Innate Thiab Adaptive Immune Abnormalities Hauv qab Cov Kab Mob autoimmune: Cov Kev Sib Txuas Txuas (1)
Dec 28, 2023
Tsuas yog qee tus neeg mob tsawg heev uas tshwm sim los ntawm ib qho kev hloov pauv noob neej, feem ntau cov kab mob autoimmune tshwm sim los ntawm kev sib cuam tshuam ntawm ib puag ncig thiab caj ces. Nyob rau hauv ib lub ntsiab lus, lub etiology ntawm cov kab mob autoimmune ntau tsis paub txawm tias kev nce qib elucidating qee cov hlwb thiab cov molecules lub luag haujlwm rau cov kab mob cuam tshuam nrog kev mob thiab cov ntaub so ntswg puas. Nyob rau hauv xyoo tas los no, cov noob caj noob ces txoj hauv kev tau txhawb nqa peb txoj kev paub zoo txog cov noob caj noob ces ntawm kev tiv thaiv kab mob autoimmunity, muab peb lub qhov rais ntawm lub sijhawm los rov tshuaj xyuas cov noob caj ces autoimmunity thiab txoj hauv kev ua tau. Hauv kev tshuaj xyuas no, peb tsom los tham txog etiology thiab pathogenesis ntawm cov kab mob autoimmune los ntawm kev xav ntawm tib neeg caj ces. Ib qho kev piav qhia ntawm lub hauv paus caj ces ntawm autoimmunity yog ua raws li 3 tshooj piav qhia txog cov noob caj noob ces koom nrog hauv kev tiv thaiv kab mob hauv lub cev, kev tiv thaiv kab mob, thiab cov txheej txheem inflammatory cell tuag raws li. Nrog rau cov kev sim no, peb cia siab tias yuav nthuav dav qhov kev xav thiab ua rau muaj kev txaus siab rau cov molecules uas tsis tshua muaj txiaj ntsig thiab txoj hauv kev ua tus tseem ceeb ntawm autoimmunity dhau ntawm 'ib txwm xav phem'ntawm ib tug txwv subset ntawm validated kho lub hom phiaj.
cistanche cog-nce kev tiv thaiv kab mob
Cov kab mob autoimmune, etiology, pathogenesis, innate tiv thaiv kab mob, yoog raws kev tiv thaiv
Taw qhia
autoimmunity yog hais txog ntau yam ntawm kev sib koom ua ke uas ua rau nws tus kheej ua siab ntev ua rau muaj kev hloov pauv ntawm cov kab mob pathological thiab cov tsos mob tshwm sim los ntawm kev tiv thaiv kab mob tiv thaiv tus kheej lub hom phiaj. Ib qho ntawm cov teeb meem loj ntawm kev kho mob autoimmune yog qhov yuav luag tsis tuaj yeem ua lub luag haujlwm ntawm kev thim rov qab ntawm kev ua siab ntev. Thaum cov neeg mob taug kev mus rau hauv cov chaw kho mob rheumatology, lawv feem ntau yws txog cov pob qij txha o los yog thaum sawv ntxov tawv thaum ob peb tus neeg yuav hais txog qhov tshwm sim ntawm cov tshuaj tiv thaiv nuclear lossis qib siab ntawm rheumatoid yam tseem ceeb rau lawv cov kws kho mob mus ntsib. Yog li ntawd, rheumatologists ntsib cov teeb meem ntawm kev kho mob uas nws etiology stems los ntawm uncharacterized txheej xwm uas tej zaum yuav traced rov qab rau ib tug ncua sij hawm, tej zaum kaum xyoo dhau los. Cov tswv yim kho mob tam sim no rau cov kab mob autoimmune yog qhov zoo sib xws rau cov kev daws teeb meem los ntawm cov neeg tua hluav taws, piv txwv li, muab cov kev sim zoo tshaj plaws los tua hluav taws tsis hais qhov laj thawj uas ua rau cov hluav taws kub hnyiab.
Cov ntaub ntawv uas tuaj yeem tso lub teeb pom kev ntawm etiology ntawm autoimmunity yog ib feem muab los ntawm qhov tseeb tias qee tus neeg muaj kev cuam tshuam rau cov kab mob ntau dua li lwm tus neeg. Kev soj ntsuam ntawm cov caj ces predispositions siv cov noob caj noob ces txoj hauv kev xws li kev tshawb fawb genomewide koom haum (GWAS) tau muab cov ntaub ntawv nplua nuj txog etiology thiab pathogenesis ntawm autoimmunity. Txawm hais tias muaj ntau qhov kev cuam tshuam loci nyob rau hauv cov ntu tsis-coding ntawm cov genome uas tsis paub meej txog kev ua haujlwm, feem ntau ntawm cov lus piav qhia poob rau hauv cov cheeb tsam protein-coding uas encode cov khoom koom nrog ntau yam ntawm cov txheej txheem lom neeg. Thaum lub subset ntawm autoimmune susceptibility genes nthuav tawm lawv tus kheej nrog kev sib raug zoo rau kev tiv thaiv kab mob phenotypes muab lub luag haujlwm zoo hauv lub cev thiab / lossis hloov lub cev tiv thaiv kab mob, kev sib txuas ntawm lwm cov noob xws li cov kev ua haujlwm feem ntau cuam tshuam rau hauv cov txheej txheem kev loj hlob thiab cov haujlwm metabolic rau autoimmunity. yog cryptic ntau. Hauv qhov kev tshuaj xyuas dav dav no, peb tham txog qhov peb tau kawm los ntawm cov kev tshawb fawb tsis ntev los no txhawm rau txhawm rau txheeb xyuas cov caj ces hauv paus ntawm autoimmunity thiab qhov kev paub zoo li cas tuaj yeem qhia peb txog kev nkag siab zoo ntawm kev tiv thaiv kab mob autoimmunity. Ua ke nrog kev paub tob zuj zus ntawm kev txhawb nqa ib puag ncig, lub hom phiaj kawg yog los muab kev nkag siab txog kev txhim kho cov kev kho tshiab tawm tsam autoimmunity thiab txo cov tsos mob lossis txawm tias ua tiav cov xwm txheej tsis muaj kab mob rau cov neeg mob autoimmune.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Lub hauv paus caj ces ntawm cov kab mob autoimmune
Genetic epidemiology ntawm tus kab mob autoimmune
Autoimmune diseases are one of the most common diseases worldwide and have a significant public impact because of their high morbidity and mortality (Rioux and Abbas, 2005). The general prevalence of autoimmune diseases ranged from less than 5 per 100,000 (e.g., uveitis (Miserocchi et al., 2013), Wegener granulomatosis (Cotch et al., 1996)) to more than 500 per 100,000, such as rheumatoid arthritis (RA) (Almutairi et al., 2021) and ankylosing spondylitis (AS) (Dean et al., 2014). Although most autoimmune diseases can occur at any age, the peaks of onset differ by illness (Amador-Patarroyo et al., 2012). For instance, type 1 diabetes (T1D) (Maahs et al., 2010) primarily occurs in childhood and adolescence, but multiple sclerosis (MS) (Schwehr et al., 2019) and systemic lupus erythematosus (SLE) (Mina and Brunner, 2013) mostly appear during the mid-adult years, and RA (Symmons, 2002) mainly among older people. In addition, autoimmune diseases present gender disparities with a greater prevalence amongst women in a 2:1 ratio (Angum et al., 2020). Furthermore, the genetic epidemiology of autoimmune diseases becomes more complicated when variations in ethnicity, geographical regions, and susceptibility genes are considered (Wang et al., 2015). Coeliac disease is a typical example, which is less prevalent in Asia. This may be due to the genetic factor that carriers of the HLA-DQ2 antigens linked to celiac disease occur in 5%– 10% of Chinese and sub-Saharan Africans when compared to 5%–20% in Western Europe. In contrast, HLA-DQ8 occurs in 5%–10% of English, Tunisians, and Iranians, but less than 5% in Eastern Europeans, Americans, and Asians (Kang et al., 2013). Collectively, autoimmune diseases are common diseases with genetic heritability and exhibit gender and age disparities with ethnic and geographic differences (Cooper and Stroehla, 2003). The genetic heritability of autoimmune disease varies greatly (Ramos et al., 2015), for instance, from very high in AS (>90%) (Brown et al., 2016) rau cov kab mob plab hnyuv qis (IBD, 12%) thiab MS (15%) (Kuusisto li al., 2008), whereas RA thiab SLE muaj qhov nruab nrab ntawm cov noob caj noob ces. kwv yees li 60% (Guerra li al., 2012). Qhov kev piav qhia rau qhov sib txawv no feem ntau yog vim muaj cov cuab yeej cuab tam thiab kev sib cuam tshuam ntawm cov kab mob epigenetic thiab ib puag ncig (Baranzini thiab Oksenberg, 2017). Tsis tas li ntawd, txoj kev tsis ncaj ncees ntawm cov tsev neeg thiab cov pej xeem rau cov kab mob sib kis loj heev yuav tsum raug coj mus rau hauv tus account (Momozawa li al., 2018). Mounting pov thawj qhia txog kev nyiam rau tsev neeg sib sau ua ke ntawm kab mob autoimmune (Cárdenas-Roldán li al., 2013). Ntau tsev neeg cov kev tshawb fawb tau qhia tias thawj cov txheeb ze (FDRs) ntawm cov tib neeg uas muaj tus kab mob autoimmune (xws li, RA, MS, AS) tau nce kev pheej hmoo ntawm tsev neeg kom tau txais qee yam kab mob autoimmune tiv thaiv kev tiv thaiv (Cooper li al., 2009), uas yog ntau dua hauv cov menyuam ntxaib monozygotic (Bogdanos li al., 2012). Tsis tas li ntawd, cov kws tshawb fawb kuj tau pom tias tsis yog FDRs nkaus xwb tab sis kuj yog cov txij nkawm ntawm cov tib neeg uas muaj kab mob autoimmune muaj kev pheej hmoo siab (Emilsson li al., 2015).
Genetic yam ntawm cov kab mob autoimmune
GWAS kiv puag ncig tau nrawm rau kev txheeb xyuas cov kab mob autoimmune uas cuam tshuam nrog kev hloov pauv.
Kev kuaj xyuas cov kab mob sib txawv thiab qhov cuam tshuam rau qhov chaw yuav pab tau peb kom nkag siab zoo txog daim ntawv qhia ntawm genotype thiab phenotype ntawm cov yam ntxwv nyuaj hauv cov kab mob (Hirschhorn li al., 2002). Txawm li cas los xij, cov txheej txheem kev sib txuas ib txwm tsis txaus rau daim ntawv qhia genomic loci kom raug vim muaj qhov sib txawv loj thiab qhov sib txuas ntawm qhov tsis sib xws (LD) ntawm feem ntau ntawm cov kab mob autoimmune (Fernando li al., 2008). GWAS kiv puag ncig nyob rau hauv thaum ntxov 2000s, uas yog ib tug haib cuab tam rau unbiasedly txheeb xyuas cov cheeb tsam ntawm lub genome ntsig txog tib neeg variation thiab kab mob, qhib txoj kev tshiab rau kev tshawb fawb thoob ntiaj teb rau hauv cov qauv qub txeeg qub teg ntawm cov kab mob autoimmune (Visscher li al., 2012). Kev sib koom ua ke ntawm Genome-wide Association txoj kev tshawb fawb tau koom tes los ntawm Wellcome Trust Case Control Consortium (WTCCC) hauv 2007 yog thawj kauj ruam tiag tiag rau pem hauv ntej hauv kev tshawb nrhiav cov caj ces tshiab ntawm cov kab mob autoimmune susceptibility los ntawm GWAS (Wellcome Trust Case Control Consortium, 2007). Qhov tseem ceeb, qhov kev tshawb fawb WTC no tau nthuav tawm ntau cov noob caj noob ces uas txuas nrog RA, T1D, thiab kab mob celiac (ib hom IBD). Thawj zaug, cov kws tshawb fawb tau tshawb pom cov noob hu ua PTPN2 uas txuas cov kab mob autoimmune no. Nyob rau tib lub xyoo, WTC tau tshaj tawm lwm qhov kev tshawb nrhiav caj ces loj hauv AS thiab MS, tshaj tawm ob qhov tshiab AS loci: ARTS1 thiab IL23R, thiab tseem ceeb tias IL23R tuaj yeem yog qhov sib koom ua rau muaj kev cuam tshuam loj rau cov kab mob loj 'seronegative' xws li AS thiab Crohn's kab mob. (CD) thiab psoriasis (Wellcome Trust Case Control Consortium thiab Australo-Anglo-American Spondylitis Consortium (TASC), 2007).
