm autoreactive T thiab B hlwb thiab tsim cov tshuaj tiv thaiv kab mob. perpetuate cov txheej txheem pathogenic [63,70,75,76].

3.1. Crosstalk ntawm lub raum lub cev tiv thaiv kab mob nrog tertiary lymphoid qauv

T hlwb tswj lub cev tiv thaiv kab mob homeostasis nyob rau hauv physiologic tej yam kev mob thiab txhawb kev zam txim rau tus kheej-antigens. Hauv autoimmuneraumKev ua haujlwm tsis zoo ntawm T-cell kam rau autoantigens tuaj yeem ua rau lub cim ntawm autoantibodies, o, tiv thaiv cell infiltration, thiab kev loj hlob ntawm ntau hom nephritis [77,78].

T hlwb tuaj yeem nkag mus rau hauv cov hlab ntsharaumcov ntaub so ntswg los yog vim hais tias lawv tau raug tshuab txais nyob rau hauv lub periphery thiab nthuav qhia adhesion molecules los yog lawv tej zaum yuav ua tsis taus pa thiab ua activated tom qab lawv nkag mus rau hauv lubraumparenchyma los ntawm podocytes los yog tubular epithelial hlwb raws li tau tham saum toj no. Activated cells qhia adhesion molecules xws li CD44 uas, thaum txuam nrog phosphorylated ESRIN / redesign / moesin [79], khi rau nws cov ligand hyaluronic acid, cov synthesis ntawm uas yog nce nyob rau hauv lub raum ntawm lupus-ntau nas [80]. Txij li thaum esrin / redesign / moesin yog phosphorylated los ntawm Rho-kinase, inhibition ntawm nws cov kev ua ub no txwv tsis pub nkag ntawm T hlwb mus rau hauv lub hlwb.raum[81]. Ib yam li ntawd, inhibition ntawm hyaluronic acid synthesis txo qhov nkag ntawm T hlwb mus rau ob lub raum ntawm lupus-ntau nas [80] Interestingly, cov naj npawb ntawm CD3 ntxiv rau CD44 ntxiv cov hlwb hauv cov ntshav peripheral ntawm cov neeg uas muaj SLE cuam tshuam nrog rau kev ua haujlwm ntawm lub raum [82] .

Feem ntau ntawm cov hlwb hauv TLS yog CD3 ntxiv rau T hlwb [74] thiab lawv suav nrog cytotoxic granule-expressing CD8 ntxiv rau T hlwb thiab CD4 ntxiv rau T hlwb uas tso saib TH1 cell phenotype thiab CD4 ntxiv Treg hlwb [83–86 ]. Nws tau xav tias cov hlwb paub tab dendritic (DCs) muaj cov tshuaj tiv thaiv rau CD4 ntxiv rau T hlwb hauv thaj tsam T-cell ntawm TLS [87], tab sis DC-LAMP ntxiv rau DCs kuj tau kuaj pom hauv cov chaw tua kab mob, qhia tias lawv muaj lub luag haujlwm hauv Kev nthuav qhia antigen rau B hlwb [88] B hlwb teeb tsa rau hauv cov chaw tua kab mob nrog cov plasma hlwb. Cov cheeb tsam B-cell muaj CD21 ntxiv rau FDCs qhov chaw T cell muaj MIDC{16}} ntxiv rau DCs [74].

Ob-negative (DN) T hlwb yog txhais los ntawm lub xub ntiag ntawm T-cell receptor (TCR) ntxiv thiab tsis muaj CD4 thiab CD8 molecules. Lawv tau nthuav dav hauv cov ntshav peripheral ntawm cov neeg mob SLE, muab kev pab rau B hlwb los tsim autoantibody [89], thiab tsim IL-17 [90]. Nws zoo li lawv muab los ntawm CD8 ntxiv rau T hlwb [91,92] hauv kev teb rau kev txhawb nqa nrog autoantigen thiab muaj IL{10}} [93]. Mechanistically, CD8 locus raug kaw los ntawm kev hloov kho epigenetic yuam los ntawm repressor cAMP response-element modulator (CREM ) [94]. Ntau qhov nthuav, DN T cells muaj nyob hauvlub raumntawm cov neeg mob nrog LN thiab lawv tsim IL-17 [90] taw tes rau lawv qhov kev pab cuam ncaj qha rauraummob.

