Innate Thiab Adaptive Immune Abnormalities Hauv qab Cov Kab Mob autoimmune: Cov Kev Sib Txuas Txuas (2)

T cell thiab kab mob autoimmune

Kev nthuav dav ntawm tus kheej-reactive T hlwb yog biomarker nyob rau hauv ntau yam kab mob autoimmune, uas yog ib qho tseem ceeb nyob rau hauv orchestrating ob innate thiab adaptive tiv thaiv kab mob thiab inducing cov ntaub so ntswg puas. Ntawm cov no, CD4+ T cell yog qhov tseem ceeb los ntawm kev zais ntau yam cytokines, chemokines, thiab cell-cell kev sib cuam tshuam. Raws li peb tau tham saum toj no, GWASs tau siv dav los txheeb xyuas cov noob raug mob hauv cov kab mob autoimmune, thiab ntau yam kev hloov pauv hauv T hlwb tau raug txheeb xyuas, suav nrog SNPs hauv IL23R, IL17A / F, IL21, JAK2, STAT2, CARD9, CCR6, thiab lwm yam. . (Kochi, 2016). Thaum qhib los ntawm antigen-presenting cells (APCs), CD4+ T hlwb sib txawv rau hauv cov kab mob sib txawv hauv cov ntsiab lus-dependant nrog cov haujlwm tshwj xeeb, suav nrog T helper (Th) 1, Th2, Th17, Th9, T follicular helper (Tfh) thiab tswj T (Treg) hlwb.

cistanche cov txiaj ntsig rau txiv neej-ua kom muaj zog tiv thaiv kab mob

T cell subsets thiab kab mob autoimmune

Th1/Th2 cells

Peb lub xyoos dhau los, Mosmann thiab Coffman tau faib T pab hlwb ua ob pawg: Th1 thiab Th2 T hlwb. Th1 hlwb qhia IFN- thiab tseem ceeb hauv kev tiv thaiv kab mob ntawm tes thiab cov kab mob autoimmune, whereas Th2 hlwb qhia IL-4, IL-5, thiab IL-13, thiab muaj feem xyuam rau kev tiv thaiv kab mob humoral thiab kev tsis haum tshuaj. (Mosmann thiab Coffman, 1989). Lub Th1/Th2 binary paradigm tau ua tiav rau yuav luag ob xyoo caum mus txog thaum cov txheej txheem tshiab ntxiv tau tshwm sim hauv nas qauv ntawm cov kab mob autoimmune thaum ntxov xyoo pua. Th1 hlwb yog cov tseem ceeb ntawm cov kab mob hauv cov kab mob autoimmune. Txoj kev loj hlob ntawm Th1 hlwb yog induced los ntawm IL-12 thiab IFN- thiab nruj tswj hwm los ntawm tus tswv transcription factor T-bet. Ib qho ntawm cov haujlwm tseem ceeb ntawm Th1 hlwb yog zais IFN-, ib qho tseem ceeb pro-inflammatory cytokine uas activates macrophage thiab upregulates MHC-II qhia ntawm APCs. Nce IFN- qhia tau pom nyob rau hauv ntau yam kab mob autoimmune, suav nrog IBD, MS, RA, SLE cov neeg mob, thiab lwm yam. T hlwb infiltrated nyob rau hauv lub hauv nruab nrab lub paj hlwb thaum lub sij hawm sim autoimmune encephalomyelitis (EAE), tus nas qauv ntawm MS, pom muaj zog IFN- thiab lymphotoxin secretion, tab sis tsis yog IL-4, qhia tias Th1 tsis yog Th2 hlwb yog qhov tseem ceeb hauv cov qauv no (Ando li al., 1989). Txawm li cas los xij, cov nas uas muaj IFN-deficiency tseem raug rau EAE. Cov kev tshawb fawb tom qab tau tshaj tawm tias IL-23, tsis yog IL-12 uas sib koom cov saw p40 nrog IL-23, yog qhov tsim nyog rau EAE pathogenicity (Cua et al., 2003), ua rau Kev txheeb xyuas ntawm autoimmune-mediated Th17 hlwb thiab cov lus nug ntawm Th1 hlwb ua haujlwm hauv cov kab mob autoimmune. Cov kev tshawb fawb hauv qab no tau qhia tias IL-12 thiab IL-23, nrog rau kev hloov pauv Th1 thiab Th17 hlwb, ua rau muaj ntau hom EAE nrog cov kab mob sib txawv thiab kab mob (Kroenke li al., 2008). Ntxiv mus, Th1 hlwb pab txhawb Th17 hlwb kom nkag mus rau hauv nruab nrab paj hlwb (O'Connor li al., 2008). Ib yam li ntawd, cov kab mob ua haujlwm ntawm Th1 hlwb, suav nrog nws cov nyhuv molecule IFN- lossis cov cai tswj hwm T-bet thiab STAT4, tau pom nyob rau hauv lwm cov kab mob autoimmune, suav nrog kev sim autoimmune uveitis (EAU), collagen-induced mob caj dab (CIA) thiab colitis. (Raphael et al., 2015).

Th2 cell txoj kev loj hlob feem ntau yog tshwm sim los ntawm IL-4 thiab IL-2 thiab siv GATA3 ua tus qauv hloov pauv. Piv nrog Th1 thiab Th17 hlwb, kev ua haujlwm ntawm Th2 hlwb hauv kev tswj cov kab mob autoimmune raug txwv thiab tsis tau kawm zoo. Lub luag haujlwm pathogenic ntawm Th2 hlwb hauv kev mob ntsws asthma tau raug tshawb fawb dav dav, thiab ntau yam tshuaj tsom rau Th2-txog cytokines tau pom zoo kom siv tau rau cov neeg mob hawb pob hnyav (Lee li al., 2021; León thiab Ballesteros-Tato, 2021 ). Lyn tsis muaj nas, ib qho tseem ceeb Th2 tsis zoo regulator, tsim muaj zog Th2 teb nrog mob hawb pob (Beavitt li al., 2005). Interestingly, cov nas no tsim cov kab mob autoimmune uas ua rau cov kab mob zoo li lupus zoo li nephritis thaum lub neej lig, nrog rau kev ua rau nws tus kheej muaj zog IgE, thiab tshem tawm Il4 zoo heev txo IgE ntau lawm thiab ameliorated kab mob hnyav (Charles li al., 2010). Xav txog kev ua haujlwm ntawm IL-4 hauv inducing B cell immunoglobulin chav kawm hloov mus rau IgG1 thiab IgE, Th2 yuav yog qhov tseem ceeb hauv kev kho B cell-dependent autoimmune teb.

Th17 cev

Qhov kev tshawb pom ntawm qhov ua haujlwm tshwj xeeb ntawm IL-23 inducing IL-17A-tsim T hlwb thiab kab mob autoimmune, tab sis tsis yog IL-12, Th1 cell inducer uas sib koom p40 subunit nrog IL-23, qhia tau hais tias muaj qhov sib txawv ntawm T cell subset (Cua et al., 2003). Xyoo 2005, peb pab pawg ua ke nrog lwm tus tau tsim T cell subset tshiab, Th17 hlwb, raws li lawv cov IL-17Ib txoj haujlwm zais cia thiab kev xav tau kev loj hlob ywj pheej.

Txawm hais tias lawv qhov tseem ceeb hauv kev tiv thaiv lub cev tiv thaiv kab mob thiab tswj cov ntaub so ntswg homeostasis, cov lus teb Th17 ntau dhau ua rau ntau cov ntaub so ntswg mob thiab ntau yam kab mob autoimmune, qhia los ntawm ntau zaus ntawm Th17 hlwb hauv cov ntshav lossis cov kab mob cuam tshuam. Hauv ntau tus kab mob sclerosis, nce IL-17A tau pom ntev ntev hauv cov kab mob ntawm cov neeg mob nquag, thiab Th17 hlwb tsiv mus zoo los ntawm cov ntshav-hlwb thaiv thiab tua cov neurons. Hauv cov neeg mob mob caj dab, IL-17Ib qib hauv cov kua dej synovial nce ntxiv, uas ncaj qha induces osteoclastogenesis. Ib yam li ntawd, IL-17Ib qho kev qhia kuj tau nce ntxiv hauv CD thiab UC cov neeg mob (Korn li al., 2009). Ntxiv mus, mucosal IL-23p19, IL-23R, thiab IL-17Ib qho kev qhia tau nce siab hauv cov tshuaj tiv thaiv TNF uas tsis teb rau cov neeg mob teb (Schmitt li al., 2019). GWAS kuj tau txuas ntau qhov kev hloov pauv ntawm kev ua haujlwm hauv Th17 / IL-17 axis rau ntau yam kab mob autoimmune, suav nrog SNPs hauv IL23R, CCR6, thiab IL17A/F (Kochi, 2016). Lub luag haujlwm tseem ceeb ntawm Th17 hlwb tau raug lees paub ntxiv los ntawm pawg loj ntawm cov kev tshawb fawb soj ntsuam tsom rau cov khoom tseem ceeb hauv Th17-txoj kev cuam tshuam, suav nrog IL-6, IL-23, IL{{27 }}, STAT3, thiab IL-17RA, uas yuav tau tham tom qab. Txoj kev loj hlob ntawm Th17 hlwb yog nruj tswj hwm los ntawm kev hloov kho epigenetic, transcriptional networks, thiab ntau yam cytokines. ROR t thiab ROR, qhia tau zoo heev hauv Th17 hlwb piv nrog rau lwm cov kab mob, yog ob qho tseem ceeb ntawm kev hloov pauv rau Th17 hlwb. Kev sib xyaw ua ke ntawm TGF- thiab IL-6 yog qhov tseem ceeb rau Th17 cell pib, thiab IL-1 thiab IL-23 ntxiv txhim kho Th17 teb. Txawm li cas los xij, hauv tib neeg, IL-21, tsis yog IL-6, yog qhov tseem ceeb dua hauv kev tsim cov Th17 hlwb ua ke nrog TGF- (Dong, 2021). Th17 cell pathogenicity yog tswj tshwj xeeb. IL-23 yog qhov tseem ceeb cytokine los tsim cov kab mob Th17 hlwb, nrog rau TGF- 3 thiab SAAs. Txoj kev tshawb fawb ib leeg kuj tau nthuav tawm ntau yam kab mob sib kis, suav nrog Gpr65, Plzp, Toso, thiab Cd5l. Qhov zoo siab, kev tshawb fawb tsis ntev los no pom tias IL-17Ib kis txwv tsis pub Th17 pathogenicity los ntawm kev ua rau autocrine secretion ntawm IL-24 (Chong et al., 2020).