Kev loj hlob ntawm kev sib koom tes thoob ntiaj teb thoob plaws ntau haiv neeg pawg nthuav dav cov qauv loj ntawm GWAS kev tshawb fawb, ua rau muaj txiaj ntsig ntau qhov kev tshawb pom kab mob autoimmune. Raws li ib qho piv txwv, International Genetics of Ankylosing Spondylitis Consortium (IGAS) consortium tau ua qhov kev tshawb fawb SNP genotyping ntom ntom hauv 10,619 tus neeg mob thiab 15,145 kev tswj hwm ntawm European, East Asian, thiab Latin American caj ces hauv 2013, uas tau nce tus naj npawb ntawm AS-koom nrog loci. 31 (suav nrog 13 loci tshiab) thiab 12 ntxiv AS-koom nrog haplotypes ntawm 11 loci, qhia lub luag haujlwm tseem ceeb ntawm kev ua haujlwm peptide ua ntej loj histocompatibility complex (MHC) chav kawm I kev nthuav qhia thiab kev hloov pauv ntawm IL-23 proinflammatory cytokine txoj hauv kev lub pathogenesis ntawm AS (International Genetics ntawm Ankylosing Spondylitis Consortium li al., 2013). Tsis tas li ntawd, ib qho kev tshuaj ntsuam meta ntawm GWAS tau dhau los ua qhov tseem ceeb, uas tuaj yeem txhim kho lub peev xwm los txheeb xyuas cov cim kev sib koom tes los ntawm kev sib txuas cov qauv los ntawm ntau pawg neeg los txheeb xyuas ntau qhov sib txawv thiab npog ntau thaj chaw genomic dua li ib cov ntaub ntawv (Zeggini thiab Ioannidis, 2009). Hauv xyoo 2014, Peb-theem trans-ethnic meta-analysis (Okada li al., 2014) tau ua rau 100,000 cov ntsiab lus ntawm European thiab Asian poj koob yawm txwv (29,880 RA mob thiab 73,758 tswj) pom 42 tshiab RA kev pheej hmoo loci thiab txheeb xyuas 98 tus neeg sib tw cov noob caj noob ces hauv tag nrho ntawm 101 qhov pheej hmoo loci. Tshwj xeeb, lawv tau tsim ib qho hauv silico pipeline tsim los ntawm cov txheej txheem bioinformatics zoo thiab raws li cov lus qhia ua haujlwm los txheeb xyuas 98 tus neeg sib tw cov noob caj noob ces ntawm 101 qhov kev pheej hmoo loci, thiab thawj zaug ua cov lus piav qhia ua haujlwm ntawm RA pheej hmoo SNPs uas lub hom phiaj los muab cov pov thawj empirical rau kev tshawb nrhiav tshuaj. . Tsis tas li ntawd, kev siv tus kab mob hla tus kab mob meta GWAS tuaj yeem txhim kho lub zog txhawm rau txheeb xyuas cov kab mob kis tau yooj yim hla ntau yam kab mob autoimmune, txawm tias lub koom haum cov cim sib txawv ntawm cov kab mob. Thaum ntxov li 2011, Zhernakova li al. (Zhernakova li al., 2011) nrhiav tau kaum plaub uas tsis yog-HLA hom loci txuam nrog cov txheej txheem ntawm kev nthuav qhia antigen thiab T-cell activation nyob rau hauv ib tug meta-kev soj ntsuam ntawm ob luam tawm GWAS ntawm kab mob celiac thiab RA ntawm European poj koob yawm txwv cohorts. Ib yam li ntawd, kev txheeb xyuas tus kab mob hla GWAS rau tsib cov ntaub ntawv luam tawm ntawm psoriasis thiab Crohn tus kab mob ua los ntawm Ellinghaus li al. (Ellinghaus et al., 2012) tau txheeb xyuas 20 qhov sib koom kab mob sib koom ua ke thiab kuaj cov kab mob sib kis hauv cov koom haum ntxiv hauv 2012. Tom qab ntawd thaum ntxov 2019, thawj tus kab mob sib kis thoob plaws genome-wide meta-analysis hauv cov kab mob seropositive rheumatic (suav nrog cov kab mob hauv lub cev. sclerosis, SLE, RA, thiab idiopathic inflammatory myopathies) (Acosta-Herrera li al., 2019) tau luam tawm, uas nthuav tawm tsib qhov kev sib koom genome-dav qhov tseem ceeb ntawm kev ywj pheej los ntawm ib pawg ntawm 11,678 tus neeg mob thiab 19,704 yam tsis muaj kev cuam tshuam los ntawm European caj ces. pab pawg.
cistanche cov txiaj ntsig-ua kom muaj zog tiv thaiv kab mob
Post-GWAS era: kev ua haujlwm genomics ntawm kab mob autoimmune
Txawm li cas los xij, thaum GWAS tau ua tiav qhov kev tshawb pom ntawm ntau txhiab loci uas tau txheeb xyuas txog kab mob thiab kev pheej hmoo, ntau qhov kev sib tw thiab kev txwv tau tshwm sim. Nrog rau kev cuam tshuam txog kev noj qab haus huv rau cov kab mob thiab kev siv tshuaj kho mob rau kev kwv yees lossis kev kho mob qeeb qeeb, tsis tuaj yeem piav qhia txog feem ntau ntawm cov caj ces ntawm cov kab mob, nrog rau kev tshawb fawb txwv ntawm qib cell (Visscher li al., 2017). Lawm, lub sijhawm tom qab GWAS tau los txog, uas yog feem ntau sib cav rau qhov ua rau thiab kev pheej hmoo ntawm cov noob caj noob ces (Pierce li al., 2020), nrog rau kev txhawb nqa kev hloov pauv ntawm kev koom tes ua haujlwm (Gallagher thiab Chen-Plotkin, 2018).
Nyob rau lub sijhawm no, ntau qhov kev tshawb fawb zoo kawg nkaus nrog kev nce qib tshiab hu ua post-GWAS txoj kev tau tshaj tawm. Ib qho ntawm cov txheej txheem zoo tshaj plaws yog "kev ua haujlwm zoo", txhawm rau txheeb xyuas qhov muaj txiaj ntsig zoo ntawm cov noob caj noob ces hauv thaj chaw genomic uas twb tau txwv lawm, uas tau ua pov thawj muaj txiaj ntsig zoo hauv kev txhais GWAS kev tshawb pom rau hauv kev kho tau (Schaid li al., 2018). Ib txoj hauv kev tshiab hu ua CC-GWAS (case-case-genome-wide Association txoj kev tshawb fawb) (Peyrot thiab Nqe, 2021) tsis ntev los no tau txais traction. Peyrot WJ et al. siv cov ntaub ntawv sau tseg los ntawm cov xwm txheej-tswj GWAS los ntsuas qhov kev hloov pauv hauv allele zaus ntawm cov xwm txheej ntawm ob qhov kev tsis sib haum xeeb, uas dhau los ntawm cov txheej txheem uas xav tau cov ntaub ntawv ntawm tus kheej. Lawv tau txheeb xyuas qhov chaw zoo nrog ntau qhov sib txawv ntawm cov neeg mob ntawm yim tus kab mob puas siab puas ntsws ntawm CC-GWAS thiab tau lees paub CCGWAS txoj kev siv peb tus kab mob autoimmune GWAS cov ntaub ntawv, uas suav nrog CD, ulcerative colitis (UC), thiab RA. Ua kom pom lub peev xwm siv lub tswv yim no los txhim kho kev kuaj mob thiab kho lwm yam kab mob autoimmune. Tsis tas li ntawd, cov kev tshawb fawb pej xeem kuj tseem ua lub luag haujlwm tseem ceeb hauv kev ua pov thawj kev ua txhaum thiab txhawb kev txhim kho tshuaj (Wijmenga thiab Zhernakova, 2018). Tsis ntev los no, ib qho kev ntsuam xyuas loj loj thoob plaws cov neeg Esxias sab hnub tuaj thiab cov neeg nyob sab Europe ntawm RA ntawm ntau yam kev tshaj tawm GWAS ua los ntawm Eunji Ha li al. (Ha li al., 2021) kev sib koom ua ke ntawm kev paub txog RA sib txawv nrog cov ntaub ntawv muaj txiaj ntsig omics uas tau coj mus rau kev txheeb xyuas ntawm 11 tshiab RA susceptibility loci. Txog tam sim no, kev vam meej loj ntawm kev tshawb nrhiav caj ces dav dav hauv kev txheeb xyuas cov caj ces ntawm cov kab mob autoimmune. Cov lus nug ntawm yuav ua li cas thiaj li siv tau cov ntaub ntawv no tseem yog qhov nyuaj.
Cov kev sib koom genetic mechanisms ntawm cov kab mob autoimmune
Cov kev tshawb fawb txog kev kis kab mob yav dhau los tau pom tias tib neeg cov kab mob autoimmune yog cov kab mob nyuaj uas tshwm sim los ntawm kev cuam tshuam ntawm genic susceptibility thiab ib puag ncig (Wang li al., 2015). Txawm hais tias cov kab mob autoimmune yog cov xwm txheej sib txawv hauv kev kho mob thiab kho cov yam ntxwv nrog kev koom tes ntawm ntau lub cev hauv nruab nrog cev (Ramos li al., 2015), nws yog qhov kev pom zoo tias cov kab mob autoimmune sib koom ua ke thiab cov keeb kwm caj ces zoo sib xws. Lub caij no, kev tshawb nrhiav caj ces tseem txhawb nqa txoj hauv kev ntawm cov kab mob sib txawv rau ntau yam kab mob autoimmune (Richard-Miceli thiab Criswell, 2012). Ib xyoo caum dhau los, cov kws tshawb fawb twb pom yuav luag ib nrab ntawm 107 lub cev tiv thaiv kab mob-kev pheej hmoo SNPs thoob plaws xya lub cev tiv thaiv kab mob thiab kab mob autoimmune (xws li CD, MS, psoriasis, RA, SLE, thiab T1D) tau sib koom, uas yog qhov xwm txheej nrog. alleles nyob rau hauv lub loj histocompatibility locus (Cotsapas li al., 2011).