Lub TH17 subset ntawm T cell yog txhais los ntawm kev qhia ntawm kab mob txiav txim siab transcription factor ROR t. Lawv txhawb nqa cov lus teb autoimmune hauv tib neeg thiab nas los ntawm kev tsim cov granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN , thiab IL-17, − 21 thiab − 22 [95,96]. TH17 hlwb qhia C-C motif chemokine receptor type 6 (CCR6) thiab raug xaiv rauraumlos ntawm C-C motif chemokine 20 (CCL20), uas yog tsim los ntawm mesangial hlwb tom qab stimulation los ntawm IL-17 (tseem tsim los ntawm neutrophils los yog δT hlwb) [97] thiab los ntawm TEC raug rau IL-23 [ 7]. TH17 hlwb tam sim no nyob rau hauv lubraumzais cia IL-17 thiab txhawb kev mob los ntawm kev tsim TLS [98], txhawb nqa B-cell activation thiab tsis kam rau siab [99,100].

Follicular T-helper (TFH) hlwb yog CD4 ntxiv rau T hlwb uas qhia txog qhov hloov pauv BCL6 thiab CXC motif chemokine receptor type 5 (CXCR5). Cov hlwb no tsiv mus rau hauv cov chaw germinal teb rau CXC motif chemokine 13 (CXCL13). Lawv kuj nthuav tawm peb qhov chaw receptors, suav nrog cov inducible T-cell costimulatory, CD40L, PD-1, thiab tsim IL-21 txhawm rau ua kom B-cell ua kom muaj zog thiab sib txawv ntawm B hlwb rau hauv nco B hlwb thiab plasmablasts [ 101–103] ib.

Qib ntawm TFH circulating hlwb yog nce rau cov neeg uas muaj kab mob autoimmune nrog rau SLE thiab cov kev tshawb fawb nyob rau hauv lupus-prone nas tau lees paub lawv lub luag haujlwm pathogenic [102]. Hauv cov neeg mob SLE, qhov zaus ntawm cov kab mob ntawm cov hlwb - extrafollicular TH hlwb - cuam tshuam nrog qib ntawm cov tshuaj tiv thaiv dsDNA thiab qhov ntau ntawm plasmablast B hlwb. Ntxiv follicular TH hlwb txhais tau CCR6 ntxiv rau subset, uas qhia txog CXCR5 tab sis tsis yog BCL6 thiab tuaj yeem tso tawm IL-17 thiab pab txhawb kev tsim cov immunoglobulin los ntawm B hlwb [103,104].

Treg hlwb yog TCR ntxiv rau Foxp3 ntxiv rau CD4 ntxiv rau T hlwb uas tsim nyob rau hauv lub thymus los yog periphery. Lawv nthuav tawm kev ua ub ua no thiab tswj feem ntau lub cev tiv thaiv kab mob los ntawm ntau yam txheej txheem [105]. Ib qho ntawm lawv qhov zoo tshaj plaws-paub luag hauj lwm nyob rau hauv lubraumyog qhov tso tawm ntawm cov tshuaj tiv thaiv kab mob cytokine IL-10 [106]. Qee qhov xwm txheej molecular uas ua rau lub cev tsis ua haujlwm ntawm Treg hlwb tau piav qhia. Cov molecules muaj xws li protein phosphatase 2A (PP2A), mammalian lub hom phiaj ntawm rapamycin complex 1 (mTORC1), phosphatidylinositol 3,4, 5-trisphosphate 3- phosphatase, dual-specificity protein phosphatase (PTEN), thiab calcium. /calmodulin-dependent protein kinase IV (CaMK4). Targeting no tej zaum yuav cawm los yog suppress Treg cell muaj nuj nqi thiab modulateraumkev kho mob [107].

Kev tshuaj xyuas ntawm T-cell clonotypes los ntawm ntau cov ntaub so ntswg ntawm LN nas, nrog rau cov ntshav peripheral lossislub raumntawm cov neeg mob nrog SLE, tau nthuav tawm nthuav dav ntawm qhov txwv tsis pub muaj ntawm TCR repertoire, qhia txog cov lus teb rau tus lej ntawm autoantigens [93]. Qhov no repertoire tseem ruaj khov rau lub hlis lossis xyoo [108,109]. Hauv cov neeg mob SLE, cov clones nyob rau hauv cov ntshav peripheral txawv ntawm cov nyob rau hauv lub raum [110], tawm tswv yim hais tias naive T hlwb yog activated ntawm nws tus kheej nyob rau hauv lub periphery thiab lub raum.raum.