Ib puag ncig yam tseem ceeb kuj koom nrog hauv kev tswj hwm Th17 cell kev loj hlob thiab pathogenicity. Microbiota, xws li cov kab mob commensal SFB, yog qhov tseem ceeb rau kev ntxias cov plab hnyuv Th17 ntawm lub xeev khov kho, thaum cov kab mob xws li Citrobacter rodentium induce transcriptional thiab metabolic sib txawv pathogenic Th17 hlwb (Omenetti li al., 2019). Ketogenic noj cov zaub mov txo plab Th17 hlwb los ntawm inhibiting bifidobacterial kev loj hlob (Ang li al., 2020). Ntxiv mus, tsis yog tsuas yog plab microbiota nkaus xwb tab sis kuj qhov ncauj qhov ncauj kab mob ntsig txog kab mob ua rau Th17 cell teb thiab pab txhawb colitis (Kitamoto li al., 2020). Qhov tseem ceeb, Th17 hlwb nrog dual-TCR uas paub txog SFB thiab tus kheej-antigen provoke ntsws autoimmunity (Bradley li al., 2017), hais txog qhov tseem ceeb ntawm microbiota-induced Th17 hlwb hauv autoimmune teb. Peb kuj pom tias ua npaws, cov tsos mob tshwm sim hauv ntau yam kab mob autoimmune, txhawb Th17 cell sib txawv thiab pathogenicity los ntawm kev txhawb nqa SMAD4 SUMOylation (Wang li al., 2020). Kev noj zaub mov muaj ntsev ntau kuj ua rau Th17 cell sib txawv thiab ua rau Th{19}}cov kab mob cuam tshuam nrog cov kab mob autoimmune, los ntawm kev ua rau cov kab mob ntsig txog cov noob xws li Tnf, Ccl20, Il23r, thiab Csf2 (Kleinewietfeld li al., 2013). Tsis zoo li Th1 thiab Th2 hlwb uas ruaj khov, Th17 hlwb muaj ntau heterogeneous thiab yas teb rau ntau yam ib puag ncig. Siv Il17acreRosaYFP txoj hmoo daim ntawv qhia nas, cov kws tshawb fawb pom tias Th17 hlwb yuav plam IL-17Lub peev xwm zais cia thiab pib qhia IFN- hauv EAE qauv, thiab yuav luag txhua IFN- - qhia CD4+ T hlwb nyob rau hauv tus txha caj qaum hloov los ntawm ex-Th17 hlwb. Th17 hlwb nrog Tbx21 tsis muaj peev xwm, uas encodes T-bet, tsis tuaj yeem ntxias EAE, ntxiv qhov tseem ceeb ntawm Th17 cell plasticity hauv cov kab mob autoimmune (Kamali li al., 2019). Hauv Peyer's thaj, Th17 hlwb sib txawv rau Tfh phenotype qhia PD-1 thiab CXCR5 thiab tsim nyog rau kev tsim IgA los ntawm GC B hlwb (Hirota li al., 2013). Tom qab ntawd, Th17 hlwb qhia IL-10, uas hloov mus rau Tr1-zoo li cov hlwb, tau txheeb xyuas ob qho tib si nyob rau hauv lub xeev khov kho lossis nyob rau hauv cov kev mob tshwm sim hauv plab (Gagliani li al., 2015). Cov ex-Th17 hlwb kuj tuaj yeem hloov mus rau IL-4- zais cov hlwb hauv tus qauv mob ntsws asthma (Tortola li al., 2020), thiab Th17 hlwb poob ROR t qhia spontaneously hloov mus rau hauv IL-4-qhia Th{{ 56}}zoo li cov hlwb (Chi et al., 2022). Tag nrho cov kev tshawb pom no ua rau muaj peev xwm xav txog kev kho lub hom phiaj ntawm Th17 hlwb. IL-17A, tus loj Th17 kos npe cytokine, ua lub luag haujlwm tseem ceeb hauv kev ua kom cov nqaij mos o thiab kev puas tsuaj hauv ntau yam kab mob autoimmune los ntawm kev hloov cov lus teb ntawm tes. IL-17Ib qho tseem ceeb hauv cov hlwb uas tsis yog hematopoietic los ntawm IL-17RA thiab IL-17RC, xws li fibroblast, epithelial cells, thiab endothelial cells (Korn et al., 2009). IL-17Ib induces ib tug cascade inflammatory teb los ntawm kev txhawb cov hlwb secreting ib tug loj cohort ntawm inflammatory cytokines, chemokines, matrix metalloproteinases, thiab antimicrobial proteins. CXCL1, CXCL2, thiab CXCL8 ntxiv nrhiav cov hlwb myeloid xws li neutrophils rau cov ntaub so ntswg. IL-17Ib kuj koom nrog kev tiv thaiv kev lom zem los ntawm kev tswj cov kab mob hauv nruab nrab cov tshuaj tiv thaiv thiab kev tsim tshuaj tiv thaiv kab mob. Hauv cov neeg mob pSS, qhov nce IL-17A yog cuam tshuam nrog GC tsim thiab qib autoantibody (Verstappen li al., 2018). IL-17A ncaj qha txhawb nqa Tfh cell localization mus rau thaj chaw teeb, B cell proliferation/isotype class switching, thiab T thiab B cell sib cuam tshuam los ntawm kev ua kom cov hlwb stromal los txhawb lub koom haum follicular (Subbarayal et al., 2016). Ntxiv rau Th17 hlwb, IL-17A kuj tau qhia los ntawm ntau lub cev tiv thaiv kab mob hauv lub cev, suav nrog ILC3, δ T, NK, NKT, thiab neutrophils, uas ua si zoo sib xws lossis rov ua haujlwm dua tab sis ua haujlwm raws li thawj kab lus teb. nyob rau hauv teb rau ntau yam kev tiv thaiv kab mob los yog tus tswv tsev yuav tsum tau (Dong, 2021).

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

Tfh cells

Ib qho ntawm cov haujlwm tseem ceeb ntawm CD4+ T hlwb yog pab B hlwb thiab cov tshuaj tiv thaiv kab mob. Tfh cell yog ib tug tshwj xeeb subset uas pab germinal center (GC) tsim, ib tug tshwj xeeb qauv nyob rau hauv lub follicles ntawm lwm yam lymphoid nruab nrog cev, thiab pab B hlwb undergo immunoglobulin somatic hypermutation, antibody isotype chav kawm ntawv hloov, thiab sib txawv rau hauv cov ntshav los yog nco B hlwb. Lawv tau piav qhia thawj zaug hauv tib neeg tonsils, qhov twg ntau pab pawg tau txheeb xyuas qhov sib txawv CD4+ cov pej xeem tau nthuav tawm cov cim saum npoo CXCR5, nrog rau cov co-stimulatory molecules ICOS thiab PD-1, cytokine IL{5}} , thiab qhov tseem ceeb ntawm kev hloov pauv BCL-6. Cov molecules deg ICOS, PD-1, thiab CD40L ncaj qha khi nrog lawv cov receptors qhia ntawm B hlwb thiab yog li ua rau B cell proliferation, maturation, thiab sib txawv, uas kuj txhawb los ntawm Tfh-secreted cytokines xws li IL{{10 }} (Crotty, 2011). Kev sib cuam tshuam TB thiab cytokine ntau lawm txhawb GC B hlwb tsim cov tshuaj tiv thaiv kab mob siab rau thaum muaj cov tshuaj tiv thaiv antigen. Tfh hlwb yog ib qho tseem ceeb hauv kev tsav tsheb autoimmune teb, tshwj xeeb tshaj yog nyob rau hauv autoantibody-mediated los yog kab mob. Hauv cov neeg mob SLE nquag, autoreactive GC B hlwb thiab nce circulating Tfh hlwb (cTfh) hauv cov ntshav tau pom ntev, nrog nce cTfh2 tab sis txo cTfh1 cov lus teb. Cov hlwb hloov pauv cTfh muaj feem cuam tshuam nrog kev mob hnyav, ntshav ntshav ntau ntau, thiab autoantibody titers. Ntxiv mus, kev ua haujlwm Tfh hlwb thiab TB aggregates tau pom nyob rau hauv lupus nephritis (Blanco li al., 2016). Ib yam li ntawd, nce cTfh hlwb qhia txog qib siab ntawm ICOS thiab PD-1 kuj tau pom nyob rau hauv ob peb lwm yam kab mob autoimmune xws li T1D, RA, MS, thiab pSS (Ueno li al., 2015). Tfh koom nrog ectopic lymphoid-zoo li qauv (ELS), uas txhawb autoantibody teb los ntawm B hlwb nyob rau hauv peripheral ntaub so ntswg, kuj tau pom nyob rau hauv cov ntaub so ntswg synovial nyob rau hauv cov neeg mob RA, meninges nyob rau hauv MS cov neeg mob, thiab cov qog salivary nyob rau hauv cov neeg mob SS (Pitzalis li al., 2014). Lub luag haujlwm pathogenic ntawm Tfh hlwb hauv cov kab mob autoimmune tau raug lees paub ntxiv hauv cov qauv nas. Sanroque (Roquinsan) nas, nrog kev tswj tsis tau cov kab mob autoantibody ntau lawm thiab nce Tfh cell xov tooj hauv B cell follicles, muaj lupus zoo li autoimmune phenotypes. Depleting Bcl6 yog txaus rau ameliorate lub lupus phenotype nrog dramatically txo spontaneous GC tsim thiab Tfh cell xov tooj, uas ncaj qha tsim lub luag hauj lwm ntawm Tfh hlwb nyob rau hauv kev tsav tsheb autoimmune teb (Linterman li al., 2009). Raws li qhov tshwm sim, cov kab mob ua haujlwm ntawm BCL-6, ICOS, OX40, CXCR5, SAP, thiab IL-21 qhia hauv cov qauv lupus, sim Sjögren syndrome (ESS) qauv lossis RA qauv kuj tau tsim (Gensous thiab ib., 2018). Lub sijhawm no, lub luag haujlwm tseem ceeb ntawm IFN- lossis IL-4/IL-13 qhia Tfh hlwb tau raug txheeb xyuas los teb rau cov kab mob kis kab mob thiab ua xua, raws li (Feng li al., 2022; Gowthaman li al., 2019). Seb Tfh plasticity-related antibody teb yog koom nrog cov kab mob autoimmune tseem yuav tau tshuaj xyuas ntxiv.

Qhov sib txawv ntawm ntau theem ntawm Tfh hlwb raug tswj nruj, tab sis tseem tsis tau nkag siab tag nrho. Kev ua kom DC tso cai rau CD4+ T cells upregulating CXCR5 thiab downregulating CCR7 qhia kom tsiv mus rau TB ciam teb. Kev sib cuam tshuam TB hauv qab no los ntawm ICOS-ICOSL thiab MHC-peptide ntxiv ua rau GC-Tfh maturation thiab txhawb nqa GC tsim (Crotty, 2011). Peb pab pawg, ua ke nrog lwm tus, tau txheeb xyuas BCL-6 ua qhov tseem ceeb ntawm kev hloov pauv ntawm Tfh cell, thaum ASCL2, tab sis tsis yog BCL-6, ncaj qha txhawb nqa Cxcr5 transcription thiab ntxiv txhawb Tfh migrating mus rau hauv cov hauv paus hniav. TOX2, induced los ntawm BCL-6, kuj tseem xav tau rau qhov zoo tshaj plaws Tfh sib txawv thiab txhawb nqa BCL{15}} kev qhia hauv lub voj voog pub rau tom ntej (Dong, 2021). Qhov sib txawv ntawm Tfh hlwb kuj raug tswj los ntawm cytokine lab. Tsis muaj peev xwm ntawm ob qho tib si IL-6 thiab IL{19}} kev taw qhia, tab sis tsis yog cytokine ib leeg, txo qis Tfh tus lej, qhia txog qhov muaj peev xwm rov ua haujlwm ntawm cov cytokines, thaum IL-7 thiab IL{{21 }} suppress Tfh kev loj hlob. Hauv tib neeg, qhov sib txawv cytokine milieu yog qhov yuav tsum tau ua kom ntxias Tfh hlwb. IL-12 yog qhov tseem ceeb tshaj hauv kev txhawb nqa BCL-6 kev qhia thaum ntxov, ua ke nrog TGF- thiab IL-23, txhawm rau ua kom muaj ntau yam Tfh kos npe noob, suav nrog CXCR5, ICOS, IL- 21, BATF, and BCL-6 (Crotty, 2014). Ib puag ncig yam tseem ceeb, xws li plab microbiota, kuj tseem koom nrog hauv kev teb Tfh cell. Hauv cov neeg mob RA, SFB-induced Tfh hlwb hauv Peyer's thaj ua rau cov kab mob hauv lub cev thiab txhawb nqa autoantibody ntau lawm kom ua rau mob caj dab (Teng li al., 2016). Kev kho cov nas mob caj dab nrog cov tshuaj tua kab mob ua rau cov kab mob loj zuj zus nrog txo Tfh xov tooj ntawm tes, tsim cov kab mob hauv nruab nrab, thiab autoantibody ntau lawm (Block li al., 2016).

Treg hlwb

Ib qho kev ua haujlwm sib txawv ntawm T cell subset uas tswj tus kheej kam rau siab thiab homeostasis tau ntev tau pom, nrog rau cov lus qhia tshwj xeeb ntawm kev hloov pauv FOXP3, txiav txim siab ua Treg hlwb. Kev loj hlob ntawm Treg hlwb yog induced los ntawm ob peb cytokines xws li TGF-, IL-2, TSLP, IL-33, thiab IL- 6, ib puag ncig yam, microbiomes xws li Clostridia hom, thiab cov metabolism hauv. ntawm plab microbiota thiab cov khoom noj xws li cov kua tsib acids, retinoic acid, luv saw fatty acids thiab amino acids (Kanamori li al., 2016).