Tsis ntev los no, Caliskan M. et al. (Caliskan li al., 2021) tau tsim ib phau ntawv teev npe ntawm 85 qhov kev tshawb fawb zoo ntawm autoimmune GWAS locus los ntawm kev sib txuas cov ntawv mining nrog kev tshuaj xyuas zoo. Lawv muab tso ua ke 230 GWAS loci uas muaj 455 kev sib txuas ntawm cov kab mob sib kis nrog 15 kab mob autoimmune. Txhawm rau kho cov noob sib koom los ntawm cov kab mob autoimmune tseem ceeb hauv txoj kev tshawb no, peb xaiv tsib yam kab mob autoimmune loj (CD, RA, T1D, IBD, MS) los tso saib cov noob sib tshooj hauv cov kab mob no nrog cov ntaub ntawv ntawm cov kab mob koom nrog loci (Daim duab 1A) . Lub 74 GWAS loci hla ntau tshaj ob hom kab mob autoimmune los ntawm cov ntawv teev npe no tau pom los ntawm kev siv daim duab chord raws li cov qhab nia ntawm cov noob cog qoob loo ntawm cov GWAS loci thiab lawv cov kab mob autoimmune cuam tshuam (Daim duab 1B). Qhov tseem ceeb, peb tuaj yeem pom tias IL2 thiab TAGAP yog ob qho tib si pom muaj nyob rau hauv plaub kab mob autoimmune (IL2 hauv CD, IBD, RA, thiab T1D, thiab TAGAP hauv IBD, MS, RA, thiab T1D, feem), uas zoo ib yam nrog cov nas ua ntej. Cov kev tshawb fawb thiab kev sim tshuaj ntsuam xyuas (Chen li al., 2020; Clough li al., 2020; Pérol li al., 2016). Qhov kev pom tau los ntawm cov kev tshuaj ntsuam no qhia txog qhov tseem ceeb ntawm kev tswj hwm T hlwb hauv kev tiv thaiv kab mob homeostasis thiab yuav pab txhawb kev txhim kho kev tswj hwm T-cell rau cov kab mob autoimmune.
cistanche cov txiaj ntsig rau txiv neej-ua kom muaj zog tiv thaiv kab mob
Nyem qhov no mus saib Cistanche Enhance Immunity khoom
【Nug ntxiv】 Email: cindy.xue@wecistanche.com / Whats App: 0086 18599088692 / Wechat: 18599088692
Ntau qhov kev hloov pauv tau pom nyob rau hauv cov kab mob autoimmune thiab lwm yam kab mob ntawm tib neeg, thiaj li hu ua "pleiotropy" (Inshaw li al., 2018). Nws tau tsim dav dav tias kev tiv thaiv kab mob tsis ua haujlwm tau txuas nrog kev pheej hmoo ntawm Parkinson's disease (PD) (Tan li al., 2020). Piv txwv li, hauv kev tshawb fawb txog kab mob sib kis ntawm 310, 000 cov neeg hauv Sweden nrog 33 yam kab mob autoimmune sib txawv, qhov feem ntau ntawm kev pheej hmoo ntawm Parkinson tus kab mob yog siab li 33% (Li et al., 2012). Hauv qhov sib piv, kev tshawb pom los ntawm GWAS loj uas suav nrog 47,580 qhov xwm txheej ntawm RA thiab 482,703 tus neeg mob PD qhia tias Rheumatoid mob caj dab txo qis kev pheej hmoo ntawm Parkinson tus kab mob (Li li al., 2021a). Kev sib koom ua ke ntawm cov kab mob autoimmune thiab Parkinson tus kab mob zoo li ua tsis tiav, uas tuaj yeem cuam tshuam nrog kev txwv loj. Txawm li cas los xij, txoj kev tshawb fawb ntawm pleiotropy ntawm cov kab mob autoimmune thiab lwm yam comorbidities tuaj yeem pab nrhiav pom cov loci tshiab uas tsis tau cuam tshuam nrog tus kab mob yav dhau los. Witoelar et al. tau tshaj tawm tias 17 qhov tshiab loci raug txheeb xyuas raws li qhov sib tshooj ntawm PD thiab cov kab mob autoimmune nrog rau 4 paub PD loci (GAK, HLA-DRB5, LRRK2, thiab MAPT) uas tau nthuav tawm hauv RA, UC, thiab CD, thiab qhia txog kev koom tes ntawm Tib neeg leukocyte. Antigen (HLA) (Witoelar et al., 2017).
Gene-environment kev cuam tshuam cuam tshuam rau tus kab mob autoimmune
Nws yog kev pom zoo tias ib puag ncig yam xwm txheej thiab kev lees paub kev tsis ncaj ncees tuaj yeem ua lub luag haujlwm hauv kev pheej hmoo kab mob ntxiv rau cov yam ntxwv ntawm caj ces. Nrog rau kev txhim kho kev lag luam kev vam meej thiab kev tshawb fawb thiab thev naus laus zis, suav nrog kev lag luam tshiab, tshuaj tshiab, thiab tshuaj. Feem ntau ntawm cov kab mob autoimmune los ntawm ib puag ncig yam tau nce. Kev txhim kho kev nkag siab ntawm "kev cuam tshuam ib puag ncig" rau cov kab mob autoimmune tuaj yeem pab tib neeg kom tsis txhob muaj kev phom sij thiab txiav txim siab txog kev kho mob (Gioia li al., 2020; Vojdani, 2014). Nyob rau hauv xyoo tas los no, kev tshawb fawb ntau ntxiv tau pom tias kev haus luam yeeb (Ishikawa thiab Terao, 2020), nqaij liab (Pattison li al., 2004), thiab kev noj zaub mov siab (Salgado et al., 2015) muaj qhov tsis zoo rau kab mob kev loj hlob, whereas ib tug neeg tsis noj nqaij noj (Kjeldsen-Kragh li al., 1991), polyunsaturated fatty acids (Fetterman Jr. thiab Zdanowicz, 2009), vitamin D (Jeffery li al., 2016), thiab probiotics (Bungau li al., 2021) pab txhawb kev ntsuas kev noj qab haus huv. Yog li ntawd, cov qauv kev noj haus thiab cov tshuaj ntxiv tau txhawb kom muaj kev kho mob ntxiv rau yav tom ntej hauv kev kho mob autoimmune, xws li Mediterranean Diet (MD), uas feem ntau muaj zaub, txiv hmab txiv ntoo, ntses, txiv roj roj, thiab cov khoom siv mis nyuj (Pocovi-Gerardino li al. Ib., 2021).
Daim duab 1 Overlapping genes (GWAS loci) kev koom tes ntawm cov kab mob autoimmune tseem ceeb. A, Cov duab UpSet tsim los ntawm UpSetR (Conway li al., 2017) qhia cov naj npawb ntawm GWAS loci uas sib tshooj rau txhua tsib kab mob autoimmune (CD, Crohn's disease; RA, rheumatoid mob caj dab; T1D, thiab hom 1 mob ntshav qab zib; IBD, inflammatory plob tsis so tswj kab mob; MS, ntau yam sclerosis), uas yog raws li cov ntaub ntawv qhia txog kab mob autoimmune GWAS zoo-mapping kev tshawb fawb. B, Daim duab chord tsim nrog R pob "lub voj voog" (Gu li al., 2014), nthuav qhia kev sib raug zoo ntawm 74 GWAS loci (sab laug) uas sib tshooj hauv ntau tshaj ob yam kab mob autoimmune loj thiab cov kab mob uas lawv cuam tshuam ( txoj cai).
Modulation ntawm plab microbiota-derived metabolites yog ib qho tseem ceeb tshaj plaws hauv kev tsis ncaj ncees ntawm kev noj zaub mov zoo li cas thiab kev noj zaub mov muaj feem cuam tshuam rau kev kis kab mob (Han li al., 2021). Hloov kho microbiota muaj pes tsawg leeg tau txuas rau txo cov plab hnyuv ua haujlwm thiab cov kab mob hauv lub cev tsis zoo (Khan thiab Wang, 2019), ib qho ntawm cov kev xav paub zoo tshaj plaws yog "lub plab-pob txha" (Zaiss li al., 2021). Txawm li cas los xij, nws tsis paub meej yog tias plab dysbiosis yog qhov ua rau lossis cuam tshuam ntawm tus kab mob autoimmune. Ib qho txiaj ntsig los ntawm cov pej xeem pej xeem ntawm txhua tus me nyuam mos nyob rau sab hnub tuaj Sweden qhov project qhia tias kev pheej hmoo ntawm caj ces rau T1D autoimmunity yog cuam tshuam nrog kev hloov pauv tshwj xeeb hauv plab microbiota (Russell li al., 2019). Cov ntaub ntawv pov thawj los ntawm kev tshawb fawb tsiaj thiab tib neeg tau qhia tias HLA alleles cuam tshuam cov txheej txheem ntawm lub plab microbiota cuam tshuam nrog kev tiv thaiv tus tswv tsev (Xu thiab Yin, 2019). Tsis tas li ntawd, ib qho kev tshawb fawb tshiab uas siv phom metagenomics ntawm AS cov neeg mob qhia tias muaj kev txhawb nqa ntawm cov kab mob sib kis uas muaj feem cuam tshuam rau cov kab mob epitopes, thiab TNFi kev kho mob muaj kev cuam tshuam rau microbiome muaj pes tsawg leeg (Yin li al., 2020).
Kev tshawb nrhiav noob caj noob ces thiab kev xav ntawm tus kab mob autoimmune
GWAS tau ua tiav zoo rau kev txheeb xyuas ntau yam ntawm cov noob caj noob ces (tsuas yog SNPs) ntawm tus kab mob thiab kev koom tes nrog ntau yam sib txawv. Txawm li cas los xij, nws muaj peev xwm kwv yees tsawg hauv cov kab mob. Tus qhab nia polygenic txaus ntshai (PRS) profileing txoj kev, uas tuaj yeem sib sau ua ke cov teebmeem ntawm kev sib txawv ntawm cov genome, tuaj yeem siv rau hauv kev kwv yees ntawm ib tus neeg txoj kev lav phib xaub rau tus cwj pwm lossis kab mob los ntawm kev suav raws li kab mob genotype profile thiab cov ntaub ntawv GWAS cuam tshuam. . Li Z. et al. (Li et al., 2021b) tau hais txog qhov tseem ceeb ntawm kev kuaj mob ntawm PRS hauv AS cov neeg mob piv rau cov kev kuaj mob ib txwm muaj xws li C-reactive protein (CRP), HLA-B27, thiab sacroiliac MRI. Rau qhov tseeb daim ntawv thov kev kho mob, kev tshawb fawb ntxiv ntawm PRS siv rau cov kab mob autoimmune nyob rau hauv ib pawg neeg tshwj xeeb yog xav tau. Xyoo 2020, Choi et al. (Choi et al., 2020) tau tshaj tawm cov lus qhia txog kev ua cov qhab nia ntawm kev pheej hmoo polygenic hauv cov txheej txheem xwm txheej suav nrog raws li lawv cov genotype profile thiab cov ntaub ntawv GWAS cuam tshuam, uas tuaj yeem pab txhais cov koom haum PRS-zoo.
Lwm qhov kev sib tw ntawm GWAS yog tias nws nyuaj rau kev lees paub cov noob caj noob ces lossis kab mob kev tswj hwm thaj chaw uas cuam tshuam rau cov cwj pwm tshwj xeeb ntawm tes. Ib leeg-cell RNA sequencing (scRNA-Seq) yog ib txoj hauv kev muaj zog rau kev sau cov noob qhia hauv ib lub hlwb los ntawm cov ntaub so ntswg uas siv cov kev sib txuas siab los ntawm kev txheeb xyuas thoob plaws tag nrho cov ntawv sau tseg. Nws twb tau pom cov txiaj ntsig tau zoo hauv MS, AS, thiab RA. Piv txwv li, kev tshawb fawb tsis ntev los no los ntawm Simone D. et al. (Simone li al., 2021) siv ib leeg-cell transcriptome tsom xam los ntawm kev siv cov ntshav peripheral thiab cov kua synovial los ntawm cov neeg mob AS thiab psoriatic mob caj dab (PsA), nrog rau cov txiaj ntsig qhia cov ncauj lus ntxaws ntxaws ntawm Tregs hlwb thiab qhia LAG-3 ncaj qha inhibits IL-12/23 thiab TNF secretion los ntawm tus neeg mob tau txais cov monocytes, uas tuaj yeem yog lub peev xwm rau SpA. Feem ntau ntawm cov kev kho mob autoimmune tam sim no cia siab rau kev tiv thaiv kab mob, uas ua rau cov neeg mob muaj kab mob. Cov tshuaj Precision raug suav hais tias yog lub hauv paus ntawm kev kho mob qog noj ntshav yav tom ntej (Shin li al., 2017), nrog rau kev txhim kho cov kev kuaj mob tshiab thiab cov tshuaj kho kom haum rau tus neeg mob cov kev xav tau raws li caj ces, biomarker, phenotypic, lossis cov yam ntxwv ntawm lub hlwb. Hauv nruab nrab -2016, Ellebrecht CT et al. (Ellebrecht et al., 2016) tau qhia tias chimeric antigen receptor T cells (CAR-T cells) tuaj yeem hloov kho los nrhiav thiab tua tus kheej-reactive B hlwb, uas tuaj yeem muab cov phiaj xwm tshwj xeeb ntawm autoreactive B hlwb hauv cov kab mob antibody-mediated autoimmune. thiab thaum kawg pab txheeb xyuas cov kev kho muaj peev xwm.