Kev tsim cov tshuaj tiv thaiv hauv zos yog qhov tseem ceeb hauv kev tsim TLS. Interestingly, lubraumLub cev tiv thaiv kab mob ntsig txog TLS gene profile hauv lupus-ntau nas yog zoo ib yam li cov qog nqaij hlav hauv lub sijhawm ua haujlwm ntawm LN [74]. TLS muab T- thiab B-cell ciaj sia taus yam tseem ceeb IL-7 thiab BAFF uas nrhiav cov lymphocytes thiab nyiam kev sib cuam tshuam ntawm T thiab B hlwb nyob rau hauv ib puag ncig [111]. Kev ua kom B-cell hauv zos tau pom nyob rau hauv TLS los ntawm kev qhia ntawm Activation Induced Cytidine Deaminase (AICDA), ib qho enzyme lub luag hauj lwm rau cov chav kawm hloov recombination thiab somatic hypermutation [112] thiab active proliferation. Kev sib txawv hauv zos ntawm autoreactive plasma hlwb kuj tau pom [113].

Nyob rau hauv tus qauv ntawm pristane-induced murine SLE, B hlwb proliferate thiab chav kawm-hloov nyob rau hauv lub TLS, thiab Sm / RNA antibody-tsim plasma hlwb thiab plasmablasts tsim autoantibodies hauv zos [114,115]. Ntxiv mus,lub raumlos ntawm LN cov neeg mob muaj cov kab mob hauv nruab nrab zoo li cov qauv uas muaj FDCs. Cov chaw zov me nyuam no tuaj yeem muaj lub luag haujlwm hauv cov ntaub so ntswg tshwj xeeb hauv lub cev tiv thaiv kab mob [41]. Kev txheeb xyuas cov xwm txheej uas pib tsim TLS yuav tsum ua kom peb nkag siab txograumkev puas tsuaj rau cov neeg mob LN. BAFF thiab serum autoantibody qib sib cuam tshuam nrog TLS tsim hauvlub raum[42]. Txo cov theem ntawm BAFF txo T-cell tooj nyob rau hauv glomeruli thiab tiv thaiv LN thiab tsim los yog tu ntawm TLS [42].

Tsis tas li ntawd, lub xub ntiag ntawm FDCs, los yog kev khi ntawm IgG-ICs rau Fc RIIB, tuaj yeem muab qhov chaw ntawm cov tshuaj tiv thaiv tsis zoo [41,116,117] rau kev nthuav dav thiab ua kom cov B hlwb, thiab tsim cov lymphotoxin 1 2, uas yuav ntxiv mus. txhawb txoj kev loj hlob ntawm TLS [118,119]. Xwb, CD11b ntxiv rau cov hlwb myeloid secrete qib siab ntawm BAFF thiab txhim kho lub peev xwm chemotactic ntawm B hlwb los ntawm kev hloov kho chemokine-induced signaling [120], yog li ua rau cov cell aggregation thiab compartmentalization ntawm TLS. Txij li thaum nce qib ntawm BAFF ua kom muaj zog hauv zos T-cell ua kom muaj zog [121], lawv tuaj yeem txhawb nqa cov haujlwm ntawm TFH thiab ua kom ntev hauv qhov chaw cov kab mob hauv cov lus teb ntawmraumTLS. Tsis tas li ntawd, hauv cov neeg mob uas muaj LN, tsuas yog kev sib cuam tshuam ntawm tes-rau-hlwb ntawm TFH hlwb thiab B hlwb induce siab Bcl -6 thiab IL-21 hauv interstitium [122]. Qhov no tuaj yeem sawv cev rau cov txiaj ntsig ntawm BAFF uas txhawb nqa kev qhia ntawm ICOSL ntawm lub tshuab ua haujlwm B hlwb [123] thiab induces tsim TFH hlwb [124,125]. Yog li,lub raumTLS tuaj yeem tsim hauv LN vim hematopoietic cell infiltration rau hauvraum, tab sis qib BAFF siab yuav tsum tau tsim los yog tswj kom raug muab faib ua TLS. Qhov no qhia tau tias qib siab lossis kev tsim khoom ntev ntev ntawm BAFF tuaj yeem yog qhov xwm txheej tseem ceeb hauv kev tsim TLS compartmentalized.