Hauv tib neeg, cuam tshuam FOXP3, tus qauv hloov pauv hloov pauv rau Treg hlwb, ua rau lub cev tsis muaj zog, polyendocrinopathy, thiab enteropathy X-txuas (IPEX) syndrome, nrog rau ntau yam kab mob autoimmune, txuas cov haujlwm tseem ceeb ntawm Treg hlwb rau cov kab mob autoimmune. Cov neeg uas muaj CD25, STAT5B, thiab CTLA4 tsis muaj peev xwm, thiab lwm yam Treg-txog cov molecules, kuj tsim cov kab mob autoimmune hnyav tsis txawv ntawm IPEX. Treg-specific variants yog cov yam ntxwv ntawm cov kab mob autoimmune. Polymorphisms hauv FOXP3, CTLA4, thiab CD25 muaj feem cuam tshuam nrog cov kab mob tshwm sim hauv autoimmune thyroid kab mob, T1D, thiab ntau tus neeg mob sclerosis raws li (Ohkura li al., 2020). Qhov tseem ceeb, Treg hlwb raug rho tawm los ntawm cov neeg mob MS yog qhov tsis zoo hauv lawv txoj kev muaj peev xwm tiv thaiv, thiab Treg hlwb hauv cov neeg mob RA qhia qis qis ntawm CTLA4 piv nrog kev tswj hwm kev noj qab haus huv (Mohr li al., 2019). Raws li tib neeg cov neeg mob, nas nrog FOXP3, CD25, thiab CTLA4 tsis muaj peev xwm kuj tsim cov kab mob autoimmune hauv ntau lub cev, thiab CD4+ CD25hi Treg cell hloov tau cawm cov lymphoproliferative syndromes (Fontenot li al., 2003). Treg hlwb txwv lub cev tiv thaiv kab mob los ntawm ntau lub tswv yim. Treg hlwb muaj TCR repertoires uas ntseeg tau tias nws tus kheej-antigen / MHC complex nyob rau hauv lub thymus, thiab yog rhiab heev rau nws tus kheej-peptides thaum ua kom zoo dua piv nrog cov pa T hlwb nyob rau hauv lub peripheral, uas enabled Treg-dependent tus kheej kam rau ua (Sakaguchi li al. , 2008). Treg hlwb nthuav tawm dav dav ntawm cov molecules nto xws li CD25, CTLA4, TIGIT, CD39, thiab CD73 los sib tw nrog effector T hlwb thiab ntxiv inhibit T cell ua kom thiab nthuav. Lub caij no, Tregs kuj zais cov tshuaj tiv thaiv kab mob cytokines xws li IL-10, TGF- thiab IL-35. Lub luag haujlwm ntawm cov cytokines hauv kev hloov kho cov kab mob autoimmune tsis nkag siab tag nrho. IL-10 ncaj qha inhibits antigen kev nthuav qhia muaj peev xwm ntawm APCs thiab ntxiv tiv thaiv kev txhim kho thiab kev ua haujlwm ntawm effector / nco T hlwb xws li Th1 hlwb, lossis ncaj qha inhibits IL-10Ra-expressing Th17 thiab Th1/Th17 hlwb pathogenicity (Huber li al., 2011). TGF- tsis tsuas yog txwv T cell proliferation thiab txhawb apoptosis los ntawm antagonizing antiapoptotic BCL-2 qhia, tab sis kuj modulates DCs thiab ncaj qha tswj Th17/Treg tshuav nyiaj li cas (Travis thiab Sheppard, 2014). Tsis tas li ntawd, Treg hlwb kuj ncaj qha zais Grzm B thiab perforin kom ntxias cov phiaj xwm tuag, suav nrog APCs.

Nyem qhov no mus saib Cistanche Enhance Immunity khoom

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Treg cells yog heterogenous. T-bet qhia Treg hlwb raug ntxias los ntawm IFN- stimulation thiab tshwj xeeb txwv IFN- tab sis tsis yog IL-17A thiab IL-4 qhia CD4+ T hlwb. GATA3- qhia txog Treg hlwb tau pom ob qho tib si nyob rau hauv lub xeev khov kho thiab thaum muaj mob. Ob qho T-thawj koom ruam thiab GATA3 qhia tau zoo heev, thiab kev tshem tawm Tbx21 thiab Gata3 hauv Tregs ua rau muaj kab mob autoimmune zoo li thaum yau hauv cov nas (Yu li al., 2015). Lub caij no, ROR texpressing Treg hlwb, feem ntau nyob hauv cov hnyuv hauv lub xeev khov kho, txwv tsis pub Th1 / Th17 kho mob colitis thiab Th2 cuam tshuam nrog helminth kab mob. Rho tawm STAT3, lwm qhov Th17- tshwj xeeb kev hloov pauv, hauv Treg hlwb ua rau mob plab hnyuv tuag nrog nce IL-17Ib qho kev qhia tab sis tsis yog IFN- thiab IL4, qhia txog kev xaiv dysregulation ntawm Th17- kho o (Qiu et al., 2020). Peb pab pawg kuj tau txheeb xyuas cov pej xeem ntawm Treg hlwb uas nthuav tawm ob qho tib si FOXP3 thiab BCL-6, hu ua Tfr hlwb. Cov hlwb no tau muab los ntawm nTregs nyob rau hauv lub peripheral thiab suppress germinal center tshua (Chung li al., 2011b). Tsis muaj peev xwm ntawm Bcl6 hauv Tregs txhawb kev lom zem autoimmunity hauv ESS qauv (Fu li al., 2018). Cov kev hloov pauv no ntawm ib txhais tes tswj qhov chaw cim qhia ntawm Treg hlwb xws li CXCR3, CCR6, thiab CXCR5, los txhawb kev tsiv teb tsaws ntawm Treg hlwb mus rau qhov chaw mob. Ntawm qhov tod tes, qhov inhibitory muaj nuj nqi ntawm Tregs tau tswj ncaj qha txij li cov nyhuv molecule qhia, xws li Il10 thiab Gzmb, tau txo qis hauv Tregs tsis muaj T-bet.

Lwm tus

TGM-CSF. Siv GM-CSF txoj hmoo-mapping nas, Becher li al. pom tias T hlwb tsim GM-CSF yog ib qho kev sib cais sib cais los ntawm IL-23 thiab IL-1 (Komuczki et al., 2019). Xav txog nws txoj haujlwm hauv kev txhawb nqa myeloid cell tsiv teb tsaws, ua kom muaj zog, thiab muaj sia nyob, GM-CSF yuav yog qhov tseem ceeb hauv kev tiv thaiv kab mob ntawm tes-nyob ntawm cov kab mob autoimmune. Txog tam sim no, GM-CSF yog tib lub cytokine uas tau pom kom tshem tawm tag nrho EAE kev nce qib tom qab tshem tawm, tab sis tsis yog IL-17A lossis IFN- (Codarri li al., 2011). Qhov kev tshawb pom no tseem ceeb rau peb tias Th17 hlwb yuav tsis yog tib lub hom phiaj ntawm IL-23. Thaiv GM-CSF kuj ua kom muaj kab mob hnyav hauv CIA qauv (Cook li al., 2001). Hauv EAU qauv, qhov mob tseem tshwm sim hauv IL-17A thiab IFN- ob leeg tsis muaj peev xwm nas, qhia tias muaj kev cuam tshuam ntxiv. Thaiv GM-CSF hauv cov nas no ntxiv txo EAU qhov hnyav, nrog txo qis eosinophil infiltration (Bing li al., 2020). Raws li cov txiaj ntsig tau zoo ua ntej kev kho mob, cov tshuaj tiv thaiv GM-CSF tau kawm dav hauv kev sim tshuaj kho mob RA thiab MS. CD8+ T cells. Kev ua haujlwm ntawm CD8+ T hlwb hauv cov kab mob sib kis thiab mob qog noj ntshav tau raug tshuaj xyuas dav dav (Guo thiab Dong, 2022; Zhao li al., 2020). Interestingly, nce cov pov thawj qhia tau hais tias CD8+ T hlwb tseem koom nrog hauv cov kab mob thiab kev tiv thaiv kab mob autoimmune. Hauv lub hauv paus paj hlwb ntawm cov neeg mob MS, infiltrated CD8+ T cells txawm tias ntau dua CD4+ T hlwb. Ntxiv mus, CD8+ T cell-mediated mob hnyav CNS mob nrog zoo sib xws rau cov neeg mob MS tsis pom nyob rau hauv CD4+ T cell-mediated EAE (Huseby et al., 2001). Lub cytotoxic muaj nuj nqi ntawm CD8+ T hlwb, suav nrog FASL thiab granules secretion, muaj peev xwm induces cell tuag thiab txhawb tus kheej-antigens raug. Lub caij no, CD8+ T cells secreted cytokines, xws li IFN- , TNF , thiab IL-17A, yog tus cwj pwm zoo pro-inflammatory hauv autoimmune teb. Tshaj li cov kab mob pathogenic ntawm CD8+ T hlwb hauv MS, SLE, T1D, thiab Grave's disease, kev tswj hwm CD8+ T hlwb kuj tau ua rau MS, colitis, lupus, RA, thiab T1D. Cov hlwb no pab tswj kev txhim kho kab mob los ntawm kev zais IL-10, txwv tsis pub tus kheej-reactive CD4+ T hlwb, thiab ua rau APC tolerogenic thiab cytotoxic kev ua haujlwm (Li et al., 2022; Yu et al., 2018 ).

Ob chav tsis zoo T hlwb. Lub TCR + CD3+ CD4− CD8− (ob npaug tsis zoo, DN) T cell yog ib feem me me ntawm peripheral CD3+ T hlwb suav 1%–3%, nrog kev nkag siab me ntsis ntawm nws cov kab mob. Kev nthuav dav ntawm DN T hlwb yog ib qho xwm txheej tshwm sim hauv autoimmune lymphoproliferative syndrome, thiab DN T xov tooj ntawm tes hauv cov ntshav yog cuam tshuam nrog autoantibody titer titer (Li et al., 2016a). Ib yam li ntawd, cov xov tooj ntawm tes ntau ntxiv ntawm DN T hlwb kuj muaj feem cuam tshuam nrog cov kab mob hnyav hauv cov neeg mob SLE, thiab cov hlwb no tuaj yeem qhia IL-4, IL-17A, IFN- , thiab TNF . Lub caij no, DN T hlwb nkag mus rau hauv cov qog ua kua qaub kuj tuaj yeem tsim IL-17A hauv SS cov neeg mob (Brandt thiab Hedrich, 2018). Luv luv, DN T hlwb tuaj yeem koom nrog hauv cov kab ke thiab cov kab mob hauv zos los ntawm kev tsim cov cytokines thiab modulating B cell teb, thiab xav tau kev tshawb fawb ntxiv kom nkag siab txog nws txoj haujlwm hauv cov kab mob autoimmune. Cov ntaub so ntswg-nyob nco T cells (Trm). Trm cells, suav nrog CD4+ thiab CD8+ Trm cells, yog lub cim xeeb ntev T cells nyob hauv cov ntaub so ntswg, tiv thaiv cov kab mob. Qhov tseem ceeb ntawm Trm hlwb hauv cov kab mob autoimmune tau nyiam nyob rau xyoo tas los no, tshwj xeeb tshaj yog nyob rau hauv cov kab mob ntawm daim tawv nqaij, suav nrog psoriasis, mycosis fungoides, thiab cov tshuaj tua kab mob ruaj khov. Cytotoxic Trm hlwb qhia IFN- los yog IL-17A tau raug txheeb xyuas hauv cov neeg mob vitiligo thiab psoriasis. Qhov tseem ceeb, tsom rau CD122, tus receptor rau IL-15 uas txhawb nqa Trm cell txoj kev loj hlob, thim rov qab vitiligo txoj kev loj hlob hauv cov qauv nas, qhia txog qhov muaj peev xwm kho mob ntawm lub hom phiaj Trm hlwb (Ryan li al., 2021). Trm hlwb uas muaj nyob rau hauv lub plab ntawm IBD cov neeg mob qhia ib tug loj npaum li cas ntawm pro-inflammatory cytokines xws li Il17a, Tnf, Ifng, thiab Il13. Kev txhawb nqa ntawm Trm hlwb, tshwj xeeb tshaj yog CD4+ Trm hlwb, muaj feem cuam tshuam nrog kev kho mob ntawm cov neeg mob IBD (Zundler li al., 2019). Trm hlwb hauv cov hnyuv kuj muab qhov kev xav ntawm qhov tsis ua haujlwm ntawm kev kho Vedolizumab hauv qee cov neeg mob IBD, uas thaiv cov qog ntshav qog ntshav. Ntau hom Trm hlwb kuj tau pom nyob rau hauv tib neeg lub hlwb, suav nrog hauv cov neeg mob MS. Qhov zoo siab, kev kis kab mob hauv lub neej thaum ntxov txhawb kev tsim CCL5- tsim Trm hauv lub hlwb, uas ua rau lub hlwb autoimmunity tom qab hauv lub neej hauv tus nas EAE qauv (Steinbach li al., 2019). Tag nrho cov kev soj ntsuam no qhia txog qhov tseem ceeb ntawm autoantigen-specific Trm cells hauv kev txhawb nqa cov kab mob autoimmune thiab lub peev xwm ntawm lub hom phiaj Trm hlwb rau kev kho mob.