Niaj hnub no, kev sib tshuam ntawm cov tshuaj precision thiab kev txawj ntse txawj ntse (tshwj xeeb yog kev kawm tshuab thiab kev kawm sib sib zog nqus algorithms) yog thaj chaw nrov hauv kev tshawb fawb txog kab mob autoimmune. Lub hom phiaj yog kom tau txais txiaj ntsig zoo dua rau cov noob sib txawv, muaj nuj nqis, thiab kev ua kom zoo, thiab cov pidnnostic, thiab prengence thiab Longo, 2015). Qhov no tuaj yeem ua rau muaj txoj hauv kev tshiab los kho tus kheej tshwj xeeb rau cov neeg mob autoimmune kab mob, tshwj xeeb yog cov uas muaj cov kab mob autoimmune tsawg, txhawm rau ua tiav kev kho mob zoo (Subramanian li al., 2020). Lub caij no, cov teeb meem kev coj ncaj ncees thiab kev cai lij choj nyob ib puag ncig kev txawj ntse-tsav kev kho mob tau txais kev cuam tshuam hauv zej zog thiab ua rau muaj kev sib tham (Amann li al., 2020).
Genetic Cheebtsam nyob rau hauv lub cev tiv thaiv kab mob txawv txav nyob rau hauv cov kab mob autoimmune
Cov lus teb autoreactive tiv thaiv kab mob yog cov kab mob tseem ceeb hauv cov kab mob autoimmune. Txawm hais tias cov kab mob autoimmune sib txawv tshwm sim lawv tus kheej nrog cov tsos mob sib txawv, qee yam kev pheej hmoo ntawm caj ces feem ntau ua rau muaj kev cuam tshuam ntawm kev tiv thaiv kab mob autoimmunity (Cho thiab Feldman, 2015). Hauv peb tshooj hauv qab no, raws li cov kev paub tau los ntawm tib neeg cov kev tshawb fawb noob caj noob ces xws li GWAS, peb tham txog cov laj thawj thiab txoj hauv kev uas yuav cuam tshuam rau kev ua kom tsis zoo ntawm lub cev tiv thaiv kab mob. Thawj ntu ntawm tshooj no luv luv tham txog cov noob caj noob ces uas muaj kev sib txuas rau lub cev tiv thaiv kab mob hauv lub cev thaum ob tshooj tom ntej no tsom mus rau T cell-txog kev tiv thaiv kab mob tsis zoo thiab cov kab mob pathogenic hauv TNF signaling. Tsis tas li ntawd, nyob rau hauv qhov thib ob thiab thib peb ntawm tshooj no, peb nthuav cov kev sib tham ntawm cov noob caj noob ces uas muaj kev sib txuas rau autoimmunity yuav tsis tshwm sim raws li pom tseeb thaum xub thawj siab ib muag, ua piv txwv los ntawm cov noob thiab txoj hauv kev paub zoo tshaj plaws rau lawv lub luag haujlwm hauv kev loj hlob thiab cov txheej txheem metabolic. .
Cov kab mob autoimmune susceptibility noob nrog cov yam ntxwv zoo hauv kev tiv thaiv kab mob hauv lub cev Risk genes hauv cov txheej txheem nthuav qhia antigen
Nyob rau hauv homeostasis, DCs yog qhov tseem ceeb inducer ntawm peripheral kam rau ua rau humoral kev tiv thaiv, nyob rau hauv uas tolerogenic DCs induce depletion los yog lub zog nyob rau hauv auto-reactive T hlwb thiab kuj polarize lub T hlwb rau hauv kev tswj T hlwb (Iberg li al., 2017). Thaum, nyob rau hauv autoimmunity activation, bypassed peripheral kam rau ua yuav tshwm sim los ntawm cov noob caj noob ces variants nyob rau hauv antigen nthuav qhia txoj kev thiab / los yog hyper-activation ntawm T hlwb (Theofilopoulos li al., 2017). Nrog rau kev tshawb nrhiav dav dav, HLA qhov kev pheej hmoo sib txawv hauv cov kab mob autoimmune muaj feem xyuam nrog cov tshuaj tiv thaiv tsis zoo uas tau nthuav tawm los ntawm DCs, thiab tsis yog-HLA muaj feem cuam tshuam kuj tuaj yeem koom nrog. Cov kab mob autoimmune ntsig txog polymorphisms hauv ERAP1 thiab ERAP2 loci tau txuas nrog kev nthuav qhia antigen tsis tsim nyog, uas tshwm sim los ntawm kev cuam tshuam antigen peptide trimming los ntawm ERAP1/2 encoded enzymes rau MHC-I kev nthuav qhia. Tsis tas li ntawd, T cells hyper-proliferation thiab inflammatory polarization tuaj yeem cuam tshuam los ntawm cov kab mob autoimmune-ua rau muaj kev pheej hmoo alleles, xws li PTPN22 rau TCR signaling, IL12A thiab STAT4 rau Th1 polarization los ntawm IL-12, thiab IL23R rau IL{{ 19}} mediated Th17 polarization.
Pathogenic kev sib cuam tshuam ntawm plasmacytoid DCs (pDCs) thiab neutrophils
Ib tus yam ntxwv ntawm cov kab mob autoimmune uas sawv cev los ntawm SLE yog qhov nce ntawm pDCs hauv kev ncig thiab hauv cov ntaub so ntswg, xws li raum (Coutant and Miossec, 2016). pDCs yog cov kws tshaj lij hom I interferon (IFN) tsim cov hlwb, uas ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob hauv lub cev. Hauv cov xwm txheej SLE, cov pDCs hauv cov hlab ntsha thiab cov ntaub so ntswg hauv zos txhawb kev mob thiab autoantibody ntau lawm, feem ntau nyob ntawm hom I IFNs (Soni thiab Reizis, 2019). Hauv SLE pathogenesis, qhov kev puas tsuaj rau pem hauv ntej yog kho los ntawm neutrophils, pDCs, thiab B hlwb. Nyob rau hauv ib puag ncig inflammatory, xws li SLE cov neeg mob lub raum cov ntaub so ntswg, neutrophils raug xaiv thiab qhib los ntawm inflammatory cytokines, xws li IL-8 thiab IL-17 (Fresneda Alarcon et al., 2021). Thaum ua kom muaj zog, neutrophils tuaj yeem raug tua cov cell tuag, NETosis, uas tso tawm DNA cov ntsiab lus los ntawm neutrophil extracellular trap (NET). Cov qauv NET muaj nuclear DNA thiab oxidated mitochondrial DNA, ob qho tib si yog cov muaj zog TLR9 agonists thiab auto-antigens rau hom I IFN ntau lawm hauv pDCs thiab autoantibody ntau lawm hauv B hlwb, raws li (Soni thiab Reizis, 2019). Nyob rau hauv xws li pDC-mediated interferonopathy, ntau yam kev taw qhia yog genetic pre-posited rau cov kab mob uas muaj kab mob (Mohan thiab Putterman, 2015). Ua ntej, polymorphism nyob rau hauv cov noob muaj feem xyuam rau TLR signaling pathway Cheebtsam tau raug txheeb xyuas nyob rau hauv cov kab mob autoimmune, xws li IRAK1 thiab IRF5. Rau predisposed TLR signaling nyob rau hauv SLE pathogenesis, uas ua rau hom I IFN ntau lawm hauv pDC tau raug suav hais tias yog ib tug loj neeg uas ua ntawv, thiab crosstalk ntawm TLR7/9 signaling thiab B cell activation kuj tau implied nyob rau hauv kev txhawb nqa ntawm autoantibody-producing plasma hlwb (Suthers thiab Sarantopoulos, 2017). Qee cov gene loci rau cov cim qhia kev tswj hwm kuj tau txheeb xyuas tias muaj kev pheej hmoo alleles, xws li TNFAIP3 thiab TNIP3 rau NF-κB signaling uas ua rau muaj kev mob phenotypes hauv cov hlwb myeloid. Qhov thib ob, qhov txawv txav ntawm hom I IFN qhov taw qhia kuj tseem tuaj yeem tsim cov caj ces hauv cov neeg mob autoimmune kab mob, qhov twg cov noob encoding hom I IFN receptor thiab downstream signaling cascade kinase, IFNAR1 thiab TYK2, tau txheeb xyuas nrog cov kab mob autoimmune ntsig txog polymorphism. Nyob rau hauv sib piv rau SLE, pDC muaj nuj nqi nyob rau hauv lwm yam kab mob autoimmune yog tsis tshua muaj tus yam ntxwv, thiab cov uas tsis tshua muaj sib koom pDC-mediated pathogenesis tau implied ntawm ntau yam kab mob. Ib yam li SLE, hauv cov qauv nas rau hom ntshav qab zib hom I, pDC tau pom tias yuav txhawb kev kis kab mob los ntawm kev tsim hom I IFN (Reizis, 2019). Thaum, tolerogenic pDC phenotypes hauv synovium thiab periphery ntawm RA cov neeg mob tau piav qhia (Cooles li al., 2018; Kavousanaki li al., 2010; Takakubo li al., 2008), thiab lub luag haujlwm tiv thaiv zoo li no tau txais kev txhawb nqa los ntawm cov kab mob hnyav zuj zus nrog pDC depletion hauv tus qauv nas mob caj dab (Jongbloed li al., 2009).
Monocyte thiab macrophage mediated o
Lub luag haujlwm tseem ceeb ntawm macrophages thiab monocytes hauv autoimmune kab mob ntsig txog cov ntaub so ntswg o yog txhawb nqa los ntawm kev ua tiav ntawm kev kho mob cov phiaj xwm inflammatory cytokines tsim los ntawm monocytes thiab macrophages (Conigliaro li al., 2019). Feem ntau, inflammatory macrophages thiab monocytes raug suav hais tias yog cov hlwb cuam tshuam rau cov kab mob ntsig txog cov ntaub so ntswg (Navegantes li al., 2017). Nrog rau kev ua haujlwm tsis zoo rau cov kev pheej hmoo feem ntau tshwm sim thoob plaws cov kab mob autoimmune sib txawv, cov kab mob ua ntej cov kab mob ua ntej tso rau hauv macrophages thiab monocytes tau unraveled. Nyob rau hauv cov lus teb inflammatory, myeloid hlwb, tshwj xeeb tshaj yog cov monocyte-derived macrophages, yog lub hauv paus ntawm lub hauv paus rau kev nkag siab txog cov kev mob tshwm sim uas ua rau muaj kev sib haum xeeb ntau lawm thiab txuas ntxiv txuas rau lub zos hloov lub cev tiv thaiv kab mob los ntawm kev nyiam qhov sib txawv ntawm cov kab mob CD{{7} } T cells thiab autoantibody-secreting plasma cells (Tsokos, 2020; Weyand and Goronzy, 2021).
Immune complex-induced inflammatory teb nyob rau hauv cov ntaub so ntswg yog universally manifested los ntawm Fc receptor signaling activation thiab ntxiv txoj kev activation nyob rau hauv myeloid hlwb, thiab kev tiv thaiv ntxiv kev kho mob thiab blockade ntawm Fc receptor qhia tau cog lus kev soj ntsuam zoo nyob rau hauv RA thiab SLE cov neeg mob (Galindo-Izquier. Pablos Alvarez, 2021; Zuercher li al., 2019). Genetic variants nyob rau hauv ob qho tib si ntxiv thiab Fc receptor pathways kuj txuam nrog autoimmune kab mob (Theofilopoulos li al., 2017). Tshwj xeeb, polymorphisms hauv ITGAM thiab FCGR2B loci tau cuam tshuam nrog kev cuam tshuam tsis zoo ntawm kev tiv thaiv kab mob ua rau mob. ITGAM encodes CD11b, tseem hu ua complement receptor CR3, los kho kom haum raws li phagocytosis rau lub cev tsis muaj zog thiab apoptotic hlwb, thiab C3b ua kom CR3 induces zus tau tej cov anti-inflammatory cytokines hauv macrophages. Rau polymorphism nyob rau hauv FCGR2B locus, qhov kev ua haujlwm tsis zoo ntawm Fc RIIB-mediated repression ntawm Fc receptor signaling tuaj yeem ua rau muaj kev cuam tshuam ntau dhau ntawm cov hlwb myeloid los ntawm lub cev tsis muaj zog. Yog li, kev sib sau ntawm lub cev tiv thaiv kab mob thiab cov khib nyiab ntawm tes thiab downstream hyper-inflammatory activation ntawm macrophages nyob rau hauv cov ntaub so ntswg hauv zos yog genetic pre-posited nyob rau hauv autoimmune kab mob los txhawb pathogenesis. Muab qhov genericity ntawm kev tiv thaiv kab mob sib sau ua ke nthuav tawm hauv cov kab mob autoimmune, xws li kev ua haujlwm tsis zoo ntawm Fc receptor signaling, thiab ntxiv txoj hauv kev tau suav tias yog kev kho mob rau cov kab mob sib txawv.