Cistanche yog qhov zoo rauraum

3.2. Molecular cues rau kev tsim ntawm tertiary lymphoid qauv

CXCL13 uas yog tsim los ntawm fibroblastic stromal hlwb yog ib qho tseem ceeb chemokine rau B thiab lymphoid-tissue inducer (LTi) hlwb. Cov nas uas tsis muaj CXCL13 tsis tsim cov qog nqaij hlav tshwj tsis yog lub ntsej muag, lub ncauj tsev menyuam, thiab mesenteric sawv daws [126]. Induction ntawm TLS tsim [127] hauv nas tuaj yeem ua tiav los ntawm kev tshaj tawm CXCL13 uas tau tsav los ntawm nas insulin txhawb nqa (RIP), uas ua haujlwm hauv cov txiav thiabraum. Qhov no ua rau kev tsim ntawm TLS uas yog tus cwj pwm los ntawm kev sib cais B- thiab T-cell zones, muaj cov pa DCs, thiab lub network ntom ntom ntawm stromal hlwb thiab siab endothelial venules (HEV)-hom hlab ntsha [128]. CXCL12 (los yog stromal cell-derived factor 1 (SDF1)) yog qhia los ntawm stromal hlwb ntawm cov pob txha pob txha thiab tseem ceeb heev hauv pob txha pob txha hematopoiesis thiab B-cell kev loj hlob [129]. CXCL12 yog qhia los ntawm HEVs hauv cov kab mob lymphoid thib ob (SLO) thiab ua raws li qhov tseem ceeb ntawm B-cell recruitment chemokine, thaum T cells feem ntau tsis teb [130] (Table 1).

Tubular epithelial hlwb los ntawm lupus-prone nas tuaj yeem qhia IL-23 receptors thiab tsim cov chemokine CCL20 uas tuaj yeem nyiam cov lymphocytes raurauminterstitium (Fig. 1) [7]. Tsis tas li ntawd, IL-23 ua yeeb yam ntawm tubular epithelial hlwb tuaj yeem cuam tshuam kev tsim cov arginase 1 uas catabolizes arginine thiab yog li ua rau muaj kev nce ntxiv ntawm arginine uas tsim nyog rau kev loj hlob hauv zos lymphocytes [7]. Los ntawm thawj cov txheej txheem, tubular epithelial hlwb muaj peev xwm tsim cov tshuaj tiv thaiv kab mob kom nyiam cov lymphocytes uas tuaj yeem ua rau hauv zos. Los ntawm txoj kev thib ob, tubular epithelial hlwb tuaj yeem tso tawm cov tshuaj tiv thaiv kab mob uas tuaj yeem ua rau obviated nyob rau hauv lub xub ntiag ntawm IL-23 thiab tej zaum lwm yam stimulants.

CCL19 thiab CCL21 tau qhia los ntawm HEVs thiab qee lub hlwb stromal. Lawv yog cov ligands rau CCR7 tam sim no ntawm T cells, DCs, thiab LTi hlwb. Plt nas uas tsis muaj CCL19 noob thiab CCL21 qhia los ntawm cov ntaub so ntswg lymphoid hauv cov hlab ntsha lymphatic qhia lub luag haujlwm tseem ceeb rau CCR7 thiab CCL19 / CCL21 hauv T-cell homing. Hauv RIP-overexpression qauv, CCL21 tau ua pov thawj tias muaj txiaj ntsig zoo dua li CCL19 hauv kev tsim TLS [131,132]. Txawm li cas los xij, txawm tias CCL21 overexpression, tsis muaj qhov tseeb tsim ntawm B-cell follicles [131]. CCL28 muaj lub luag haujlwm hauv kev nrhiav neeg ua haujlwm thiab kev ua haujlwm ntawm B thiab T hlwb thiab txhawb kev hloov lub cev tiv thaiv kab mob [133–135]. Cov teeb liab los ntawm kev sib cuam tshuam ntawm CCL28 thiab CCR3 / CCR10 tsav cov txheej txheem no thiab nyiam ntau lub cev tiv thaiv kab mob los ntawm cov zej zog hauv zej zog [135,136]. Tsis ntev los no, kev nrhiav neeg ua haujlwm ntawm Treg hlwb los ntawm CCL28 tau pom, pom tias nws muaj lub luag haujlwm hauv kev hloov kho ntawm lub cev tiv thaiv kab mob, tswj kev ua siab ntev rau tus kheej-antigens, thiab tiv thaiv kev txhim kho cov kab mob autoimmune [137,138] (Table 1).