T-cell tsom txoj kev kho 

Qhia txog qhov tseem ceeb ntawm T hlwb hauv kev kho cov kab mob autoimmune thiab cov kev xaiv tshuaj kho mob tsawg, tsom rau T hlwb tau txais kev saib xyuas ntau. Anti-TNF cov tshuaj tiv thaiv tau ua tiav loj hauv cov kab mob autoimmune. Nrog ntau lub hom phiaj txheeb xyuas, tshwj xeeb tshaj yog cov cytokines pro-inflammatory, tsom T hlwb tau ua tiav zoo, thiab cov txheej txheem tshiab kuj tau kawm dav hauv kev sim ua ntej.

Targeting Th17 cells

Tam sim ntawd tom qab lawv tshawb pom, Th17 hlwb tau txuas nrog ntau yam kab mob autoimmune thiab tau txais kev saib xyuas zoo los ntawm ob qho tib si kev tshawb fawb thiab cov tuam txhab tshuaj. Lub luag haujlwm tseem ceeb ntawm Th17 hlwb kuj tau raug lees paub ntxiv los ntawm pawg loj ntawm cov kev tshawb fawb soj ntsuam tsom cov khoom tseem ceeb hauv Th17-txoj kev cuam tshuam, suav nrog IL-6, IL-23, IL{{ 5}}A, STAT3, thiab IL-17RA. Txog tam sim no, cuaj cov tshuaj tiv thaiv kab mob monoclonal thiab ib qho me me molecular inhibitor tsom rau txoj hauv kev Th17 tau pom zoo rau kev kho mob ntawm ntau yam kab mob autoimmune los ntawm FDA (Table 2). Cov no suav nrog 2 lub hom phiaj IL-6 receptor (Tocilizumab thiab Sarilumab), 4 monoclonal antibodies targeting IL-23 (Ustekinumab, Tildrakizumab, Guselkumab thiab Risankizumab) thiab 3 lub hom phiaj IL-17 lossis IL{{16} }}RA (Secukinumab, Ixekizumab, Brodalumab), as Well as Tofacitinib, JAK1/3 inhibitor uas inhibits STAT3 activation. Txawm hais tias tag nrho cov tshuaj no thaiv Th17 cov lus teb ntawm tes, lawv pom cov teebmeem sib txawv ntawm cov kab mob autoimmune sib txawv, tej zaum vim lawv cov teebmeem pleiotropic ntawm lub cev. Piv txwv li, IL-6→ STAT3 txoj hauv kev kuj tseem ceeb hauv kev tswj cov kab mob hauv nruab nrab thiab cov lus teb humoral, uas tej zaum yuav yog ib qho laj thawj uas cov tshuaj muaj feem cuam tshuam tau zoo dua hauv kev kho mob ntawm kev sib koom ua ke nrog cov lus teb siab, suav nrog nruab nrab mus rau hnyav RA thiab sJIA (Hunter thiab Jones, 2015), thaum cov hom phiaj IL-23 lossis IL-17 tau pom zoo tsuas yog rau kev kho mob ntawm cov neeg mob nruab nrab mus rau mob hnyav plaque psoriasis, PsA thiab AS. Ustekinumab, uas lub hom phiaj rau ob qho tib si IL-12 thiab IL-23 thiab inhibits hom 1 thiab hom 17 tiv thaiv kab mob, tau raug pom zoo rau kev kho mob ntawm tus kab mob me me mus rau Cohn's disease (CD) thiab UC vim nws cov txiaj ntsig zoo. . Txawm li cas los xij, IL-17A-txog monoclonal antibodies, suav nrog Secukinumab thiab Ixekizumab, tuaj yeem ua rau tus kab mob phem zuj zus ntxiv hauv cov neeg mob CD, yuav yog vim nws txoj haujlwm tiv thaiv hauv kev tswj hwm kev cuam tshuam (Hueber et al., 2012). Brodalumab, monoclonal antibody tiv thaiv IL-17RA, tuaj yeem ua rau muaj kev pheej hmoo tua tus kheej hauv cov neeg mob, uas tsis tau pom zoo rau IL-17A monoclonal antibodies suav nrog Secukinumab thiab Ixekizumab, tej zaum vim IL-17RA kuj tseem yuav tsum tau xa cov teeb liab los ntawm lwm cov cytokines (Greig, 2016). Zuag qhia tag nrho, vim lawv qhov ua tau zoo heev hauv kev kho mob autoimmune syndromes dhau ib txwm muaj TNF- ntsig txog cov kab mob lom neeg, tshwj xeeb tshaj yog cov kab mob psoriasis, Th17- ntsig txog kev lag luam tshuaj tau nthuav dav sai.

Cov tshuaj saum toj no tag nrho cov hom phiaj tseem ceeb cytokine signaling txoj hauv kev koom nrog hauv Th17 cell sib txawv thiab cov txiaj ntsig ua haujlwm. Tsis ntev los no, ROR t, tus tswv transcription tseem ceeb hauv Th17 hlwb, kuj tau txais kev saib xyuas zoo los ntawm cov tuam txhab tshuaj. Nyob rau hauv 2011, peb pawg neeg ntawm nws tus kheej tau ua pov thawj-ntawm-lub tswv yim ntawm lub hom phiaj ROR t nyob rau hauv kev kho mob ntawm Th17-txog autoimmune kab mob nyob rau hauv cov tsiaj qauv. Txij thaum ntawd los, ntau tshaj 10 ROR t me me molecular inhibitors tau nkag mus rau theem I lossis II kev kuaj mob, rau kev kho mob psoriasis, mob qhov muag qhuav, thiab MS. Nws cia siab tias cov ROR t inhibitors tuaj yeem muab lwm txoj hauv kev los kho tus nqi zoo hauv kev kho mob ntawm Th17-txog cov kab mob autoimmune tshaj cov tshuaj lom neeg. Cov kev tshawb pom no tsis tsuas yog lees paub lub luag haujlwm tseem ceeb ntawm Th17 / IL-17 axis hauv tib neeg cov kab mob autoimmune, tab sis kuj qhia txog qhov nyuaj ntawm cov kab mob no, thiab qee qhov ntawm lawv tuaj yeem cuam tshuam nrog ntau yam kab mob thiab kev pheej hmoo, uas muaj kev sib xyaw ua ke. Cov tswv yim kho mob tej zaum yuav xav tau thiab yuav tsum tau tshawb xyuas ntxiv rau yav tom ntej.

Table 2 Summary of FDA-pom zoo tshuaj muaj feem xyuam rau Th17 hlwb

Lwm tus

Targeting cell migration. Thaum priming nyob rau hauv cov qog nqaij hlav hauv nruab nrog cev, T hlwb rov nkag mus rau hauv cov hlab ntsha thiab tsiv mus rau qhov sib txawv peripheral qhov chaw nyob ntawm qhov nthuav tawm qhov chaw receptors xws li integrins thiab chemokine gradients. Targeting lymphocytes homing molecule 4 tseem ceeb ameliorates spontaneous thiab T-cell hloov-induced colitis (Neurath, 2019). Cov kev soj ntsuam no ua rau kev txhim kho cov tshuaj tsom rau kev lag luam lymphocyte hauv kev kho IBD. Txawm li cas los xij, Natalizumab, lub hom phiaj 4, muaj peev xwm ua rau muaj kev phiv loj heev hauv kev ua rau muaj kev loj hlob ntawm ntau cov kab mob leukoencephalopathy, uas tej zaum yuav yog vim muaj kev cuam tshuam rau 4 1 cov kab mob uas tiv thaiv kab mob hauv hlwb (Van Assche li al., 2005). Tom qab ntawd, Vedolizumab tsom rau 4 7, qhov tshwj xeeb lub plab-homing receptor, tau txais txiaj ntsig zoo hauv kev kho mob thiab tau pom zoo los ntawm FDA rau kev kho mob UC thiab CD. Ntxiv nrog rau inhibiting lymphocytes homeing rau hauv txoj hnyuv, lwm cov tswv yim kuj tau pom cov txiaj ntsig kho mob, suav nrog cov tshuaj tiv thaiv kab mob E7 uas thaiv cov plab hnyuv ntawm lymphocytes, thiab S1PR1 agonist uas sequesters T hlwb hauv cov qog nqaij hlav (Neurath, 2019). Lub caij no, Natalizumab kuj tau pom zoo rau MS kev kho mob nrog cov lus ceeb toom.

Targeting co-stimulatory molecules. GWASs tau nthuav tawm ntau qhov SNPs cuam tshuam nrog cov co-stimulatory molecules xws li CD28, CTLA4, ICOS, CD40, thiab OX40L, uas yog qhov tseem ceeb hauv kev hloov kho T-cell teb. CTLA4-Ig molecule Abatacept tau txais kev pom zoo rau kev kho mob RA thiab tseem muaj txiaj ntsig zoo hauv kev kho mob rau menyuam yaus idiopathic mob caj dab (JIA) raws li theem 3 kev sim tshuaj. Cov tshuaj tsom rau CD40-CD40L, OX40-OX40L, thiab lwm yam kuj tau kawm hauv kev sim ua ntej lossis kev sim tshuaj thaum ntxov. Cov tshuaj tiv thaiv BAFF Belimumab tau pom zoo rau kev kho SLE, thiab tseem tau pom cov txiaj ntsig hauv theem 2 kev sim tshuaj kho mob thawj zaug Sjögren syndrome thiab RA, thiab tshuaj tiv thaiv OX40 antibody GBR830 hauv kev txhim kho qhov nruab nrab mus rau mob atopic dermatitis (Edner li al., 2020). Kev sib xyaw ntawm cov tshuaj tiv thaiv co-stimulatory molecules thiab lwm yam tshuaj tiv thaiv kab mob yog nyob rau hauv kev sim. Treg cell kho. Xav txog qhov tseem ceeb ntawm Treg hlwb hauv inhibiting inflammatory teb, cog lus preclinical cov txiaj ntsig tau raug tshaj tawm ntawm kev saws Treg hloov hauv kev kho cov kab mob autoimmune, xws li MS, SLE, T1D, thiab graft-tiv thaiv tus tswv tsev kab mob. Antigen-specific Treg hlwb qhia tau zoo dua kho cov teebmeem piv nrog polyclonal Tregs. Kev sib xyaw ua ke ntawm CRISPR-raws li kev hloov kho noob nrog Treg hlwb tuaj yeem ua tiav nws txoj haujlwm hauv kev tswj lub cev tiv thaiv kab mob (Ferreira li al., 2019).

TNF receptor signaling thiab auto-inflammatory kab mob: NF-κB thiab Necroptosis

Tumor necrosis factor (TNF) receptor signaling yog ib qho kev tswj xyuas nruj thiab muaj ntau txoj hauv kev koom nrog ntau yam txheej txheem ntawm tes nrog rau kev loj hlob ntawm tes, cell ciaj sia, cell tuag, thiab o. Dysregulation ntawm TNF receptor signaling los ntawm kev hloov pauv caj ces tau koom nrog ntau yam kab mob tib neeg thiab tsiaj autoimmune xws li IBD, psoriasis, thiab RA. Txog tam sim no, feem ntau kawm cov noob sib txawv hauv qab ntawm TNF receptor nyob rau hauv cov kab mob autoinflammatory no koom nrog dysregulated NF-κB ua kom muaj xws li OTULIN tsis txaus, thiab haploinsufficiency ntawm A20. Txawm li cas los xij, kev nce qib tsis ntev los no tau tshawb nrhiav lub luag haujlwm tseem ceeb ntawm TNFR-mediated cell tuag qhov teeb meem tshwj xeeb tshaj yog necroptosis hauv cov kab mob autoinflammatory. Hauv kev tshuaj xyuas no, peb yuav tham txog lub luag haujlwm tseem ceeb ntawm necroptosis hauv cov kab mob ntawm cov kab mob autoimmune los ntawm kev hloov pauv ntawm NF-κB txoj hauv kev cuam tshuam nrog cov noob suav nrog NEMO, LUBAC, OTULIN, thiab A20. Tsis tas li ntawd, peb sau cov kev nce qib tsis ntev los no hauv kev hloov pauv caj ces ntawm necroptosis teeb liab cov khoom hauv cov kab mob autoinflammatory xws li RIPK1-kev cuam tshuam autoinflammation thiab lwm yam necroptosis-mediated inflammatory kab mob. Ua ke, qhov kev tshuaj xyuas no nthuav dav cov kev nkag siab ntawm kev sib cuam tshuam ntawm NF-κB thiab necroptosis downstream ntawm TNF receptor signaling nyob rau hauv cov kab mob autoimmune thiab muab cov lus qhia yav tom ntej ntawm kev kho lub hom phiaj necroptosis hauv kev hloov kho ntawm tib neeg cov kab mob.