Txawm hais tias muaj kev sib koom ua ke ntawm kev pheej hmoo ntawm caj ces thiab cov kab mob inflammatory myeloid tuaj yeem pom nyob rau hauv ntau yam kab mob autoimmune, kev teb ntawm cov neeg mob sib txawv ntawm cov kab mob autoimmune rau kev kho mob myeloid-targeting tuaj yeem sib txawv kiag li. Rau kev kho mob los tiv thaiv GM-CSF, cov neeg mob RA tau txais cov kab mob tseem ceeb los ntawm kev kho mob, tab sis cov kab mob tau ua phem zuj zus los ntawm kev cuam tshuam los ntawm GM-CSF hauv cov neeg mob SLE (Lotfi li al., 2019). Cov txheej txheem hauv qab qhov sib txawv no tseem tsis tau paub meej, tab sis nws qhia tias cov hlwb myeloid tau txais GM-CSF teeb liab hauv cov neeg mob SLE tuaj yeem tiv thaiv. Qhov teeb meem no qhia tau hais tias kev lees paub txog qhov sib txawv ntawm cov kab mob inflammatory pab txoj kev txhim kho ntawm kev kho mob los ntawm kev tsom mus rau cov kws kho mob tshwj xeeb hauv cov kab mob tshwj xeeb. Macrophages thiab monocytes tuaj yeem ua haujlwm dhau los ntawm ntau yam ntawm cov kab mob inflammatory stimuli hauv cov kab mob autoimmune, uas ntxiv ua rau cov kab mob hauv lub cev hu ua macrophage activation syndrome (Crayne li al., 2019). Cov kab mob zoo li no tau kho los ntawm macrophages thiab monocytes tuaj yeem tsim cov tsos mob thoob ntiaj teb thiab txawm tias muaj kev phom sij rau lub neej. Macrophage activation syndrome tuaj yeem pom nyob rau hauv cov menyuam yaus idiopathic mob caj dab (sJIA), qhov twg cov phenotypes pro-inflammatory phenotypes tau nthuav tawm nyob rau hauv periphery, vim cov ntshav monocytes ntawm cov neeg mob tsim ib qho array ntawm inflammatory cytokines, xws li TNF, IL-6, IB-1 . Nyob rau hauv xws li hyper-inflammatory macrophage activation, dysregulated inflammatory pathways nyob rau hauv lub cev tiv thaiv kab mob yuav tshwm sim los ntawm noob caj noob ces variants, xws li IRF5 rau hom I IFN signaling, NLRC4 rau IL-1 - ua inflammasome txoj kev, thiab TNFAIP3 rau NF-κB signaling ( Schulert thiab Cron, 2020).
Notch signaling yog caj ces cuam tshuam nrog cov kab mob autoimmune
Raws li tau hais dhau los, cov kev pheej hmoo ntawm caj ces cuam tshuam nrog kev ua siab ntev rau tus kheej thiab cov kab mob inflammatory ua rau cov kab mob autoimmune. Lub caij no, cov noob caj noob ces tsis tuaj yeem ncaj qha mus rau qhov txawv txav ntawm lub cev tiv thaiv kab mob tau ua haujlwm ua haujlwm nrog kev paub ntau ntxiv (Daim duab 2), nyob rau hauv uas peb yuav tham txog cov txheej txheem pathological tau koom nrog Notch signaling thiab mitochondria-centric metabolism, ob txoj hauv kev nrog caj ces cuam tshuam. rau cov kab mob autoimmune. Notch signaling yog ib txoj hauv kev tseem ceeb rau embryonic cov ntaub so ntswg thiab kev loj hlob ntawm lub cev, tom qab ntawd Notch signaling kuj tswj cov homeostasis hauv zos hauv ntau cov ntaub so ntswg. Hauv cov tsiaj nyeg, plaub Notch signaling receptors (Notch1–4) thiab tsib Notch ligands tau txheeb xyuas. Raws li kev ua haujlwm los ntawm Notch ligands, tus receptor proteolytically tso tawm Notch intracellular domain (NICD) thiab tswj cov noob qhia los ntawm kev cuam tshuam nrog RBPJ uas yog lub hauv paus nuclear transcription regulator hauv canonical Notch signaling pathway. Notch signaling yog dav cuam tshuam nrog lub cev tiv thaiv kab mob, qhov twg Notch signaling koom nrog hauv kev txhim kho cov kab mob hauv lub cev hauv ob qho tib si lymphoid thiab myeloid kab mob thiab tseem tswj cov kev ua haujlwm ntawm cov kab mob sib txawv ntawm lub cev kom zoo kho cov kab mob hauv lub cev thiab cov kab mob (Vanderbeck thiab Maillard, 2021). Nyob rau hauv cov kev tshawb fawb tsis ntev los no, accumulating pov thawj ntawm Notch signaling-nrog pathogenesis nyob rau hauv ntau yam kab mob autoimmune qhia lub hom phiaj ntawm Notch-txog txoj hauv kev yuav yog ib qho kev cog lus kho mob cuam tshuam. Yog li ntawd, cov ntsiab lus ntawm kev paub tam sim no ntawm kev tswj hwm ntawm pathogenesis, tshwj xeeb tshaj yog cov lus teb inflammatory, nyob rau hauv cov kab mob autoimmune los ntawm txoj kev Notch yog cov ntaub ntawv thiab kev pom zoo rau kev tsim kho.
Peb ntawm plaub qhov Notch receptor gene loci tau raug txheeb xyuas tias muaj kev pheej hmoo alleles hauv cov kab mob autoimmune (Table 1). Tsis tas li ntawd, cov gene locus ntawm RBPJ tau raug txheeb xyuas tias yog ib qho kev pheej hmoo ntawm RA, thiab loci ntawm DLL1 thiab DLL4 tau raug txheeb xyuas tias muaj kev pheej hmoo alleles hauv SLE, ntau yam sclerosis, thiab hom I ntshav qab zib (Table 1). Yog li, dysregulated Notch signaling yog genetic implied nyob rau hauv cov kab mob autoimmune. Ntawm no, peb yuav tham txog cov kev cai hais txog Notch thaum lub sij hawm pathogenesis ntawm RA thiab SLE, ob yam kab mob autoimmune cuam tshuam nrog kev pheej hmoo ntawm kev hloov pauv hauv Notch receptors, ligands, thiab RBPJ loci nrog kev nthuav dav thiab dav dav.
Daim duab 2 Kev ua haujlwm qeb ntawm cov caj ces hauv qab cov kab mob autoimmune
Upregulated Notch signaling pab txhawb rau RA pathogenesis
Hauv cov neeg mob RA, Notch receptor activation tau pom nyob rau hauv ob qho tib si tiv thaiv kab mob thiab tsis muaj kab mob. Nyob rau hauv cov kab mob lymphoid, kev ua kom muaj Notch1 tau pom nyob rau hauv synovial T hlwb (Yabe li al., 2005), thiab peripheral T hlwb ntawm cov neeg mob RA active qhia upregulated Notch2, 3, 4 qhia thiab Notch signaling activation (Jiao li al., 2010). Nyob rau hauv cov nas collagen II-tiv thaiv kab mob, lub Notch teeb liab yog qhib rau hauv lub synovium, thiab RA-zoo li manifestations yog alleviated raws li Notch signaling inhibition los ntawm -secretase inhibitors (Choi li al., 2018; Jiao li al., 2014; Jiao et al. , 2011; Park et al., 2015). Hauv feem ntau ntawm cov kev tshawb fawb no, qhov hloov pauv Th1 / Th17 rau Treg piv los ntawm Notch signaling txoj hauv kev tau pom zoo rau cov kab mob tshwm sim hauv cov qauv nas (Choi et al., 2018; Jiao et al., 2014; Jiao et al., 2011) , qhov twg Notch3 thiab DLL1 txhawb nqa Th1 thiab Th17 expansion (Jiao li al., 2011), DLL3 txhawb Th17 expansion (Jiao li al., 2014), thiab Notch1 suppresses Treg pejxeem (Choi li al., 2018). Txawm li cas los xij, cov ntsiab lus-dependent Notch signaling muaj nuj nqi nthuav tawm los ntawm cov kev tshawb fawb sib txawv tuaj yeem yog qhov tshwm sim ntawm kev hloov pauv ntawm cov kev sim sib txawv. Txawm hais tias kev nce qib ntawm Th17 nthuav dav los ntawm DLL1 tau qhia los ntawm Jiao li al. ntawm DLL1 kev kho mob hauv vitro splenic mononuclear hlwb (Jiao li al., 2011), hauv lwm txoj kev tshawb fawb, DLL1 ua tsis tiav los txhawb Th17 expansion (Jiao li al., 2014). Yog li ntawd, qhov muaj txiaj ntsig zoo ntawm kev thaiv Notch signaling tau zoo ib yam hauv RA kab mob nas qauv, cov ncauj lus kom ntxaws, tshwj xeeb tshaj yog cov txiaj ntsig tshwj xeeb los ntawm txhua qhov Notch receptor thiab ligand tseem yuav tsum tau qhia meej. Lineage-specific knockout nas rau Notch receptors thiab ligands yuav tsum muaj txiaj ntsig tshwj xeeb rau kev soj ntsuam Notch signaling muaj nuj nqi hauv T cell-mediated RA pathogenesis.
Notch signaling activation kuj pom nyob rau hauv myeloid hlwb nyob rau hauv ob qho tib si RA cov neeg mob thiab RA kab mob nas qauv (Sekine li al., 2012; Sun li al., 2017). Raws li tau hais hauv RA pathogenesis, myeloid hlwb, tshwj xeeb yog monocytes, thiab monocyte-derived hlwb, tuaj yeem ua haujlwm xws li macrophages lossis osteoclasts los txhawb kev mob thiab pob txha yaig. Thaum, Notch signaling, qhov tseeb, koom nrog ob qho tib si, modulating polarization ntawm macrophages thiab sib txawv ntawm osteoclasts. Notch signaling txhawb inflammatory polarization ntawm macrophages nyob rau hauv ntau yam mob (Shang li al., 2016). Txawm li cas los xij, kev ua haujlwm proinflammatory ntawm Notch signaling hauv macrophages yog qhov tsis tshua muaj tshwm sim hauv RA-txog o. Tseeb, lub ntiaj teb no inhibition ntawm notch signaling tshwm sim nyob rau hauv lub reversed hyper-inflammatory phenotype nyob rau hauv macrophages nyob rau hauv tus kab mob RA nas qauv (Sun li al., 2017). Raws li tau tham hauv Notch muaj nuj nqi hauv RA T hlwb, nws tseem ceeb heev rau kev tshawb xyuas qhov kev koom tes tshwj xeeb ntawm Notch receptor-ligand khub hauv macrophages rau cov lus teb inflammatory hauv RA pathogenesis. Rau osteoclastogenesis, Notch signaling tau pom rau ob qho tib si zoo thiab tsis zoo tswj hwm kev sib txawv ntawm osteoclast (Shang li al., 2016), uas tuaj yeem yog qhov tshwm sim ntawm qhov sib txawv receptor-ligand Notch signaling activation lossis qhov hloov pauv hauv kev sim sib txawv. Qhov tseeb, kev tswj hwm los ntawm qhov sib txawv ntawm Notch receptor-ligand khub hauv RA-txog osteoclastogenesis tuaj yeem xav txog, raws li kev tshawb fawb yav dhau los qhia tias Notch2 / DLL1 txhawb nqa, tab sis Notch1 / Jagged1 suppress osteoclast txoj kev loj hlob raws li kev sib koom ua ke (Sekine li al., 2012 ). Notch signaling kuj ua lub luag haujlwm tseem ceeb hauv synovial fibroblast-mediated RA pathogenesis. Lub pathogenesis pab txhawb los ntawm Notch-mediated pathogenic fibroblasts yog cov ntaub ntawv zoo, vim tias feem ntau cov kev tshawb pom tau muab los ntawm cov neeg mob kuaj, thiab tau ua kom zoo los ntawm kev tswj hwm hauv vitro system. Ua ntej, qhov kev ua kom tsis muaj zog hauv synovial fibroblast tau txheeb xyuas hauv RA cov neeg mob 'synovium (Ando li al., 2003; Ishii li al., 2001; Nakazawa et al., 2001a; Nakazawa et al., 2001b; Wei, 20 et al., 2001b. ; Yab et al., 2005). Tsis tas li ntawd, kev ua haujlwm ntawm Notch signaling yog induced los ntawm inflammatory ib puag ncig, xws li ntau dhau TNF thiab hypoxia (Ando li al., 2003; Gao li al., 2015; Gao et al., 2012; Jiao et al., 2012; Nakazawa et al. ., 2001a; Nakazawa et al., 2001b). Inhibition of Notch activation los ntawm -secretase inhibitor tsis tsuas yog txo qhov mob-induced fibroblast proliferation tab sis kuj txo inflammatory cytokine ntau lawm, xws li IL-6 (Jiao li al., 2012; Nakazawa li al., 2001a). Rau cov txheej txheem tshwj xeeb, Notch1 signaling tau ua haujlwm cuam tshuam rau RA fibroblasts (Gao li al., 2015; Nakazawa li al., 2001a; Nakazawa li al., 2001b), thiab Notch3 signaling tau tsis ntev los no tau txheeb xyuas los kho cov kab mob nthuav dav ntawm KOJ1-qhia RA fibroblasts (Wei li al., 2020). Muab qhov kev sim ua tiav hauv cov qauv tsiaj sim, qhov kev taw qhia kev taw qhia yuav sawv cev rau qhov kev cog lus kho mob ntawm RA. Txawm hais tias cov txheej txheem ntxaws ntxaws, tshwj xeeb tshaj yog cov cim qhia txog kev tswj hwm Th1 / Th17 cov lus teb hauv RA pathogenesis, tseem yuav tsum tau tshawb xyuas ntxiv. Ntxiv mus, rau kev tsim kho kom zoo dua qub, qhov kev ntsuam xyuas ntawm RA pathogenesis uas yog kho los ntawm qhov sib txawv Notch receptors lossis ligands yuav tsum tau ua tiav, raws li pov thawj los ntawm kev txo qis tus kab mob los ntawm kev thaiv Notch1 piv rau Notch3 blockade hauv K / BxN nas cov ntshav hloov pauv RA nas. qauv (Wei et al., 2020).