Cov tswv cuab ntawm TNF superfamily (TNFSF), uas yog TNF, lymphotoxin (LT), thiab , thiab lawv cov signaling receptors TNFRI / II thiab LT R, tau hais kom txhawb kev tsim TLS. Tsis tas li ntawd, ectopic qhia ntawm TNF lossis LT, tab sis tsis yog LT, nyob rau hauv kev tswj ntawm RIP coj mus rau tsim TLS [139,140]. Cov txiaj ntsig tseem ceeb tshaj plaws tau pom thaum LT thiab LT tau sib koom ua ke, ua rau muaj kev cuam tshuam ntawm leukocytes nyob rau hauv cov islets ntawm pancreatic, thiab loj TLS ntau dua li cov tsim hauv LT transgenic nas [139]. TNFR-I yog lub hauv paus tswj hwm ntawm lymphoid cov ntaub so ntswg organogenesis thiab germinal-center tsim, es tsis yog TNFR-II [141], thiab nws mediates LT -induced pancreatic TLS [142]. Kev ua kom TNFR-I thiab LT R kuj tau cuam tshuam rau hauv aortic TLS, nyob rau hauv uas aberration ntawm LT R signaling ua rau muaj kev cuam tshuam ntawm CCL21 thiab CXCL13 qhia, nrog rau qhov tshwm sim ntawm txo HEV tsim thiab cuam tshuam TLS txoj kev loj hlob [143,144] (Fig. 2).

Txawm hais tias qhov cuam tshuam ntawm LT, ib leeg lossis nrog LT, pom meej, lub luag haujlwm ntawm TNF yog qhov tsis sib haum xeeb. Hauv qee cov kab mob inflammatory, nrog rau cov uas koom nrog TLS, TNF muaj cov tshuaj tiv thaiv kab mob [144]; Insulitis hauv NOD nas thiab lupus hauv New Zealand nas txhim kho tom qab txhaj tshuaj TNF [144,145].

Transgenic overexpression ntawm IL-6 thiab IL-6R ua rau perivascular tsub zuj zuj ntawm B hlwb thiab mature plasma B hlwb [146]. IL-1 tsim los ntawm MSCs yog overexpressed nyob rau hauv lupus-nrhiav nas thiab tej zaum yuav pab tau rau TLS tsim [47]. Stimulation ntawm T hlwb nrog IL-4 lossis IL-7 induced qhia ntawm LT ; IL-7 yog qhov muaj zog tshaj plaws rau CD4 ntxiv rau T hlwb [131]. IL-17 tsev neeg noob yog qhov tseem ceeb hauv kev tiv thaiv cov kab mob thiab tau cuam tshuam rau ntau yam xwm txheej mob ntev. Zoo li cov tswv cuab ntawm TNFRSF, IL-17 receptor signals los ntawm NF-κB thiab IL-17 T hlwb raug ntxias los ntawm IL-6, TGF, thiab IL-23, tab sis inhibited los ntawm IB-27. IL-17 yog, yog li ntawd, tus neeg nruab nrab tseem ceeb rau lipopolysaccharide-induced txog [147]. IL-7R yog qhia los ntawm LTi hlwb thiab nrog rau CXCR5) IL-7 txhawb nqa lawv tsim hauv SLOs [126].