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

Tam sim no paub txog TNF receptor signaling

TNF-TNFR1 induced NF-κB activation for survival Tumor necrosis factor (TNF) yog ib qho tseem ceeb heev pro-inflammatory cytokine uas yuav khi rau cognate receptor TNFR1 thiab TNFR2 los pib inflammatory signaling nrog rau ntau txoj kev tuag ntawm tes nrog rau apoptosis thiab necroptosis (Apostolaki et ib., 2010). Raws li TNF ligation, TNFR1 tau dhau los ua trimerization thiab sai sai ua ib qho kev sib txuas lus ntau lub npe hu ua TNFR1 signaling complex (TNFR1-SC) lossis complex I (Micheau and Tschopp, 2003). Ligated TNFR1 tuaj yeem nrhiav cov protein ntau ntxiv nrog rau receptor-interacting protein kinase-1 (RIPK1) thiab TRADD, uas tig mus rau TRAF2 thiab TRAF5. Tom qab ntawd E3 ubiquitin ligases, cIAP1 thiab cIAP2, tuaj yeem raug xaiv rau TNF-RSC, thiab tsim K63- txuas ubiquitin chains ntawm ntau yam tswj xws li RIPK1 thiab cIAP1 nws tus kheej. Qhov kev tshwm sim ubiquitination no tuaj yeem nrhiav cov linear ubiquitin chain assembly complex (LUBAC) los tsim cov kab ubiquitin chains (tseem hu ua Met1-linked) ntawm ntau yam ntawm complex I nrog rau RIPK1 thiab NEMO. Cov K63-linked thiab linear (Met1-linked) ubiquitin chains kho qhov kev nrhiav neeg ua haujlwm thiab ua kom TAK1-TAB1-TAB2 thiab IKK1-IKK{ {32}}IKK kinase complexes los ntawm ubiquitin khi. TAK1 phosphorylates thiab ua rau IKK complex, ua rau phosphorylation, tom qab ubiquitination, thiab proteasome-mediated degradation ntawm IκB, thiab ua kom NF-κB. Tsis tas li ntawd, TAK1 tseem tuaj yeem phosphorylate thiab qhib lub MAPK signaling, uas ua haujlwm nrog NF- κBmediated inflammatory teb los txhawb kev ciaj sia ntawm tes (Yuan li al., 2019) (Daim duab 3).

TNF-mediated death signaling: RIPK1-dependent apoptosis, necroptosis, thiab pyroptosis

Ntxiv nrog rau cov noob caj noob ces muaj sia nyob, kev ua kom TNFR1 kuj tseem tuaj yeem ua rau cov cell tuag los ntawm apoptosis, necroptosis, thiab pyroptosis signaling. Zoo ib yam li lwm cov neeg tuag uas muaj cov receptors thiab adapter proteins xws li Fas thiab FADD, TNFR1 muaj ib qho kev tuag intracellular kev cuam tshuam nrog RIPK1 thiab TRADD raws li TNF stimulation, uas cuam tshuam nrog TNF-induced apoptosis lossis necroptosis (Yuan li al., 2019). Yog li, RIPK1 ua raws li ib qho tseem ceeb regulator ntawm TNF receptor signaling, tswj qhov sib npaug ntawm cell ciaj sia taus thiab cell tuag. RIPK1 muaj N-terminal kinase domain (KD), intermediate domain (ID), thiab C-terminal Death Domain (DD). kinase domain yog qhov tseem ceeb rau RIPK1 autophosphorylation ntawm S166 thiab kinase activation-dependent apoptosis thiab necroptosis induction los ntawm TNF. Qhov nruab nrab ntawm RIPK1 yog qhov tseem ceeb rau kev muaj sia nyob NF-κB thiab MAPK teeb liab los ntawm ntau yam kev hloov kho ubiquitination. Lub chaw nruab nrab kuj tseem muaj cov receptor-interacting protein homotypic interaction motif (RHIM) uas kho cov kev sib cuam tshuam nrog lwm cov RHIM-muaj proteins, xws li RIPK3 rau necroptosis induction. Txoj kev tuag ntawm RIPK1 yog koom nrog kev khi rau lwm tus neeg tuag hauv tsev neeg hloov pauv cov proteins xws li TNFR1, TRADD, thiab FADD rau nws txoj kev nrhiav neeg ua haujlwm rau TNF-RSC los txhawb kev ciaj sia lossis cell tuag complexes kom ua rau apoptosis (Yuan li al., 2019).

Hauv qhov xwm txheej ib txwm muaj nrog TNF stimulation ib leeg, lub xov tooj ntawm tes tuag taw qhia tau raug tshem tawm vim NF-κB thiab MAPK-kev qhia tawm ntawm cov tshuaj tiv thaiv apoptotic xws li cIAP1 thiab c-FLIP. Raws li c-FLIP muaj cov qauv zoo sib xws rau Caspase-8 tab sis tsis muaj kev ua haujlwm enzymatic, c-FLIP tuaj yeem heterodimerize nrog Caspase-8 thiab inhibit tag nrho ua kom Caspase-8. Thaum NF-κB activation yog inhibited los ntawm protein synthesis inhibitor cycloheximide (CHX), anti-apoptotic c-FLIP qhia tau thaiv thiab Caspase -8 tuaj yeem tsim homodimers nquag thiab cell tuag complex II nrog TRADD thiab FADD kom ua rau apoptosis. . Txawm li cas los xij, RIPK1 kinase kev ua haujlwm yog dispensable rau cov txheej txheem no vim RIPK1 kinase inhibition tsis cuam tshuam rau apoptosis induction (Wang li al., 2008). Ntawm qhov tod tes, kev cuam tshuam ntawm TNF-RSC tsim los ntawm cIAP1/2, LUBAC, TAK1, MK2, TBK1, los yog NEMO / IKK deficiency, uas inhibits qhov ubiquitination thiab phosphorylation ntawm RIPK1, tuaj yeem txhawb kev ua haujlwm ntawm RIPK1 kinase thiab tsim los ntawm RIPK1-FADDCaspase-8 complex los ua rau RIPK1-dependent apoptosis (Delanghe et al., 2020; Peltzer et al., 2016). Txawm li cas los xij, thaum apoptosis raug thaiv los ntawm qhov tsis txaus lossis inhibition ntawm Caspase-8, cov hlwb tseem rhiab rau TNF-induced caspase-independent cell tuag. Hloov chaw ntawm apoptosis, qhov caspase-kev ywj pheej ntawm tes tuag hu ua necroptosis tuaj yeem ua rau cell membrane rupture thiab o. Thaum lub sij hawm necroptosis induction, RIPK1 yog pib-phosphorylated thiab qhib kom tsim tau ib tug necrosome nrog RIPK3, uas ntxiv txhawb oligomerization ntawm phosphorylated MLKL (Nws li al., 2009). Yog li, necroptosis yog nruj tswj hwm los ntawm caspase-dependent cleavage thiab kinase kev ua ntawm RIPK1 thiab RIPK3. Tsis tas li ntawd, kev tsim ntawm RIPK1/Caspsae-8/ FADD complex ua rau tsis muaj kab mob apoptosis-mediated cell tuag. Txawm li cas los xij, cov kev tshawb fawb tsis ntev los no tau pom tias kev ua kom RIPK1 thiab Caspase-8 los ntawm TNF nrog TAK1 lossis IKK inhibitors hauv macrophages tuaj yeem ua rau ob qho tib si apoptosis thiab pyroptosis, lwm hom lytic thiab pro-inflammatory cell tuag los ntawm Caspase-8- Kev sib haum xeeb cleavage ntawm GSDMD (Orning li al., 2018). Yog li, RIPK1 thiab Caspase-8 yog qhov chaw kuaj xyuas tseem ceeb hauv kev tswj hwm ntawm TNF-induced apoptosis, necroptosis, thiab pyroptosis (Daim duab 3).

Posttranslational modifications: checkpoints nyob rau hauv cell destiny txiav txim

Tam sim no, nws tseem tsis tau paub meej tias qhov kev hloov pauv uas txiav txim siab seb RIPK1 tau khaws cia hauv txoj haujlwm I txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhim kho apoptosis thiab necroptosis. Qhov kev piav qhia muaj peev xwm rau qhov no tuaj yeem yog qhov kev hloov pauv tom qab kev hloov pauv ntawm qhov chaw kuaj xyuas protein RIPK1, tshwj xeeb tshaj yog ubiquitination, phosphorylation, thiab cleavage (Yuan li al., 2019). Muaj ntau yam ubiquitinating thiab deubiquitinating enzymes koom nrog hauv kev tswj hwm ntawm cell tuag thiab pro-survival NF-κB signaling (Peltzer li al., 2016). Cov kev kawm dav ubiquitin E3 ligases uas tswj tau qhov zoo ntawm NF-κB kev ua kom muaj zog thiab cov kab mob qis qis yog cIAP1/2 thiab LUBAC complex (suav nrog HOIP, HOIL-1, thiab SHARPIN). Ntxiv mus, cov kev tshawb fawb tsis ntev los no tau pom tias lwm qhov tseem ceeb ntawm cov E3 ligases yog txhawm rau txhawm rau RIPK1 kinase kev ua thiab induction ntawm cell tuag. Deficiency ntawm cIAP1/cIAP2 los yog LUBAC complex impairs K63-txuas los yog Met1- txuas ubiquitination ntawm RIPK1 thiab txhawb RIPK1 kinase activation thiab kev hloov ntawm complex I mus rau complex II rau induced apoptosis thiab necroptosis (Peltzer li al. , 2018; Zhang et al., 2019b). Tsis tas li ntawd, kuj tseem muaj ntau yam deubiquitinating enzymes (DUB) ua haujlwm hauv TNF receptor signaling pathways thiab tsis zoo tswj cov xwm txheej ntawm ubiquitination hauv complex I los hloov kho NF-κB thiab cell tuag signaling, tseem ceeb tshaj yog A20, CYLD, SPATA2, thiab OTULIN (Lork et al., 2017). A20 yog upregulated nyob rau hauv teb rau TNF stimulation thiab yuav tsis zoo tswj NF-κB-dependent noob qhia los ntawm kev tshem tawm K63 ubiquitin ntawm ob peb substrates xws li RIPK1 thiab NEMO. A20 tseem muaj lub luag haujlwm tseem ceeb hauv kev tswj hwm RIPK1 kev ua haujlwm hauv cell tuag, vim A20 tsis txaus tuaj yeem ua rau Met1 ubiquitination ntawm RIPK1 hauv kev teb rau TNF thiab txhawb RIPK1 kinase-dependent apoptosis thiab necroptosis (Draper li al., 2015). Ntxiv mus, txoj kev tshawb fawb tsis ntev los no kuj tau qhia tias kev poob ntawm ABIN1, qhov tseem ceeb rau kev nrhiav neeg ua haujlwm ntawm A20, tuaj yeem cuam tshuam phosphorylation ntawm A20 thiab txhim kho K63 ubiquitination ntawm RIPK1 los txhawb RIPK1 kinase activation thiab cell tuag (Dziedzic li al., 2018). OTULIN yog ib qho tshwj xeeb protease rau hydrolyzes Met1 ubiquitin chains thiab xav kom txwv LUBAC-mediated NF-κB ua kom. Kev poob ntawm OTULIN kuj tseem tuaj yeem ua rau lub sijhawm pro-inflammatory cytokine ntau lawm thiab ua rau mob (Fiil li al., 2013). Txawm li cas los xij, ib txoj kev tshawb fawb tsis ntev los no pom tias catalytically inactive OTULIN xav tsis thoob txhim kho LUBAC auto-Met1 ubiquitination nrog me ntsis cuam tshuam rau NF-κB ua kom thiab zoo li LUBAC tsis txaus los txhawb RIPK1 kinase-dependent cell tuag thiab mob (Heger li al., 2018). Yog li, cov kev tshawb fawb no qhia txog lub luag haujlwm nyuaj thiab tseem ceeb ntawm K63 thiab Met1-txuas mus rau ubiquitination xwm txheej ntawm complex I hauv dictating qhov hloov ntawm kinase activation ntawm RIPK1 los txiav txim txoj hmoo ntawm tes. Txawm li cas los xij, cov txheej txheem hauv qab uas cov hlwb paub qhov txawv ntawm cov xwm txheej ubiquitination hauv txoj haujlwm kuv los txiav txim siab txog txoj hmoo ntawm tes hauv TNF receptor signaling tseem tsis meej. Cov qauv tam sim no tau tsim tau zoo tias ubiquitin binding proteins xws li TAB2/3 thiab NEMO yog cov sensors tseem ceeb rau kev hla lub teeb liab los ntawm ntau yam ubiquitination txheej xwm nyob rau hauv complex kuv txij li thaum K63 thiab Met1 ubiquitin chains muaj ib tug siab affinity rau TAB2 / TAB3 thiab NEMO khi rau tag nrho qhib TAK1-TAB2-TAB3 thiab IKK / IKK /NEMO complex thiab downstream NF-κB thiab MAPK signaling (Yuan et al., 2019). Tsis tas li ntawd, cov kev tshawb fawb tsis ntev los no tau nthuav tawm ntau yam kinases suav nrog TAK1, IKK / IKK, TBK1 thiab MK2 tuaj yeem ncaj qha lossis ncaj qha phosphorylate RIPK1, ntxiv inhibiting RIPK1 kinase kev ua thiab RIPK1-dependent apoptosis thiab necroptosis (Delanghe li al., 202). . Yog li, cov kev cai kinase-mediated tej zaum yuav pab downstream ntawm ntau yam kev hloov kho ubiquitination rau dictate lub teeb liab complexes kev hloov thiab kev txiav txim ntawm txoj hmoo ntawm tes. Cov kev cai ntawm TNFR1 complex I mus rau complex II kev hloov pauv tau raug kawm ntau, txawm li cas los xij, qhov nyuaj npaum li cas II thaum lub sij hawm apoptosis hloov mus rau necrosome los ntawm Caspase-8 inhibition-mediated necroptosis tseem tsis tau meej meej. Caspase-8, qhib thaum lub sij hawm apoptosis, tau ua kom pom tseeb kom tshem tawm ntau qhov chaw kuaj xyuas cov protein hauv NF-κB thiab cov teeb liab necroptosis xws li cFLIP, HOIP, RIPK1, RIPK3, thiab CYLD (Newton, 2020). Txij li thaum RIPK1 thiab RIPK3 yog qhov tseem ceeb rau kev tsim necrosome, Caspase-8-kev sib haum xeeb ntawm RIPK1 thiab RIPK3 tuaj yeem yog txoj cai tseem ceeb ntawm necroptosis. Caspase-8 cleaves RIPK1 ntawm D325 thiab cleavage-inactive D325A RIPK1 qhia thaum ntxov embryonic lethality thiab ua rau ob qho tib si enhanced apoptosis thiab necroptosis (Lalaoui et al., 2020; Newton et al., 2019a; 2019a., Tao. et al., 2019c). Cov kev tshawb fawb hauv vitro kuj qhia tau tias RIPK3 tuaj yeem raug tshem tawm ntawm D328 los ntawm Caspase{104}} txhawm rau tiv thaiv necroptosis (Feng li al., 2007). Raws li RIPK3 kuj muaj kev ua haujlwm hauv apoptosis thiab inflammasome, qhov ua haujlwm tau zoo ntawm D328-dependent cleavage ntawm RIPK3 tseem xav tau kev tshawb nrhiav ntxiv.