Table 1 Summary of Notch receptors, ligands and RBPJ-related risk alleles txheeb xyuas los ntawm GWAS kev tshawb fawb hauv cov kab mob autoimmune
Dysregulated Notch signaling yog txuam nrog SLE pathologies
Hauv cov neeg mob SLE, kev txhim kho ntawm Notch signaling tau pom nyob rau hauv cov ntaub so ntswg puas lawm. Tshwj xeeb tshaj yog, Notch3 qhia tau kho nyob rau hauv cov ntaub so ntswg raum ntawm cov neeg mob nrog lupus nephritis piv rau cov tib neeg noj qab haus huv (Breitkopf li al., 2020). Ntxiv mus, qhov ua kom muaj Notch signaling nyob rau hauv lub raum cov ntaub so ntswg nrog lupus nephritis yog pov thawj los ntawm lub cleavage ntawm Notch1 thiab Notch2 thiab lub nuclear localization ntawm Notch1 thiab Notch3 nyob rau hauv podocytes (Lasagni li al., 2010; Murea li al., 2010). Ntxiv rau cov neeg mob, qhov kev sim nas tus qauv qhia pom cov kab mob zoo li lupus kuj pom tau hloov pauv Notch signaling hauv lub raum cov ntaub so ntswg (Breitkopf li al., 2020; Lemos et al., 2019; Zhang et al., 2010). Txawm hais tias lub ntiaj teb no Notch signaling inhibition alleviates qhov kev puas tsuaj ntawm lub raum cov ntaub so ntswg thiab autoantibody ntau lawm nyob rau hauv ib tug lupus nas qauv (Teachey li al., 2008; Zhang li al., 2010), qhov kev koom tes los ntawm Notch signaling nyob rau hauv tej cell hom rau lub SLE pathogenesis yog. tseem nyob rau hauv kev ntsuam xyuas. Ntawm ib sab, Notch signaling yuav tsum tau ua kom txaus Th1 lus teb thaum lub sij hawm T-cell activation, thiab Th17 sib txawv kuj tau ua pov thawj zoo heev nyob ntawm Notch signaling (Tindemans li al., 2017). Ntawm qhov tod tes, Treg hlwb tuaj yeem raug tswj tsis zoo los ntawm Notch signaling hauv nas qauv rau cov kab mob autoimmune (Tindemans li al., 2017). Raws li tau hais nyob rau hauv RA kab mob teeb tsa, lub luag haujlwm txhawb kev ua haujlwm ntawm Notch signaling hauv T cell teb tuaj yeem raug ntxiv los ntawm cov kev paub tam sim no tias qhov siab ntawm Notch signaling hauv RA T hlwb suav rau kev txhim kho Th1 thiab Th17 tab sis txo qis Treg teb. Hauv cov neeg mob SLE, Notch signaling nyob rau hauv T hlwb yog dysregulated nyob rau hauv lub opposite lus qhia ntawm lub zos puas cov ntaub so ntswg thiab peripheral ntshav. Nyob rau hauv sib piv rau upregulation ntawm Notch signaling nyob rau hauv lub raum puas cov ntaub so ntswg (Breitkopf li al., 2020), cov pov thawj uas qhia tau hais tias txo qis Notch signaling nyob rau hauv peripheral T hlwb tau sau raws li, ua ntej, tus tuag Notch1 qhia nyob rau hauv SLE cov neeg mob 'T hlwb yog kho los ntawm cAMP-responsive element modulator (CREM) cuam tshuam rau kev tswj hwm epigenetic (Rauen li al., 2012); Thib ob, Notch signaling activation kuj tseem tuaj yeem txo qis hauv SLE cov neeg mob 'T hlwb ntawm soluble CD46 cuam tshuam kev cuam tshuam ntawm Jagged1 thiab Notch receptor (Ellinghaus li al., 2017). Txawm hais tias inhibition of Notch signaling with -secretase inhibitor in lupus-prone nas ho alleviates lupus-related autoantibody production, nephritis, and local o, Notch signaling mediated T cell teb zoo li ua lub luag haujlwm tiv thaiv kab mob SLE. Hauv cov neeg mob SLE thiab lpr nas, cov kab mob cuam tshuam nrog guanidinylated YB-1 ua haujlwm raws li ligand rau Notch3 kom muaj peev xwm kho tau Notch activation hauv lub raum cov ntaub so ntswg thiab txhawb IL-10 ntau lawm hauv T hlwb ntawm Notch3 (Breitkopf li al. , 2020). Ib yam li ntawd, hauv SLE peripheral ntshav, cuam tshuam Notch activation los ntawm soluble CD46 impedes kev hloov ntawm IFN- + Th1 hlwb rau IL-10 tsim IFN- + Th1 hlwb (Ellinghaus li al., 2017), uas tau raug hu ua Tr1 hlwb thiab ua lub luag haujlwm hauv kev tiv thaiv kab mob peripheral (Pot li al., 2011). Lub caij no, cov nyhuv T-hlwb hauv cov neeg mob SLE tiv taus cov kev tswj xyuas los ntawm Treg (Vargas-Rojas li al., 2008; Venigalla li al., 2008). Mechanistically, Notch activation nyob rau hauv effector T hlwb potentiates tau txais TGF- signaling los ntawm Treg mus rau nruab nrab lub cev tiv thaiv kab mob (Grazioli li al., 2017). Yog li, bypass ntawm kev tsuj los ntawm Treg hauv SLE T hlwb yog qhov ua tau kom raug ntaus nqi kom txo qis Notchcoopted TGF- signaling. Muab lub luag haujlwm tseem ceeb ntawm Treg hauv kev tiv thaiv kab mob, qhov ntau thiab qhov tsis zoo hauv Treg kuj tau txheeb xyuas hauv cov neeg mob SLE (Valencia li al., 2007; Vargas Rojas li al., 2008). Tom qab ntawd, tuaj yeem txo qis kev ua haujlwm hauv T hlwb tuaj yeem ua rau tsis ua haujlwm Treg cov lus teb hauv cov neeg mob SLE thiab? Tam sim no, cov kev tshawb fawb los ntawm kev ua haujlwm tshwj xeeb ntawm Notch signaling hauv nas Treg hlwb qhia txog kev ua haujlwm ntawm Notch signaling hauv Treg txij nkawm lossis ua haujlwm hauv cov kab mob autoimmune-hais txog kev teeb tsa (Charbonnier li al., 2015; Rong et al., 2016). Txawm li cas los xij, txoj cai hais txog Notch hauv Treg txoj kev loj hlob thiab kev ua haujlwm yog qhov nyuaj, ua piv txwv los ntawm cov lus xaus tsis sib haum ntawm Notch-mediated FOXP3 qhia tau kos los ntawm kev tshawb fawb nrog ntau yam kev sim, thiab qhov tshwm sim ntawm Notch activation thaum Treg txoj kev loj hlob thiab kev saib xyuas nyob ntawm cov ntsiab lus. , qhov sib txawv ua ke ntawm Notch receptor-ligand khub, ntau hom Treg hlwb, thiab cov ntaub so ntswg tshwj xeeb, uas tau raug tshuaj xyuas los ntawm Paola G. et al. (Grazioli et al., 2017). Rau Treg hauv cov neeg mob SLE, qhov tsis tshua muaj CD25 qhia yog lwm yam kab mob ntsig txog Treg tsis xws luag uas tuaj yeem cuam tshuam nrog Notch signaling (Horwitz, 2010). Txawm hais tias IL2RA (CD25) gene locus tau raug txheeb xyuas tias yog ib qho ntawm cov kev pheej hmoo rau SLE, xws li kev hloov caj ces tuaj yeem piav qhia qhov tsis tshua muaj CD25 qhia hauv so SLE T hlwb (Costa li al., 2017). Interestingly, Notch signaling tuaj yeem tuav CD25 qhia hauv T hlwb (Adler li al., 2003), ua rau nws muaj peev xwm hais tias kev txo qis ntawm Notch signaling tuaj yeem ua rau qhov tsis zoo ntawm CD25 qhia hauv SLE cov neeg mob 'T cells. Yog li ntawd, qhov txo qis kev ua haujlwm hauv SLE cov neeg mob 'T hlwb tuaj yeem xav tias yog ib qho ntawm cov laj thawj rau qhov tsis xws luag hauv Treg, thiab qhov kev txiav txim siab ntxiv ntawm Notch signaling hauv SLE Treg hlwb yuav yog cov ntaub ntawv los piav qhia txog cov lus teb ntawm Treg thaum lub sij hawm SLE pathogenesis. .