BAFF tuaj yeem txhawb cov ntaub so ntswg raug mob los ntawm kev cuam tshuam qhov zoo thiab ntau ntawm T-cell-tsav cytokines xws li IL-17, IL-4, thiab IFN . Kev nce qib ntawm BAFF hauvlub raumTej zaum yuav ua rau glomerular puas los ntawm invading T hlwb hauv lub glomeruli, los yog inducing tsim TH17 hlwb. Nws tsis paub meej tias txoj haujlwm ntawm T hlwb yog ib qho kev sib txuas lossis cov txheej txheem codependent uas txhawb nqa glomerulonephritis thiab tubulointerstitial nephritis. Nws tau raug pom tias thaiv T-cell co-stimulation [148] lossis neutralizing IFN thiab IL-4 [149,150], ua rau muaj kev txhim kho lossis qeeb hauvlub raumkab mob. Piv txwv li, T-cell infiltration thiab aggregation tau pom nyob rau hauvraumbiopsies los ntawm cov neeg mob SLE [151]. Immune-cell infiltration rau hauv tubulointerstitial thaj chaw hauv SLE yog txuam nrog LN [41], qhia tias txoj hauj lwm ntawm T hlwb hauv lub raum yog qhov tseem ceeb hauv tus kab mob.

3.3. Cov hlab ntsha hauv cov txheej txheem lymphoid tertiary

TLS zoo ib yam li cov qog ntshav hauv cov qauv, vasculature, cellular muaj pes tsawg leeg, thiab chemokine profile. Lub cev tiv thaiv kab mob muaj xws li T thiab B-cell zones thiab antigen-presenting cells, suav nrog FDCs thiab DCs paub tab. Cov hlab ntsha hauv TLS feem ntau faib ua cov qog ntshav thiab cov hlab ntsha (Fig. 3).

Lub raumCov hlab ntsha lymphatic (LVs) raug suav hais tias yog ib feem ntawm interstitium vim tias lawv tsis muaj cov ntaub so ntswg hauv qab daus, thiab lawv qhov muag tsis pom thiab tsis muaj pericytes [152]. Lymphatic capillaries nthuav qhia PROX-1, LYVE-1, CCL21, podoplanin, VEGFR-2, thiab VEGFR-3 [153]. Cov hlab ntsha lymphatic ntawm TLS qhia cov cim lymphatic xws li LYVE-1, PROX-1, podoplanin (hauv cov nas thiab tib neeg), thiab D2-40 (hauv tib neeg) [154], raws li qhia los ntawm ntau yam kev tshawb fawb ntawm mobraumkev tsis lees paub [155,156], cardiac allografts [157], transgenic nas qauv [158] thiab tus qauv nas ntawm lub hnub nyoog ntsig txog thawj Sjogren's-zoo li ¨ kab mob [159]. Txawm li cas los xij, tseem muaj ntau yam yuav tsum tau piav qhia.

Nws tsis paub tias TLS cov hlab ntsha ua haujlwm zoo ib yam li cov hauv cov qog ntshav. Nws zoo nkaus li tias lawv ua rau cov kua dej ntws tawm, tab sis qhov no tsis tau tshawb pom tag nrho. Nws tseem tsis tau paub tias LVs nqa cov tshuaj tiv thaiv thiab cov hlwb hauv TLS thiab cov hlwb kom deb ntawm TLS, zoo li cov hlab ntsha afferent thiab efferent hauv cov qog ntshav. Tias TLS LVs feem ntau muaj cov hlwb [159,160], qhia tias lawv muaj lub luag haujlwm ua cov neeg thauj khoom los ntawm kev qhia ntawm CCL21, uas cuam tshuam nrog CCR7- qhia cov hlwb. Txawm li cas los xij, LVs hauv qee qhov TLSs khaws cov hlwb, qhia tias lawv tsis pab txhawb nqa cellular thiab muaj kev ua haujlwm tsis zoo.

Lymph node cov neeg nyob hauv hlwb qhia sphingosine{0}} phosphate (S1P) thiab nws cov kev cuam tshuam nrog S1P1 receptor ntawm lymphocytes yog ib qho tseem ceeb rau lawv egression los ntawm cov qog nqaij hlav. FTY720 (fingolimod) yog ib qho S1P1 agonist uas ua rau nws cov internalization thiab tsub zuj zuj ntawm lymphocytes nyob rau hauv lymph nodes [161], yog li ua hauj lwm raws li ib tug immunosuppressant. Thaum NOD nas nrog pancreatic TLS raug kho nrog FTY720, lawv tsis mus rau kev tsim cov islet puas thiab ntshav qab zib [162]. FTY720 inhibits kev loj hlob ntawm tus kab mob tsuas yog thaum lub sijhawm cov nas pom TLS [163]. Lawv cov pancreatic TLS tau cuam tshuam nrog cov qhab nia siab insulitis tom qab kev kho FTY720, qhia tias cov hlwb raug kaw hauv lawv. Islet kev puas tsuaj thiab ntshav qab zib tau tshwm sim nyob rau hauv hnub ntawm kev tso tseg FTY720 kev kho mob [162,164]. Yog li, nws zoo li S1P gradient cuam tshuam rau kev lag luam lymphocyte hauv TLS LVs. Fingolimod tuaj yeem yuam TLS kom yaj hauv cov neeg mob thiab nas nrog lupus.