Daim duab 3 Txheej txheem cej luam ntawm gene activation thiab cell tuag nyob rau hauv TNF receptor signaling. A, Nyob rau hauv TNF stimulation, RIPK1 thiab lwm yam signaling molecules xws li TRADD, TRAF2/5, E3 ligase cIAP1/2 thiab linear ubiquitin chain assembly complex (LUBAC, muaj li ntawm HOIL-1, HOIP, thiab SHARPIN) yuav tau sai recruited los tsim TNFR1 signaling complex (TNF-RSC, kuj hu ua complex I). E3 ubiquitin ligases cIAP1/cIAP2 thiab linear ubiquitin chain assembly complex (LUBAC) tuaj yeem tsim K63-txuas lossis Met1- txuas ubiquitin chains ntawm ntau yam regulators xws li RIPK1 thiab NEMO. Cov K63-linked thiab linear Met1- txuas ubiquitin chains tuaj yeem kho qhov kev nrhiav neeg ua haujlwm thiab ua kom TAK1-TAB1-TAB2 thiab IKK1-IKK{{ 22}}IKK kinase complexes los ntawm ubiquitin binding, uas tom qab ntawd ua rau cov dej ntws los ntawm kev muaj sia nyob MAPK thiab NF-κB signaling. B, Thaum tsim TNF-RSC raug cuam tshuam (cIAP1/2, LUBAC, TAK1, MK2, TBK1, lossis NEMO/IKK deficiency) lossis NF-κB ua kom raug thaiv, RIPK1 thiab / lossis TRADD tuaj yeem hla ntawm TNF-RSC mus rau daim ntawv complex II nrog FADD thiab Caspase-8 nyob rau hauv cytoplasm, uas yog li ua rau apoptosis. Txawm li cas los xij, thaum apoptosis yog inhibited los ntawm inactivation ntawm Caspase-8, RIPK1 hauv cytosolic complex II kuj tseem tuaj yeem txhawb RIPK1-RIPK3-MLKL necrosome tsim nyob rau hauv txoj kev kinase-dependent kom ua rau necroptosis activation. . C, Thaum Yersinia kab mob, TLR thiab TNF signaling yuav ua rau kom NF-κB thiab transcription ntawm proinflammatory genes nyob rau hauv macrophages. Kev zais ntawm Yersinia effector protein YopJ ua rau inhibition ntawm TAK1 thiab IKK thiab ua rau kev ua kom RIPK1-dependent caspase-8 ua kom thiab apoptosis. Ib txhij, Caspase-8 kuj cleaves GSDMD ua rau tsim GSDMD pores thiab NLRP3 inflammasome activation, ntxiv inducing pyroptosis.

Gene mutations hauv TNF receptor signaling Cheebtsam ua rau cov kab mob autoinflammatory

Tib neeg cov kab mob caj ces tshwm sim los ntawm kev hloov pauv ntawm TNF receptor signaling Cheebtsam tau sau tseg hauv Table 3.

NF-κB-hais txog noob kev hloov pauv thiab kab mob pib-inflammatory: interplay nrog necroptosis Qhov tseem ceeb ntawm TNF -induced NF-κB signaling nyob rau hauv cov kab mob autoinflammatory tau dav tshawb xyuas ob qho tib si hauv tib neeg cov neeg mob thiab cov qauv nas. Kev hloov pauv ntawm TNF, TNFRSF1A (TNFR superfamily tus tswv cuab 1A), A20, thiab OTULIN uas ua rau muaj kev tso tawm TNF los txhim kho NF-κB kev ua kom muaj zog, tau cuam tshuam nrog cov kab mob sib txawv hauv tib neeg xws li mob hawb pob, steatohepatitis, thiab mob caj dab rheumatoid (Rezaza). , 2006; Valenti et al., 2002). Ntxiv mus, kev nce qib tsis ntev los no tau ntxiv dag zog rau peb txoj kev nkag siab txog kev tswj hwm ntawm NF-κB thiab cov txheej txheem proinflammatory necroptosis. Hauv seem no, peb yuav tham txog qhov cuam tshuam ntawm cov noob hloov pauv ntawm NF-κB-koom nrog cov noob suav nrog NEMO, LUBAC, OTULIN, thiab A20 ntawm necroptosis hauv cov kab mob autoinflammatory. (i) NEMO cov kab mob ntsig txog. Kev hloov pauv ntawm NEMO / IKBKG uas nyob ntawm X chromosome tau txuas nrog ntau yam X-txuas caj ces kab mob xws li X-txuas recessive ectodermal dysplasia thiab immunodeficiency (EDA-ID) thiab incontinentia pigmenti (IP). Cov neeg mob nrog EDA-ID pom qhov txawv txav ntawm cov ntaub so ntswg ectodermal nrog rau lub cev tsis muaj zog, tsis muaj tshuaj tiv thaiv kab mob, thiab NK cell dysfunction, uas yog feem ntau vim poob ntawm NEMO protein thiab cuam tshuam NF-κB ua kom (Mancini li al., 2008). Txawm li cas los xij, nyob ib ncig ntawm 20% ntawm cov neeg uas muaj EDAID muaj cov kab mob cuam tshuam nrog kev mob tshwm sim xws li IBD thiab SLE (Hanson li al., 2008). Ntxiv mus, incontinentia pigmenti (IP), thawj tus kab mob NEMO-tsis muaj tus kab mob, yog tus cwj pwm los ntawm cov tawv nqaij mob hnyav nrog rau cov pob khaus khaus thiab hyperproliferation ntawm keratinocytes nyob rau hauv lub epidermis (Smahi li al., 2000). Cov pom inflammatory phenotypes ntawm NEMO deficiency nyob rau hauv tib neeg cov neeg mob tsis zoo li vim inflammatory NF-κB ua kom.