Raws li tus cwj pwm ncaj qha ntawm Notch signaling nyob rau hauv lub raum cov ntaub so ntswg ntawm SLE cov neeg mob, Notch signaling activation tau muaj pov thawj los ntawm nce cleavage ntawm Notch1 thiab Notch2 thiab nce kev qhia ntawm Jagged1 nyob rau hauv glomerulus (Murea li al., 2010), thiab muaj zog nuclear Notch1 thiab Notch3. hauv PDX+ podocytes thiab nce nuclear Notch3 hauv CD24+ lub raum podocyte progenitor hlwb hauv raum cov ntaub so ntswg ntawm cov neeg mob SLE (Lasagni li al., 2010). Ntxiv mus, qhov hnyav ntawm glomerulosclerosis zoo sib xws rau qhov nce ntawm cleaved Notch1 hauv podocytes (Murea li al., 2010). Podocytes yog cov txheej txheem tseem ceeb ntawm glomerulus, thiab lupus nephritis manifests qhov poob ntawm podocytes. Pathologically, Notch signaling pab kom poob ntawm podocytes thaum pathogenic hloov dua siab tshiab nyob rau hauv lub raum ntaub so ntswg los ntawm regulating podocyte regeneration. Rau cov ncauj lus kom ntxaws, tib neeg podocyte progenitor hlwb raug cais thiab kab lis kev cai kom sib txawv rau hauv podocytes hauv vitro, thiab kev txo qis ntawm Notch signaling muaj feem xyuam rau G2 / M cell voj voog raug ntes thaum sib txawv (Lasagni li al., 2010). Txawm hais tias tswj hwm lub Notch signaling activation los ntawm overexpressing Notch3-NICD hauv podocyte progenitor hlwb txhawb kev qhia ntawm podocyte marker noob, progenitor hlwb raug thawb los ntawm lub cell voj voog checkpoint los ntawm activated Notch signaling, uas ntxiv ua rau cell tuag ntawm podocytes. los ntawm defected mitosis (Lasagni li al., 2010). Ntxiv rau lupus nephritis, lwm cov qauv nephropathic hauv nas kuj qhia tau tias Notch signaling activation, tshwj xeeb tshaj yog Notch1, thiab Notch3, hauv podocytes ua rau poob ntawm podocytes, lub raum cov ntaub so ntswg puas, thiab lub raum tsis ua hauj lwm (Asanuma li al., 2017). Txawm li cas los xij, kev ua kom Notch2 hauv podocytes zoo li ua haujlwm raws li kev tiv thaiv kev tawm tswv yim los txwv kev tuag ntawm tes (Asanuma li al., 2017). Muab qhov ua kom Notch2 nce ntxiv hauv podocytes ntawm SLE cov neeg mob (Murea li al., 2010), lub ntiaj teb inhibition ntawm Notch signaling los ntawm -secretase inhibitor tej zaum yuav ua rau tsis ua haujlwm ntawm txoj hauv kev tiv thaiv kab mob. Tsis zoo li tag nrho cov kab mob tshwm sim ntawm cov teeb meem tsis txaus ntseeg hauv cov kab mob RA, kev cuam tshuam ntawm Notch signaling hauv SLE cov neeg mob kho cov kev cai sib txawv rau cov kab mob kev loj hlob hauv cov ntsiab lus ntawm cov yam ntxwv. Yog li ntawd, lub hom phiaj ntawm Notch signaling rau kev kho lub hom phiaj nrog lub ntiaj teb no inhibition rau kev ua kom yog undesirable (Grosveld, 2009), thiab kev cuam tshuam nrog tshwj xeeb rau Notch signaling nyob rau hauv SLE txoj kev kho yog xav tias yuav. Ntawm qhov kev ceeb toom, DLL4 kev qhia hauv DCs raug kho raws li kev mob tshwm sim hauv tib neeg thiab nas, thiab DLL4 hauv DCs tuaj yeem qhib Notch signaling hauv T hlwb kom ntxias Th1 thiab Th17 cov lus teb, uas qhia txog qhov muaj peev xwm kho tau zoo los ntawm kev tsom DLL4 kom thim rov qab Th1 / Th17 dominant inflammatory teb (Meng et al., 2016). Tsis tas li ntawd, kev nthuav dav ntawm thymic DCs los ntawm DLL4 blockade txhawb Treg sib txawv (Billiard li al., 2012), thiab inactivation ntawm DLL4-kev kho kom haum Notch signaling nyob rau hauv autoimmune kab mob nas qauv ua rau muaj kab mob remission thiab tsawg inflammatory T cell teb ( Billiard et al., 2012; Reynolds et al., 2011). Raws li saum toj no, tsis yog tsuas yog kev sib txuas ntawm caj ces, tab sis kev tsis sib haum xeeb ntawm Notch signaling nyob rau hauv cov kab mob autoimmune ua rau cov kab mob mus rau hauv cov kab mob autoimmune. Muab cov receptors, ligands thiab txawm tias cov enzymes tseem ceeb hauv Notch signaling tau cog lus rau cov phiaj xwm tshuaj, kev tshawb nrhiav kev txhais lus ntxiv uas tsom rau cov ntsiab lus-raws li kev tswj hwm los ntawm Notch, tshwj xeeb tshaj yog rau T hlwb hauv cov kab mob autoimmune, yuav tsum muaj kev ntsuam xyuas ntxaws rau qhov tshwj xeeb Notch receptor-ligand khub uas. pab txhawb rau qhov tsis txaus ntseeg Th1 / Th17 autoimmune teb. Qhov kawg tab sis tsis kawg, qhov tshwm sim ntawm caj ces ntawm Notch signaling tseem tsis tau paub ntau hauv cov kab mob autoimmune. Feem ntau ntawm kev txheeb xyuas cov caj ces sib txawv raws li Notch signaling tau muab faib rau hauv cov cheeb tsam uas tsis yog coding (Table 1), uas qhia tau hais tias cov noob caj noob ces sib haum xeeb los ntawm kev tswj hwm ntawm DNA, tab sis tsis txhob cuam tshuam nrog kev txhais lus. Yog li ntawd, txoj cai zoo los yog tsis zoo ntawm Notch signaling yuav tsum tau soj ntsuam ntxiv nrog cov txheej txheem siab, xws li CRISPR-Cas system-ua genome kho, thiab cov kev cai tshwj xeeb ntawm tes yuav tsum tau txiav txim siab thaum lub sij hawm ntsuam xyuas (Stewart li al. , 2020).
Mitochondria-centric metabolism-uas cuam tshuam cov noob hauv autoimmunity
Ntawm ntau pua qhov kev pheej hmoo loci pom nyob rau hauv cov kab mob autoimmune, muaj cov noob muaj feem xyuam rau kev ua haujlwm mitochondrial thiab cellular metabolism. Piv txwv li, C4orf52 hauv RA thiab CMC1 hauv AS encode cov khoom ntawm mitochondrial kev txhais lus tswj kev sib dhos nruab nrab ntawm cytochrome c oxidase (MITRAC) (Ellinghaus li al., 2016; Okada et al., 2014; Timón-Gómez, 20 thiab ). Xws li SNPs qhia txog dysregulated electron thauj nyob rau hauv lub puab daim nyias nyias ntawm mitochondria, thiab tom ntej no mitochondrial hyperpolarization thiab impaired ATP synthesis tuaj yeem ua rau ROS ntau lawm, metabolic kev hloov pauv, thiab qhov tsis zoo rau kev mob ntawm tes tuag (McGarry li al., 2018). Txhawm rau tham txog lub luag haujlwm pathogenic ntawm mitochondria malfunction nyob rau hauv cov kab mob autoimmune, peb yuav tsom mus rau mitochondria-centric ROS ntau lawm thiab metabolic cuam tshuam thaum lub sij hawm tus kab mob loj hlob thiab metabolic-txog kev cai ntawm inflammatory teb nyob rau hauv autoimmunity, xws li RA thiab SLE-koom nrog pathological txheej txheem. Nyob rau hauv ntau yam mob, cov tsub zuj zuj ntawm ROS ua rau oxidative kev nyuaj siab. Feem ntau, ROS raug suav hais tias yog tus kws kho mob uas muaj kev sib haum xeeb, uas ua rau mob hnyav dhau los ntawm ntau qhov sib npaug. Ua ntej, ROS tuaj yeem txhawb kev ua kom muaj kev cuam tshuam ntawm cov teeb liab, xws li TNF-induced NF-κB activation (Blaser li al., 2016). Thib ob, ROS tuaj yeem ua haujlwm kho kom haum rau oxidation ntawm cov ntsiab lus ntawm tes, suav nrog cov neutrophilic mitochondrial DNA uas ua rau muaj txiaj ntsig zoo rau hom I IFN ntau lawm hauv SLE pDCs (Caielli li al., 2016; Lood et al., 2016). Thib peb, mitochondria dysfunctional nyob rau hauv oxidative kev nyuaj siab yog txuam nrog reprogrammed metabolic profiles ntawm lub cev tiv thaiv kab mob nyob rau hauv cov kab mob, uas zoo sib cuam tshuam nrog lub zos inflammatory cheeb tsam thiab modulate inflammatory phenotypes ntawm lub cev tiv thaiv kab mob (Huang thiab Perl, 2018). Muab cov ntaub ntawv pov thawj ntawm cov txheej txheem metabolic- tswj kev mob hauv cov kab mob autoimmune, lub hom phiaj reprogrammed metabolic profiles tau raug suav tias yog ib qho kev cog lus kho mob rau kev kho kab mob autoimmune.
cistanche cov txiaj ntsig rau txiv neej-ua kom muaj zog tiv thaiv kab mob
Glycolysis, oxidative phosphorylation, thiab ROS hauv RA thiab SLE T hlwb
Txawm hais tias cov piam thaj metabolism yog ib qho ntawm lub zog loj hauv lub cev tiv thaiv kab mob, cov txheej txheem metabolic hauv qab no muaj ntau haiv neeg, xa mus rau glycolysis, oxidative phosphorylation, thiab pentose phosphate pathway. Glycolysis (los yog aerobic glycolysis) thiab oxidative phosphorylation tsim ATP los txhawb lub cev tiv thaiv kab mob, tab sis ob txoj hauv kev yog polarized rau hauv ob qho kev taw qhia los tswj hwm qhov sib txawv phenotypes ntawm lub cev tiv thaiv kab mob (O'Neill li al., 2016). Feem ntau, nce glycolysis yog txuam nrog inflammatory kab mob ntawm lub cev, thiab oxidative phosphorylation yog txuam nrog anti-inflammatory los yog non-inflammatory phenotypes. Hauv T hlwb, kev sib koom ua ke ntawm cov txheej txheem metabolic thiab T cell ua haujlwm nyob rau hauv cov subsets sib txawv los yog sib txawv ua kom lub xeev tau kawm ntau (Saravia li al., 2020). Hauv luv luv, glycolysis-featured Th1 thiab Th17 hlwb kuj xav tau ib txoj hauv kev glycolytic rau kev sib txawv, thiab FOXP3 qhia hauv Treg hlwb tswj kev ua haujlwm ntawm mitochondrial oxidation siab thiab qis glycolysis metabolism. Hauv cov neeg mob SLE, T hlwb nthuav tawm cov piam thaj ntau dua piv nrog cov T hlwb los ntawm cov tib neeg noj qab haus huv (Doherty li al., 2014; Yin et al., 2015). Glucose uptake yog kho los ntawm glucose transporters, thiab cov kev tshawb fawb zoo tshaj plaws glucose transporter, GLUT1, tau qhia ntau heev hauv SLE T hlwb (Koga li al., 2019). Interestingly, cov nas tshaj qhia GLUT1 txhim kho lupus-zoo li phenotypes (Jacobs li al., 2008), xws li autoantibody ntau lawm thiab kev tiv thaiv kab mob hauv lub raum cov ntaub so ntswg, uas qhia txog lub luag haujlwm ntawm kev txhim kho cov piam thaj metabolism. Lub caij no, ob qho tib si nce oxidative phosphorylation thiab nce glycolysis tus nqi tau pom nyob rau hauv SLE T hlwb (Doherty li al., 2014; Yin et al., 2015), tab sis xws li cov piam thaj ntau ntxiv tsis tuaj yeem tsim ATP thiab ua rau ATP-depriving. Cov xwm txheej hauv SLE T hlwb, uas yog ib feem ntawm qhov tseem ceeb oxidative kev nyuaj siab hauv SLE pathogenesis uas mitochondria hyperpolarization tso nyiaj rau kev ua tsis tiav ntawm ATP tiam thiab txhawb kev tsim khoom ntawm ROS (Perl, 2013). Tsis tas li ntawd, kev sib sau ntawm ROS tuaj yeem tshwm sim los ntawm kev cuam tshuam ROS-neutralizing system, antioxidant-glutathione, thiab NADPH los ntawm txoj kev pentose phosphate, hauv cov neeg mob SLE (Gergely li al., 2002; Perl et al., 2015). Yog li, nce glycolysis tuaj yeem txhawb Th1 lossis Th17 qhov sib txawv hauv SLE cov neeg mob raws li kev tshawb pom yav dhau los. Tsis tas li ntawd, oxidative kev ntxhov siab tshwm sim los ntawm kev sib sau ntawm ROS kuj tuaj yeem ua rau hloov pauv T-cell cov lus teb, qhov uas muaj zog oxidative kev ntxhov siab cuam tshuam nrog kev txhim kho Th1 / Th17 cov lus teb thiab kev mob SLE (Scavuzzi li al., 2018). Lub ntsiab lus ntawm kev txhawb nqa ntawm Th17 qhov sib txawv los ntawm ROS hauv ntau yam kev tiv thaiv kab mob autoimmunity tau raug sau tseg yav dhau los (Peng li al., 2021). Yog li, nrog rau kev tswj hwm glycolysis thiab redox signaling hauv SLE T hlwb, Th1 / Th17 tseem ceeb T cell teb tuaj yeem tau txais los ntawm cov txheej txheem metabolic rewired. T hlwb hauv RA cov neeg mob kuj raug kev txom nyem ATP tsis txaus, uas tuaj yeem tshwm sim los ntawm kev puas tsuaj mitochondrial biogenesis uas tshwm sim los ntawm qhov tsis muaj nuclease MRE11A hauv RA T hlwb (Li li al., 2016b; Li et al., 2019b). Lwm lub tswv yim rau ATP deprivation yog rewired qabzib metabolism hauv RA T hlwb. Hauv kev sib piv rau kev txhim kho glycolysis hauv SLE T hlwb, RA T hlwb qhia tias tsis muaj glycolytic metabolism profile (Yang li al., 2013; Yang et al., 2016). Qhov tseeb, cov piam thaj metabolism tseem siv los ntawm RA T hlwb, tab sis glycolysis tau hloov mus rau pentose phosphate txoj hauv kev los ntawm kev qhia tsis txaus ntawm glycolytic enzyme 6-phosphofructo-2-kinase (PFKFB3) thiab upregulation ntawm qabzib{{43} }phosphate dehydrogenase (G6PD) (Yang et al., 2013). Yog li ntawd, hyperproduction ntawm NADPH los ntawm txoj kev pentose phosphate neutralizes ROS hauv RA T hlwb, thiab redox-sensitive kinase, ataxia telangiectasia mutated (ATM), tseem tsis ua haujlwm thaum lub sij hawm T cell proliferation, uas tso cai rau RA T hlwb kom hyper-proliferate bypassing. lub G2/M cell voj voog checkpoint thiab ntxiv sib txawv rau Th1 thiab Th17 hlwb (Yang li al., 2016). Yog li, cov piam thaj metabolism txhawb nqa RA pathogenesis ntawm pentose phosphate txoj hauv kev kho mob inflammatory T-cell teb.