LVs thauj cov tshuaj soluble lossis cell-associated antigens mus rau hauv cov qog ntshav. Plasmalemma vesicle-associated protein (PLVAP) yog qhia los ntawm cov hlab ntsha lymphatic endothelial hlwb hauv lymphatic sinus hauv cov qog ntshav. PLVAP-zoo lymphatic endothelial hlwb pab txhawb rau lub sieving ntawm lymphocytes thiab high-molecular-yuag antigens nkag mus rau cov qog nqaij hlav [165]. Txij li thaum TLS muaj cov kab hluav taws xob [166], nws tsim nyog los nug seb LVs hauv TLS thiab cov qog ntshav qog ua haujlwm zoo ib yam. Antigen kev thauj mus los yuav tsis tshua tseem ceeb dua li hauv SLOs vim tias cov antigen yog ib feem ntawm TLS. Txawm li cas los xij, txij li cov kab mob antigen-presenting feem ntau muaj nyob hauv TLS, qhov no yog qhov sib cav.

Raws li tau sau tseg saum toj no, LVs hauv cov qog ntshav qab zib tam sim no nws tus kheej-antigens [167–169] ncaj qha los ntawm kev qhia ntawm qhov loj histocompatibility complex (MHC) molecules lossis antigen ntawm 'classical' antigen-presenting cells. Kev nthuav qhia ntawm tus kheej-antigen los ntawm LVs [167] tuaj yeem pab txhawb kev ua siab ntev lossis T-cell ua rau hauv cov qog ntshav lossis TLS. Cov kev tshawb fawb soj ntsuam lub peev xwm ntawm TLS LVs los nthuav tawm cov tshuaj tiv thaiv thiab ua rau ib qho ntawm cov txiaj ntsig no tsis tau ua.

HEVs yog tshwj xeeb peripheral-node addressin (PNAd)-cov hlab ntsha zoo nrog cov qauv sib txawv. HEVs zoo li muaj lub luag haujlwm hauv kev thauj cov ntshav lymphocytes rau hauv TLS. Qhov tshwm sim no yog ib hom kev tshwj xeeb infiltration uas feem ntau nco T hlwb nrog ib qho kev qhia qis ntawm L-selectin (tejzaum nws yog vim qhov kev qhia ntawm PNAd) tuaj yeem nkag mus rauraum[139]. Ib qho kev sim hauv cov nas uas tsis muaj peev xwm ntawm LT lossis LT LN pom tias kev txhim kho ntawm PNAd-expressing HEVs yog stunted, ua rau txo qhov loj thiab cellularity ntawm lymphoid infiltrates [139]. Yog li, LT R signaling tej zaum yuav xav tau rau kev txhim kho lymphoid aggregation thiab HEV tsim.

4. Cov lus xaus thiab qhib cov lus nug

Txawm hais tias cov tshuaj tiv thaiv kab mob hauv SLOs tuaj yeem tsim kev tiv thaiv kab mob, cov tshuaj tiv thaiv kab mob hauv TLS tuaj yeem ua rau puas tsuaj. Cov chaw tua kab mob hauv TLS muaj cov yam ntxwv zoo sib xws rau cov chaw tua kab mob hauv SLOs thiab muab lub hauv paus rau kev tiv thaiv kab mob ntawm tes clonal expansion thiab somatic hypermutation [41]. Txawm hais tias muaj kev tiv thaiv kab mob hauv lub cev tau suav tias yog qhov tseem ceeb hauv kev tsim TLS, cov pov thawj tsis ntev los no qhia tau tias nyob rau hauv kev cuam tshuam ntawm cytokines tubular epithelial hlwb tuaj yeem tsim cytokines tuaj yeem nyiam T hlwb [7].