Qhov tseem ceeb, ntau cov kev tshawb fawb genetic nas tau muab peb cov kev nkag siab tshiab rau hauv autoinflammatory syndromes ntawm NEMO deficiency. Cov nas tsis muaj NEMO ua rau embryonic lethality nyob rau hauv cov txiv neej thiab inflammatory ntawm daim tawv nqaij nyob rau hauv heterozygous poj niam (Makris li al., 2000). Deficiency ntawm NEMO nyob rau hauv daim tawv nqaij epithelium ua rau mob hnyav ntawm daim tawv nqaij thiab TNF-mediated apoptosis thiab necroptosis, uas tuaj yeem ncua los ntawm kev sib koom ua ke ntawm TNFR1 (Nenci li al., 2006). Tsis tas li ntawd, plab hnyuv epithelium-tshwj xeeb NEMO-tsis muaj nas pom tau tias Paneth hlwb tuag hnyav thiab tsim cov kab mob colitis, uas tiv thaiv thaum TNF ntau lawm. Qhov tseem ceeb, cov kab mob colitis tuaj yeem raug thaiv los ntawm kev tshuaj ntsuam genetic lossis pharmacological inhibition ntawm RIPK1 kinase, qhia txog lub luag haujlwm tseem ceeb ntawm RIPK1-mediated necroptosis hauv cov kab mob autoinflammatory los ntawm NEMO deficiency (Vlantis et al., 2016). Cov kev tshawb fawb tsis ntev los no tau qhia ntxiv tias NEMO mediated IKK complex tuaj yeem phosphorylate RIPK1 ntawm Ser25 thiab inhibit RIPK1 kinase kev ua thiab necroptosis los tswj kev mob thiab kab mob hauv nas (Dondelinger li al., 2019). Cov kev tshawb fawb no qhia tias kev hloov pauv NEMO hauv tib neeg cov neeg mob kuj tseem muaj feem cuam tshuam nrog RIPK1-dependent necroptosis signaling ua rau mob tsis zoo. (ii) A20 haploinsufficiency. A20, ib qho ubiquitin-editing enzyme encoded los ntawm TNF -induced protein 3 (TNFAIP3) gene, yog ib qho tseem ceeb los tiv thaiv regulator ntawm NF-κB ua kom koom nrog hauv ob qho tib si Hu-xws li receptor (TLR) thiab TNF receptor (TNFR) signaling. TNFAIP3 gene polymorphisms tau cuam tshuam nrog ntau yam kab mob autoimmune xws li SLE, RA, psoriasis, hom 1 mob ntshav qab zib, kab mob plawv, kab mob hauv plab, thiab mob hawb pob (Zhou et al., 2016a). Ntxiv rau qhov inhibitory nyhuv ntawm proinflammatory NF-κB ua kom, A20 muaj lub luag haujlwm tseem ceeb hauv kev txwv tsis pub RIPK1 kev ua hauv apoptosis thiab necroptosis signaling los ntawm kev hloov kho K63-, K48-, thiab Met1- txuas ubiquitination (Draper li al., 2015; Dziedzic li al., 2018). Cov kev tshawb fawb no qhia ntxiv txog lub luag haujlwm ntawm necroptosis-mediated o hauv pathogenesis vim A20 haploinsufficiency. Qhov tseem ceeb ntawm A20 nyob rau hauv cov kab mob auto-inflammatory tau tshwm sim ntxiv nyob rau hauv A20-cov nas uas tsis muaj zog nrog ntau hom phenotypes ntawm tes. Kev tshem tawm ntawm tes tshwj xeeb ntawm A20 hauv keratinocytes ua rau cov tsos mob autoinflammatory xws li polyarthritis thiab enteritis, uas zoo li tib neeg cov kab mob autoimmune (Lippens li al., 2011). Feem ntau cov kev tshawb fawb tau ascribed autoimmunity ntawm A20 haploinsufficiency kom poob ntawm inhibition ntawm NF-κB signals. Txawm li cas los xij, cov kev tshawb fawb caj ces hauv cov nas no muab pov thawj ncaj qha tias RIPK1 kinase-dependent necroptosis plays lub luag haujlwm tseem ceeb hauv cov kab mob xws li RIPK3 lossis RIPK1 inhibition tuaj yeem cawm cov kab mob hauv A20-cov nas tsis muaj zog (Onizawa li al., 2015 ). Tsis ntev los no, cov kws tshawb fawb pom muaj kev hloov pauv ntawm A20 ZnF7 ubiquitin-binding domain ua rau muaj kev mob caj dab mob tshwm sim los ntawm kev ua kom RIPK1-dependent necroptosis, tawm tswv yim tias ubiquitin-kev tswj kev ua haujlwm ntawm A20 yog qhov tseem ceeb rau kev txwv cov cell tuag thiab o (Polykratis et ib., 2019). Yog li, cov kev tshawb fawb ntxiv yuav tsum tau tshawb xyuas cov scaffold, deubiquitinating, thiab K48- ubiquitinating enzyme kev ua haujlwm ntawm A20 hauv necroptosis, mob, thiab lwm yam kab mob ntawm tib neeg. (iii) LUBAC deficiency (HOIP/HOIL/SHARPIN). Lub LUBAC complex, tsim los ntawm HOIP, HOIL-1, thiab SHARPIN, tsuas yog E3 ligase complex uas tuaj yeem tsim tau Met1- txuas ubiquitination ntawm ntau lub substrates los tswj kev tiv thaiv kab mob (Peltzer li al., 2016) . Cov neeg mob uas muaj qhov tsis xws luag hauv LUBAC cov khoom tsim cov kab mob tiv thaiv kab mob thiab cov kab mob autoimmune uas tshwm sim los ntawm cov kab mob rov tshwm sim, cov leeg nqaij amylopectinosis, thiab kub taub hau. Loss-of-function mutations ntawm HOIP thiab HOIL-1 ua rau lub cev tsis muaj protein ntau thiab ua kom tsis muaj zog ntawm lwm cov khoom siv LUBAC, uas txuas ntxiv ua rau qis qis NF-κB ua kom muaj zog thiab tiv thaiv kab mob (Boisson li al., 2015; Boisson li al., 2012). Txawm li cas los xij, LUBAC kuj tseem tuaj yeem tsim Met-1 ubiquitin chains ntawm RIPK1 thiab suppress RIPK1 kinase-mediated cell tuag (Peltzer li al., 2018), uas tuaj yeem suav rau autoinflammatory phenotypes hauv cov neeg mob uas muaj cov kev hloov pauv no. Lub luag haujlwm tseem ceeb ntawm LUBAC hauv cov kab mob autoimmune yog kawm tau zoo los ntawm kev siv cov qauv ntawm cov nas tsis muaj caj ces. Cov nas uas tsis muaj HOIP- thiab HOIL-1 ua rau cov kab mob tuag ntxov ntxov thiab ua rau muaj TNFR cuam tshuam nrog cell tuag thiab mob. Txawm li cas los xij, qhov tsis txaus ntawm TNFR1 lossis TNF tsis tuaj yeem cawm tau tag nrho tab sis tsuas yog ncua sijhawm nws, thaum Caspase-8- thiab MLKL-ob qhov tsis txaus tuaj yeem tiv thaiv embryonic lethality (Peltzer li al., 2018; Peltzer li al., 2014). Cov txiaj ntsig no qhia txog lub luag haujlwm tseem ceeb ntawm LUBAC hauv kev tiv thaiv kev tuag ntawm tes thiab kev mob kom ua rau embryogenesis. Tsis tas li ntawd, SHARPIN-tsis muaj cov nas, tseem hu ua cov kab mob proliferative dermatitis nas (cpdm), raug kev txom nyem los ntawm qhov pib mob hnyav hauv daim tawv nqaij zoo li atopic dermatitis thiab psoriasis hauv tib neeg (Seymour et al., 2007). Cov tawv nqaij o ntawm cpdm nas tuaj yeem thaiv los ntawm qhov tsis txaus ntawm TNF lossis kev ua haujlwm ntawm RIPK1 kinase kev ua haujlwm (Berger li al., 2014), ntxiv qhia txog lub luag haujlwm tseem ceeb ntawm RIPK1 kinase kev ua haujlwm thiab necroptosis hauv cov kab mob pathogenesis los ntawm LUBAC deficiency. (iv) Otulipenia/OTULIN-related autoinflammatory syndrome. OTULIN (tseem hu ua gumby) yog tib lub npe hu ua deubiquitylating enzyme, tswj TNFR inflammatory signals ntawm hydrolyzation ntawm Met1- txuas Ubiquitin chains tsim los ntawm LUBAC complex hom phiaj, xws li NEMO, RIPK1, TNFR1 (Damgaard li al., 2016). ). Cov neeg mob uas tau txais kev hloov pauv ntawm kev ua haujlwm tsis zoo hauv OTULIN tsim cov kab mob autoinflammatory hnyav, hu ua OTULIPENIA lossis OTULIN-related autoinflammatory syndrome (ORAS). Cov tsos mob tshwm sim thaum ntxov ntawm OTULIN tsis muaj peev xwm suav nrog kev sib koom tes o, ua npaws ntev, raws plab, sterile neutrophilia, thiab lipodystrophy (Damgaard li al., 2016; Zhou et al., 2016b). Tsis zoo li cov neeg mob uas muaj lub cev tsis muaj zog LUBAC, cov neeg mob uas muaj OTULIN-tsis muaj kev hloov pauv tsis muaj qhov pom tseeb ntawm kev tiv thaiv kab mob vim muaj ntau tshaj NF-κB. Txawm li cas los xij, OTULIN-deficient lossis catalytically inactive C129A nas qhia thaum ntxov embryonic lethality vim mob RIPK1-dependent cell tuag thiab o, uas tuaj yeem ncua los ntawm TNF blockage, RIPK1 kinase inhibition, lossis RIPK3 deficiency (Damgaard li al., 2016; Heger et al., 2018). Qhov tseem ceeb, OTULIN deficiency lossis catalytic inactivation kuj ua rau txo qis LUBAC kev ua haujlwm uas tseem tswj hwm tus kheej-Met1 ubiquitination. Cov txiaj ntsig no qhia tau tias muaj kev cuam tshuam loj heev ntawm RIPK{114}}nyob ntawm lub cell tuag thaum lub sij hawm embryogenesis ntawm OTULIN-tsis muaj zog lossis catalytically inactive nas tuaj yeem yog vim poob ntawm LUBAC kev ua. Hauv cov ntsiab lus, kev tshawb nrhiav caj ces los ntawm tib neeg cov neeg mob thiab cov qauv nas qhia tau hais tias OTULIN tsis muaj peev xwm ua rau muaj kev nce ntxiv Met1 ubiquitination thiab txhawb nqa proinflammatory NF-κB thiab necroptosis ua kom ua rau muaj kab mob autoimmune.

Table 3 Summary of genetic mutations in TNF receptor signaling and autoinflammatory disease