Metabolic abnormality nyob rau hauv lwm lub hlwb tiv thaiv kab mob autoimmunity
Nyob rau hauv ob qho tib si RA thiab SLE cov kab mob ntsig txog, dhau li T hlwb, cov kab mob metabolic ntawm macrophages thiab lwm lub hlwb tsis paub ntau. Nyob rau hauv ib puag ncig inflammatory, activated macrophages hloov mus rau dysfunctional mitochondria thiab txhawb glycolysis los ntsuas kom txaus ATP ntau lawm (Kelly thiab O'Neill, 2015). Lub caij no, qhov txo qis ntawm oxidative phosphorylation yuav ua rau cov metabolites hauv tricarboxylic acid (TCA) lub voj voog sib sau, uas tuaj yeem hloov kho cov kab mob inflammatory, xws li succinate-stabilized HIF1 rau Il1b qhia (Murphy thiab O'Neill, 2018). Macrophages lossis monocytes tuaj yeem ua raws li cov txheej txheem metabolic zoo sib xws hauv cov kab mob autoimmune. Piv txwv li, hauv RA synovium, tsis tsuas yog enriched lactate qhia txog qib siab ntawm glycolysis hauv cov ntaub so ntswg (Fujii li al., 2015; Haas et al., 2015; Kim et al., 2014), tab sis tsub zuj zuj ntawm intermediate metabolites nyob rau hauv cov ntaub so ntswg. TCA lub voj voog kuj pom tseeb hauv RA synovial kua (Kim li al., 2014). Txawm hais tias yuav tsum tau txiav txim siab macrophage-specific metabolic profile hauv RA synovium, autocrine lossis paracrine ntawm succinate tau raug cuam tshuam los kho cov kab mob IL-1 ntau lawm hauv RA synovial macrophages ntawm macrophage-expressed succinate receptor, GRP91 (Littlewood-Evans) et al., 2016). Yog li ntawd, metabolic reprogramming nyob rau hauv cov ntaub so ntswg inflammatory profoundly cuam tshuam lub pathogenic lub luag hauj lwm ntawm macrophages nyob rau hauv cov kab mob autoimmune, tshwm sim los ntawm intrinsic los yog extrinsic metabolic signals (Liang li al., 2020). Ntxiv metabolic characterization ntawm macrophages thiab lwm lub cev tiv thaiv kab mob nyob rau hauv cov kab mob autoimmune yuav tsum qhia kom tob rau peb nkag siab txog lub cev tiv thaiv kab mob metabolic mechanisms.
Yav tom ntej foundations: nkag siab autoimmunity ntawm ib leeg-cell theem
Ib leeg-cell sequencing ntawm mRNA qhia theem rau txhua tus neeg ntawm tes hauv cov mob inflammatory muab lub sijhawm tshwj xeeb los txiav cov kab mob phenotypes hauv cov kab mob autoimmune ntawm kev daws teeb meem tsis tau pom dua. Ib leeg cell qhia profiles tuaj yeem pab txheeb xyuas cov kab mob tshwj xeeb ntawm cov kab mob tshwj xeeb hauv cov ntaub so ntswg thiab kev ncig nrog rau kev nthuav dav ntawm cov kev sib txuas lus sib txuas ntawm cov xovtooj ntawm tes. Ib qho piv txwv ua tau zoo ntawm kev tshawb nrhiav kab mob autoimmune pathogenesis nrog scRNA-seq yog nyob rau hauv RA synovial cov ntaub so ntswg. Xyoo 2019, Lub Koom Haum Saib Xyuas Kev Noj Qab Haus Huv Kev Noj Qab Haus Huv (Rheumatoid Arthritis thiab Systemic Lupus Erythematosus) (AMP RA/SLE) Consortium tau tshaj tawm lawv cov kev tshawb nrhiav ntau qhov chaw ntawm cov yam ntxwv ntawm cov cellular Cheebtsam hauv RA synovial cov ntaub so ntswg (Zhang li al., 2019a). Txoj kev tshawb no tau nthuav tawm qhov kev npaj txhij txog inflammatory phenotypes ntawm lub cev tiv thaiv kab mob hauv zos thiab fibroblasts, qhov twg HLA-DRAhi subliming fibroblasts, tab sis tsis yog monocytes, yog ib qho ntawm IL6 loj qhia cov xov tooj ntawm tes hauv RA synovial cov ntaub so ntswg, thiab CD8+ T hlwb, tab sis tsis yog CD4+ T hlwb, yog cov koom haum loj rau IFNG qhia cov hlwb hauv RA synovial cov ntaub so ntswg. Lub caij no, qhov nthuav dav THY1 (CD90) + HLA-DRAhi subliming fibroblasts, IL1B + pro-inflammatory monocytes, ITGAX + TBX21+ autoimmune-associated B hlwb, thiab PDCD1+ peripheral pab T hlwb thiab follicular pab T hlwb tau txheeb xyuas los ntawm scRNA-seq raws li RA-kev koom tes ntawm tes sib piv rau cov neeg mob osteoarthritis cov ntaub so ntswg synovial (Zhang li al., 2019a). Cov kev tshawb pom pom ntawm RA-txuas nrog cov xov tooj ntawm tes tsis tau tsuas yog ua kom muaj lub luag haujlwm yav dhau los txheeb xyuas cov kab mob ntawm peripheral pab T hlwb hauv RA synovium (Rao li al., 2017) tab sis kuj tau coj cov kev tshawb fawb hauv qab no mus nrhiav RA pathogenesis kho los ntawm Notch-induced subliming fibroblasts. thiab pathogenic HBEGF + monocyte subset (Kuo et al., 2019; Wei et al., 2020). Hauv qhov no, qhov kev vam meej ntawm scRNA-seq tsom xam rau RA synovial cov ntaub so ntswg tuaj yeem siv dav rau cov ntaub so ntswg inflammatory hauv cov kab mob autoimmune, thiab cov cuab yeej bioinformatics siab heev tuaj yeem siv los txheeb xyuas cov kev taw qhia tseem ceeb uas muaj feem cuam tshuam rau kev tsim thiab kev ua haujlwm ntawm Cov kab mob sib txuas ntawm tes (Armingol li al., 2021). Ob peb xyoos dhau los, cov kab mob autoimmune tau txheeb xyuas los ntawm txoj hauv kev ntawm ib leeg-cell qhia profile (Baglaenko li al., 2021). Cov kev tshawb fawb ntawm tus kheej hom kab mob tau ua tiav qee yam kev vam meej xws li kev txheeb xyuas cov kab mob sib txuas nrog cov kab mob hauv lub cev. Txawm li cas los xij, piav qhia txog cov kab mob sib txawv ntawm cov kab mob tshwj xeeb phenotypes thoob plaws ntau yam kab mob autoimmune tseem nyuaj vim qhov nyuaj ntawm kev sib koom ua ke cov ntaub ntawv sib txawv los ntawm ntau qhov chaw (Stuart thiab Satija, 2019). Lwm qhov kev cia siab rau kev soj ntsuam cov ntaub ntawv ntawm ib leeg yog ib leeg-cell immunome metabolism (Artyomov thiab Van den Bossche, 2020). Nyob rau hauv cov pa metabolism hauv profileing rau lub cev tiv thaiv kab mob, cov metabolites yog ntsuas nyob rau hauv tej cell pejxeem, uas yuav tsum tau ib tug loj npaum li cas ntawm purified hlwb nyob rau hauv tej yam hom. Txawm li cas los xij, qhov txwv me me thiab cov qauv ntawm cov ntaub so ntswg xav tau lwm cov tswv yim sim los ua tus yam ntxwv ntawm cov kab mob metabolic ntawm lub cev tsis muaj zog hauv cov ntaub so ntswg los ntawm cov neeg mob autoimmune. Nrog rau kev ua tiav ntawm cov txheej txheem metabolic los ntawm cov ntaub ntawv transcriptome hauv lub cev tiv thaiv kab mob, cov txheej txheem tam sim no rau transcriptome-based metabolic tsom xam yog tsim los ntawm txoj hauv kev-raws li kev txheeb xyuas lossis flux tshuav nyiaj li cas (FBA)-raws li txoj hauv kev, uas tau ua rau kev soj ntsuam tshwj xeeb. Txoj hauv kev metabolic lossis lub ntiaj teb tus yam ntxwv ntawm kev sib tham sib txuas nrog cov metabolic network, raws li (Artyomov thiab Van den Bossche, 2020). Zoo siab heev, ob qho tib si kev soj ntsuam raws li txoj hauv kev thiab kev ntsuas qhov sib npaug tau ua tiav rau kev tshawb nrhiav scRNA-seq hauv cov kab mob cuam tshuam txog kev tiv thaiv kab mob metabolic (Miragaia li al., 2019; Wagner li al., 2021). Yog li ntawd, kev sib txuas ib leeg-cell qhia profiles thiab cov cuab yeej bioinformatics siab heev tuaj yeem yog txoj hauv kev muaj zog rau kev txiav cov txheej txheem metabolic ntawm cov hlwb hauv cov kab mob autoimmune.
Cov kev pheej hmoo ntawm caj ces tau raug txheeb xyuas nyob rau hauv ntau yam kab mob autoimmune, ntawm qee qhov gene loci encode Cheebtsam ntawm ntau txoj hauv kev nrog cov haujlwm tshwj xeeb hauv kev tiv thaiv kab mob. Qhov txawv txav ntawm txoj hauv kev no cuam tshuam nrog kev ua rau tus kheej ua siab ntev thiab ua rau mob ntau dhau, ua rau muaj kab mob, xws li HLA alleles thiab ERAP1/2- hais txog kev nthuav qhia antigen, thiab IFNAR1- ntsig txog hom I IFN txoj kev. Lub caij no, qee qhov kev hloov caj ces tsis tuaj yeem ncaj qha mus rau autoimmunity thiab o. Txoj hauv kev tom qab cov kev hloov pauv no tau ua haujlwm cuam tshuam nrog cov kab mob autoimmune nrog kev paub ntau ntxiv, xws li Notch signaling thiab metabolic pathway-related immuno-pathogenesis. Nyob rau hauv lub neej yav tom ntej, annotating lub variants uas tsis paub functionality nyob rau hauv cov txheej txheem pathological yuav muab ib tug in-deb dissection ntawm predisposed kab mob-nrhiav tej yam kev mob nrog kho kev pom.