B hlwb tam sim no nyob rau hauv TLS tau pom tias tau dhau los ntawm somatic hypermutation [41] thiab yog li kev tsim khoom hauv zos ntawm autoantibodies thiab tsim muaj nyob hauv situ ICs yog qhov tseeb. Th17 hlwb muaj nyob rau hauv lublub raumntawm tib neeg thiab nas nrog lupus qhia qhov kev koom tes ncaj qha ntawm cov hlwb hauv cov lus teb inflammatory thiabraumkev puas tsuaj [101,170–172]. Qhov tseeb tias TCR repertoire ntawmrauminfiltrating hlwb nyob rau hauv nas thiab cov neeg uas muaj lupus yog txwv [93] qhia tias lub raum tshwj xeeb antigens, tseem nyob rau hauv loj, raug lees paub. Th17 hlwb yog qhov tseem ceeb hauv kev tsim TLS hauv kev nthuav tawm ntawm qhov mob hauv nruab nrab paj hlwb thiab lub ntsws neonatal [173-175]. Lub luag haujlwm zoo sib xws tuaj yeem raug kwv yees rau cov hlwb hauv kev tsim thiab tswj kev mob hauv LN.

Lub xub ntiag ntawm Treg hlwb nyob rau hauv lubraumTLS thiab lawv txoj haujlwm ua tau tsis paub. Nws yog qhov ua tau tias lawv raug cais los ntawm cov txheej txheem tsis paub lossis yog tias tam sim no lawv dhau los ntawm lawv txoj haujlwm xav tau. Nws paub tias Treg hlwb nyob rau hauv lub xub ntiag ntawm ib puag ncig inflammatory plam lawv cov kev tswj hwm [78].

Txawm hais tias nws tau raug thov tias qhov kev siv ntawm interstitial o yog ib qho kev qhia tsis zoo ntawmlub raumua haujlwm nws tseem tsis tau paub tias TLS pab txhawb li casraumkev puas tsuaj. T hlwb yuav ua kom puasraumcov neeg nyob hauv cov hlwb zoo li nws tau qhia rau podocytes [21], los ntawm kev ncaj qha cytotoxicity lossis los ntawm kev cuam tshuam cov haujlwm ntawm lub raum hlwb los ntawm kev ua ntawm cytokines raws li tau qhia rau IL-23 [7] thiab BAFF [123].

Ua tiav unchartered yog thaj tsam ntawm kev koom tes ntawm TLS rau kev txhim kho ntawmraumfibrosis uas yog irreversible thiab txhais qhov kawg ntawm kev ua haujlwm. Cytokines tsim los ntawm cov hlwb infiltrating nrog rau kev koom tes ntawm lwm yam tsim los ntawm lub raum cov neeg nyob hauv lub raum yuav txhawb nqa collagen ntau lawm los ntawm fibroblasts.

Tom ntej no technologies suav nrog ib leeg-cell RNA sequencing [176] thiab spatial transcriptomics yuav ua rau tus cwj pwm ntawm kev sib cuam tshuam ntawm cov hlwb uas muaj TLS thiabraumcov nyob hauv hlwb. Lawv kuj tseem tuaj yeem tso cai rau tus cwj pwm ntawm subsets ntawm cov neeg mob nrog LN, vim nws paub tseeb tias LN yog qhov chaw kho mob thiab cov kab mob sib txawv. Kev siv zog rov qab raum pathology los ntawm kev xa cov tshuaj rauraumcov neeg nyob hauv cov hlwb (podocytes [22], tubular epithelial cells [7]) yuav tsum tso cai kom rov zoo dua ntawm kev ua haujlwm ntawm lub raum hlwb thaum cov kev mob tshwm sim los ntawm kev tswj hwm lub cev yog obviated.

Kev lees paub

Txhawb nqa los ntawm Northern Norway Lub Chaw Saib Xyuas Kev Noj Qab Haus Huv Hauv Cheeb Tsam Kev Tshawb Fawb Kev Tshawb Fawb HNF 1427-18.

Los ntawm: 'Interplay of immune andraumCov neeg nyob hauv cov hlwb hauv kev tsim cov tertiary lymphoid qauv hauv lupus nephritis 'los ntawmSimin Jamaly et al

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