Necroptosis cuam tshuam nrog autoinflamation

Cov kab mob TNF-induced proinflammatory cell tuag tshwj xeeb tshaj yog necroptosis tsis ntev los no tau pom tias ua lub luag haujlwm tseem ceeb hauv cov kab mob autoimmune xws li cov kab mob neurodegenerative, psoriasis, thiab kab mob plab hnyuv. TNF -induced necroptotic cell tuag tuaj yeem tso kev puas tsuaj rau cov qauv molecular (DAMPs), uas txhawb cov kab mob inflammatory teb. Yog li, hauv ntu no, peb yuav tham txog kev hloov pauv noob ntawm necroptosis signaling Cheebtsam hauv cov kab mob autoinflammatory. (i) RIPK1- kho mob inflammatory kab mob. Receptor-interacting protein kinase-1 (RIPK1) yog tus thawj tswj hwm ntawm TNF receptor signaling thiab kev txiav txim siab txoj hmoo ntawm tes. Raws li scaffold protein, RIPK1 tuaj yeem pab txhawb TNFR complex I tsim thiab txhawb nqa proinflammatory NF-κB ua kom muaj sia nyob. Tsis tas li ntawd, RIPK1 tseem muaj cov haujlwm protein kinase los txhawb txoj kev ua haujlwm II thiab necrosome tsim los ua rau apoptosis thiab necroptosis (Yuan li al., 2019). Cov neeg mob uas tau txais kev hloov pauv ntawm kev ua haujlwm tsis zoo hauv RIPK1 tsim cov kab mob tiv thaiv kab mob thiab cov kab mob autoimmune uas tshwm sim los ntawm cov kab mob hauv plab nrog qhov pib sib txawv thiab mob hnyav thiab polyarthritis (Cuchet-Lourenço li al., 2018; Li et al., 2019a). Tsis zoo li RIPK1-cov nas tsis muaj peev xwm, uas tuag sai tom qab yug me nyuam, cov neeg mob RIPK1- tsis muaj kev hloov pauv tuaj yeem muaj sia nyob ntev tom qab yug me nyuam, qhia tias RIPK1 tsis yog qhov tseem ceeb rau kev ciaj sia nyob hauv tib neeg (Dillon li al., 2014; Rickard et al., 2014). Kev poob ntawm RIPK1 nyob rau hauv daim tawv nqaij fibroblasts hauv tib neeg cov neeg mob impairs lub activation ntawm NF-κB txoj kev tab sis ua rau kom cov kev ua ntawm necroptosis mediated los ntawm RIPK3 thiab MLKL (Cuchet-Lourenço li al., 2018; Li et al., 2019a). Kev hloov pauv hloov pauv ntawm RIPK1 hauv TNFR1 cov teeb liab tau tshaj tawm kom nruj tswj hwm los ntawm kev hloov kho tom qab kev txhais lus, feem ntau tseem ceeb los ntawm phosphorylation, ubiquitination, thiab Caspase -8-kev sib haum xeeb cleavage (Yuan li al., 2019). Caspase-8 cleaves tib neeg thiab nas RIPK1 tom qab cov seem D324 thiab D325 feem, uas tuaj yeem ua rau RIPK1 tsis ua haujlwm thiab txo qis RIPK1-kho cov necroptosis. Qhov tseem ceeb, cov kev tshawb fawb tsis ntev los no tau qhia tias tib neeg cov neeg mob tau txais kev ua haujlwm D234N / Y hloov pauv tau tsim cov kab mob autosomal autoimmune uas tshwm sim los ntawm kev kub taub hau thiab lymphadenopathy. Cov nas uas muaj D325A knock-in mutation qhia thaum ntxov embryonic lethality thiab mob hnyav, uas yuav cawm tau los ntawm inactivating ob leeg necroptosis thiab apoptosis los ntawm ob deficiency ntawm RIPK3 thiab FADD, los yog MLKL thiab FADD (Lalaoui li al., 2020; Newton li al. , 2019a; Tao et al., 2020; Zhang et al., 2019c). Ntau cov kev tshawb fawb caj ces hauv cov nas tau qhia ntxiv qhov tseem ceeb ntawm RIPK1 hauv necroptosis signaling los tswj cov kab mob autoinflammatory. RIPK1 tsis muaj peev xwm lossis kev poob ntawm tes tshwj xeeb ntawm RIPK1 ua rau cov kab mob o thiab thaum muaj xwm txheej ceev hematopoiesis vim kev txhim kho necroptosis activation (O'Donnell li al., 2018; Rickard li al., 2014). Tsis tas li ntawd, ubiquitination ntawm RIPK1 tseem ua lub luag haujlwm tseem ceeb hauv kev tswj hwm nws txoj haujlwm scaffold thiab kinase hauv TNFR1 signaling. Peb thiab lwm pab pawg tsim K376R knock-in nas thiab qhia tias K63- txuas ubiquitination ntawm RIPK1 ntawm K376 yog qhov tseem ceeb rau kev txhawb nqa NF-κB ua kom thiab txwv RIPK1 kinase-dependent cell tuag thaum lub sij hawm embryogenesis thiab o (Tang li al. , 2019; Zhang et al., 2019d). Tsis tas li, peb nyuam qhuav pom K612 residue yog qhov chaw tseem ceeb rau LUBAC-mediated linear ubiquitination n ntawm RIPK1. Los ntawm kev tsim K612R khob-hauv nas, peb pom tias Met1 ubiquitination ntawm RIPK1 ntawm K612 yog qhov tseem ceeb rau kev tiv thaiv kev tuag ntawm tes kom txwv tsis pub muaj kab mob (Tu li al., 2021). Lub peev xwm ntawm RIPK1 los pab txhawb kev ua kom necrosome xav tau receptor-interacting protein homotypic kev sib cuam tshuam motif (RHIM) - kev sib haum xeeb ntawm RIPK1, RIPK3, thiab ZBP1. Los ntawm kev tsim cov nas uas muaj kev hloov pauv hauv RHIM motif ntawm RIPK1, ntau pab pawg pom RIPK1 RHIM mutant nas qhia postnatal lethality thiab mob hnyav vim kev txhim kho necroptosis activation (Lin et al., 2016; Newton et al., 2016). Ntxiv mus, cov kev tshawb fawb tsis ntev los no tau tshaj tawm phosphorylation ntawm RIPK1 ntawm Ser25/321/335 kho los ntawm TAK1, p38 / MK2, TBK1 / IKKε, thiab IKK / muab lub zog ntawm lub cev los tiv thaiv TNF-induced RIPK1 kinase-dependent cell tuag thaum lub sij hawm embryogenesis, kab mob thiab kab mob. neuroinflammation (Delanghe li al., 2020). Yog li, cov kev tshawb fawb ntawm cov kev hloov pauv ntawm kev hloov pauv tom qab kev hloov pauv ntawm RIPK1 tuaj yeem muab kev nkag siab ntxiv rau cov kab mob inflammatory uas cuam tshuam nrog tib neeg polymorphisms. (ii) Lwm cov kab mob inflammatory uas cuam tshuam nrog kev hloov ntawm necroptosis. Caspase {98}}, tau txais thaum lub sij hawm apoptostomes hauv Necrosomes suav nrog DIPPRESSOSTICE (Yuan li al., 2019). Cov neeg mob uas muaj cov noob caj noob ces poob ntawm kev ua haujlwm hloov pauv ntawm Caspase{104}} qhia ALPS-zoo li kab mob nrog lymphadenopathy thiab splenomegaly. Tsis tas li ntawd, cov neeg mob no kuj muaj kev tiv thaiv kab mob tsis zoo uas tshwm sim los ntawm kev kis tus kab mob sinopulmonary thiab herpes simplex virus, uas yog vim muaj kev cuam tshuam los ntawm antigen-induced activation ntawm T thiab B lymphocytes (Chun et al., 2002; Niemela et al., 2015). Txawm li cas los xij, tsis zoo li thaum ntxov embryonic lethality ntawm Caspase{109}} cov nas uas tsis muaj peev xwm, Caspase{110}} cov neeg mob poob ntawm kev ua haujlwm tuaj yeem muaj sia nyob tom qab yug tau ntev uas tej zaum yog vim qhov ua tsis tiav ntawm Caspase{113 }} hauv tib neeg (Kaiser et al., 2011; Varfolomeev et al., 1998). Tsis tas li ntawd, Caspase-8 kuj tau tsis ntev los no tau qhia kom tshem GSDMD thaum lub sijhawm ua kom apoptotic thiab ua rau pyroptosis ntxiv los txhawb tus tswv tsev tiv thaiv kab mob (Orning li al., 2018). Cov kev tshawb fawb tsis ntev los no kuj tseem qhia tau tias Caspase{118}} catalytically inactive C326A/S mutant nas qhia thaum ntxov embryonic lethality thiab mob hnyav vim txhim kho apoptosis, necroptosis, thiab pyroptosis (Fritsch li al., 2019; Newton li al., 2019b) , qhia txog lub luag haujlwm tseem ceeb ntawm Caspase-8 hauv kev hloov pauv ntawm cell tuag mediated autoinflamation. GWAS txoj kev tshawb nrhiav pom ob lub CASP8 variants, p.K148R thiab p.I298V raws li kev pheej hmoo alleles hauv Alzheimer's kab mob (Rehker li al., 2017). Txawm li cas los xij, yuav ua li cas K148R kev hloov pauv ntawm Caspase-8 cuam tshuam rau nws cov haujlwm thaum lub sijhawm apoptosis thiab necroptosis tseem xav tau kev tshawb nrhiav caj ces ntxiv. RIPK3 yog lwm qhov tseem ceeb kinase uas ua rau qis qis MLKL thiab necroptosis induction. RIPK3 cov nas uas tsis muaj peev xwm siv tau thiab tsis muaj qhov cim qhia ntawm autoinflamation, thiab tsis muaj ntawv ceeb toom ntawm tib neeg kev hloov pauv ntawm RIPK3 cuam tshuam nrog cov kab mob autoinflammatory. Txawm li cas los xij, ib txoj kev tshawb fawb tsim RIPK3 kinase-tuag D161N cov nas mutant pom tias cov nas no tau pom tias muaj apoptosis, o, thiab thaum ntxov embryonic lethality (Newton li al., 2014). Tsis tas li ntawd, MLKL, lwm qhov tseem ceeb ntawm necroptosis, tsis ntev los no tau pom tias muaj kev cuam tshuam nrog cov kab mob autoinflammatory hauv nas thiab tib neeg kev tshawb fawb. Ib tus nas hom nrog D139V kev hloov pauv hauv MLKL, nyob rau hauv ob-helix 'brace', tsim kom tuag o tom qab yug me nyuam yam ntxwv los ntawm necroptosis thiab inflammatory infiltration nyob rau hauv salivary qog thiab pericardium. Cov kev soj ntsuam no hauv tus qauv nas muab qhov kev pom tseem ceeb rau lub luag haujlwm autoinflammatory ntawm peb tus tib neeg MLKL polymorphisms nyob ib sab ntawm thaj tsam brace ntawm MLKL (Hildebrand li al., 2020).

Xaus cov lus thiab cov kev xav yav tom ntej

Peb qhov kev nkag siab ntawm TNFR signaling, suav nrog kev muaj sia nyob NF-κB thiab pro-death apoptosis thiab necroptosis teeb liab, tau txhim kho zoo heev nyob rau xyoo kaum xyoo dhau los. Kev saib xyuas kom zoo thiab ua tau zoo TNF receptor-mediated immune teb yog qhov tseem ceeb rau kev tiv thaiv kab mob hauv lub cev thiab tiv thaiv kev tiv thaiv kab mob los yog kab mob autoinflammatory. Txawm hais tias lub hom phiaj hyperactivation ntawm NF-κB los ntawm TNF lossis IKK blockade tau siv los kho qee tus tib neeg cov kab mob, nws tseem muaj qee qhov kev mob tshwm sim vim kev txhim kho ntxiv RIPK1- kho cytotoxicity. Ntau cov kev tshawb fawb caj ces hauv nas tau qhia txog lub luag haujlwm tseem ceeb ntawm kev tuag ntawm tes, tshwj xeeb tshaj yog necroptosis-mediated o nyob rau hauv cov kab mob ntawm cov kab mob autoinflammatory. Yog li, cov kev tshawb fawb ntxiv yog xav tau los tshawb nrhiav thiab txheeb xyuas lub luag haujlwm nyuaj ntawm NF-κB thiab lub xov tooj ntawm tes tuag taw qhia thaum muaj kab mob inflammatory pathogenesis tshwm sim los ntawm cov kev hloov caj ces. Qhov tseem ceeb, kev hloov pauv ntawm TNF cov cim qhia cov khoom xws li NEMO, thiab LUBAC thaiv NF-κB ua kom thiab ua rau muaj kev tiv thaiv kab mob, tab sis ntawm qhov tod tes nws kuj tuaj yeem ua rau TNF -mediated cell tuag thiab ua rau autoimmunity. Txawm li cas los xij, ob lub ntsej muag lub ntsej muag no qhia meej txog qhov nyuaj thiab kev zoo nkauj ntawm peb lub cev tiv thaiv kab mob, vim tias kev ua haujlwm ntawm cov noob hauv lub cev tiv thaiv kab mob muaj qhov tshwj xeeb ntawm tes. Innate lub cev tiv thaiv kab mob xws li macrophages thiab dendritic hlwb uas ib txwm ntsib cov kab mob muaj kev nkag siab ntau dua rau TNF-mediated cell tuag thiab nyiam autoimmunity. Txawm li cas los xij, cov kab mob hloov pauv xws li T hlwb muaj kev nkag siab ntau dua rau Fas-mediated cell tuag thaum lub sij hawm kev loj hlob thiab ua kom muaj zog. Yog li, gene deficiency nyob rau hauv cov hlwb no feem ntau thaiv antigen-induced NF-κB activation thiab ua rau immunodeficiency. Txij li thaum tsis muaj peev xwm ntawm cov noob no ua rau muaj kev tiv thaiv kab mob hnyav thiab cov lus teb hauv lub cev tiv thaiv kab mob uas ua rau muaj kev puas tsuaj loj rau tus tswv tsev, kev tiv thaiv kab mob ib txhij tuaj yeem muab kev tawm tswv yim tsis zoo rau dampen cov lus teb. Yog li, cov kev tshawb fawb ntxiv yuav tsum tau tshawb fawb txog kev ua haujlwm ntawm cov noob caj noob ces hauv ntau hom kev tiv thaiv kab mob hauv lub cev hauv kev tswj hwm ob qho tib si hauv lub cev thiab hloov lub cev tiv thaiv kab mob thaum lub sij hawm muaj kab mob pathogenesis.

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

Ib lo lus nug tseem ceeb uas tseem nyob hauv TNFR1 teeb liab yog yuav ua li cas cov hlwb txiav txim siab hloov ntawm NF-κB kev ua kom muaj feem cuam tshuam txog kev tsim kuv rau cell tuag-txog nyuaj II lossis necrosome tsim teb rau TNF stimulation. Cov kev tshawb fawb yav dhau los qhia tias RIPK1, uas koom nrog NF- κB ua kom muaj zog, apoptosis, thiab necroptosis teeb liab, zoo li yog qhov chaw kuaj xyuas tseem ceeb txij li ntau TNFR complex I Cheebtsam suav nrog A20, LUBAC, IKK, thiab TBK1 tag nrho tau pom tias inhibit RIPK1 kev ua haujlwm rau suppress cell tuag. Tsis tas li ntawd, cov kev tshawb fawb tsis ntev los no siv cov qauv ntawm tib neeg cov neeg mob tau qhia txog lub luag haujlwm tseem ceeb ntawm RIPK1 thiab nws cov cleavage hauv kev txwv cov necroptosis thiab cov kab mob autoinflammatory. Nws yuav muaj txiaj ntsig zoo los tshawb xyuas cov kev cai ntawm necroptosis thiab kev hloov pauv tom qab kev hloov pauv ntawm RIPK1 los ntawm kev siv cov noob caj noob ces khob tawm thiab khob nas los yog tshuaj xyuas cov qauv ntawm tib neeg cov neeg mob. Txij li thaum RIPK1 kinase kev ua haujlwm yog qhov tseem ceeb rau kev ua kom apoptosis thiab necroptosis, nws tsa ib lo lus nug tias yuav ua li cas cov kinase kev ua ntawm RIPK1 yog suppressed nyob rau hauv TNFR complex los ntawm post-translational modifications. Interestingly, kinase kev ua ntawm RIPK1 yuav tsum tau nws autophosphorylation nyob rau hauv N-terminal kinase domain tab sis lub inhibitory phosphorylation ntawm RIPK1 feem ntau nyob rau hauv lub intermediated domain thiab nyob ib ncig ntawm lub cleavage site ntawm RIPK1. Yog li, ntxiv kev tshawb fawb biochemical thiab cov qauv tsim nyog yuav tsum tau tshawb xyuas qhov muaj peev xwm crosstalk ntawm inhibitory phosphorylation thiab autophosphorylation lossis cleavage ntawm RIPK1. Tsis tas li ntawd, txoj kev loj hlob ntawm kev xaiv, muaj zog, thiab muaj kev nyab xeeb me me-molecule inhibitors tsom necroptosis xws li RIPK1, RIPK3, thiab MLKL yuav pab txhawb kev kho mob yav tom ntej rau cov kab mob autoinflammatory.

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