Thaum nws tsis tshwm sim tias feem pua ​​​​ntawm TEX nce nrog cov kab mob hnyav (Cov duab ntxiv 6C), lossis raws li cov tsiaj muaj hnub nyoog lupus (6), tag nrho cov naj npawb ntawm infiltrating T hlwb nce nrog cov kab mob hnyav hauv cov qauv no thiab tib neeg cov neeg mob. Yog li, tej zaum yuav muaj ib qho taw tes tshaj qhov kev qaug zog tuaj yeemtsis tswj tus kab mob lawm. Kev ua haujlwm ua ntej tau qhia tias cov neeg mob uas muaj cov ntshav peripheral CD8 ntxiv rau TEX kos npe tsis tshua muaj tshwm sim piv nrog cov tsis muaj qhov kos npe no (52). Txawm li cas los xij, dab tsi tshwm sim nyob rau theem ntawm lub hom phiaj ntawm lub cev tseem yog cov lus nug tseem ceeb, thiab nws yuav nthuav, hauv kev ua haujlwm yav tom ntej, los txiav txim seb qhov feem pua ​​​​ntawm cov hlwb puas hauv biopsy tuaj yeem cuam tshuam nrog cov txiaj ntsig ntawm cov kab mob.

Raws li cov kev tshawb fawb muaj feem xyuam, cistanche yog ib txwm suav tshuaj ntsuab uas tau siv rau ntau pua xyoo los kho ntau yam kab mob. Nws tau raug tshawb fawb pov thawj tias muaj cov tshuaj tiv thaiv kab mob, tiv thaiv kev laus, thiab antioxidant zog. Cov kev tshawb fawb tau pom tias cistanche muaj txiaj ntsig zoo rau cov neeg mob uas muaj kab mob raum. Cov khoom xyaw nquag ntawm cistanche paub tias txo qhov mob, txhim kho lub raum ua haujlwm thiab rov ua kom lub raum tsis zoo. Yog li, kev sib koom ua ke cistanche hauv txoj kev npaj kho mob raum tuaj yeem muab txiaj ntsig zoo rau cov neeg mob hauv kev tswj hwm lawv tus mob. Cistanche pab txo qis proteinuria, txo qis BUN thiab creatinine qib, thiab txo qhov kev pheej hmoo ntawm lub raum puas. Tsis tas li ntawd, cistanche kuj pab txo cov roj cholesterol thiab triglyceride uas tuaj yeem ua rau muaj kev phom sij rau cov neeg mob uas muaj kab mob raum.

Nyem rau ntawm Cistanche Tubulosa Ntxiv

【Yog xav paub ntxiv: david.deng@wecistanche.com / WhatApp:86 13632399501 】

Nws yuav yog ib qho tseem ceeb los txheeb xyuas cov txheej txheem uas txhua yam ntawm cov cell uas muaj feem cuam tshuam thiab cov xwm txheej raug cuam tshuam los ntawm lub raum thiab yuav ua li cas cov kev kho tshiab thiab tshiab tuaj yeem cuam tshuam rau lawv. Nws cia siab tias txoj haujlwm no yuav tso cai rau peb thiab lwm tus los tsom rau cov neeg T-cell sib txawv tshwj xeeb, yog li qhib txoj kev kho tshiab.

Cov txheej txheem

Tsiaj txhu. C57BL/6 nas tau yuav los ntawm Jackson Laboratory. MRL / lpr nas tau pib los ntawm Jackson Laboratory thiab tau khaws cia hauv peb lub chaw kuaj mob. Fc R2B–/–.Yaa nas tau txais los ntawm Silvia Bolland (National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland, USA) thiab tau khaws cia hauv peb lub chaw kuaj mob. Cov nas tau muaj hnub nyoog thiab cov proteinuria raug ntsuas ua ntej kev txi, raws li sau tseg hauv Daim Ntawv Ntxiv 2.

Kev sib cais ntawm T cell ntawm lub raum thiab tus po. T hlwb raug cais raws li tau piav ua ntej (6). Hauv luv luv, tom qab kev txi, spleens raug tshem tawm, thiab cov tsiaj tau perfused nrog 40 mL ntawm HBSS kom txog thaum ua tiav blanching ntawm daim siab thiab lub raum tshwm sim. KITs raug cais tawm siv Octodissociator (Miltenyi Biotec) nyob rau hauv muaj 1600 Kunitz units/mL collagenase D (Roche Diagnostics) thiab 0.2 mg/mL DNAse IV (MilliporeSigma) rau 30 feeb ntawm 37 degree. RBC lysis tau ua tiav, thiab cov hlwb raug lim los ntawm cov xov tooj ntawm tes (100 μM nylon; Falcon, Corning). Splenocytes raug cais tawm siv kev sib cais ntawm 2 frosted iav slides thiab lim los ntawm 70 μm mesh lim tom qab RBC lysis.

Cells raug stained raws li tau piav qhia yav dhau los (6) nrog lub vaj huam sib luag hauv qab no: anti-CD8 (Lyt-2/TIB-105, Pac-Blue, tsim hauv tsev), anti-CD4 (GK{{9}) }}.5, hauv PE, yuav los ntawm BioLegend), thiab anti-CD90.2 (Thy1.2/30H12, Al488, tsim hauv tsev) rau MRL/lpr nas lossis anti-CD90.2 (Thy1.2/30H12 , Al647, tsim nyob rau hauv-tsev) rau Fc R2B–/–.Yaa Dab BV510 (Tonbo) tau siv los tshem tawm cov hlwb tuag. Rau tag nrho cov "hauv-tsev" cov tshuaj tiv thaiv, hybridoma clones yog muag thiab cov tshuaj tiv thaiv raug ntxuav raws li tau piav qhia (6).

T hlwb raug txheeb xyuas siv FACSAria (BD Biosciences). Tom qab txheeb xyuas, cov hlwb raug ntxuav ob zaug nrog 2 feem pua ​​BSA hauv PBS. Tom qab ntawd anti-CD45 HTO reagents tau ntxiv ntawm 1:50 dilution rau txhua tus qauv txheeb. Anti-CD45 TotalSeq-A0096 30-F11 (BioLegend) tau siv rau hauv Main-Seq cohort, thiab TotalSeq-C0096 30-F11 (BioLegend) tau siv rau ob pawg TCR-Seq. Tom qab HTO staining hlwb raug ntxuav ob zaug hauv 2 feem pua ​​BSA hauv PBS.

Kev npaj tsev qiv ntawv thiab RNA-Seq ntawm T cells. Cells raug suav thiab thauj mus rau hauv 10x Genomics Chromium system raws li cov chaw tsim khoom cov lus qhia. Gene qhia, TCR, thiab antibody hashtag / feature barcode cov tsev qiv ntawv tau tsim, lawv qhov zoo tau raug soj ntsuam los ntawm Agilent TapeStation High Sensitivity D5000 Screentape, thiab lawv cov nyiaj tau raug suav nrog KAPA Cov Tsev Qiv Quantification Kit rau Illumina Platforms. Rau lub Main-Seq cohort, 3PrimeV2 tsev qiv ntawv tau siv; lub tsev qiv ntawv barcode feature tau tsim tawm raws li New York Genome Center raws tu qauv (56). Rau TCR-Seq cohorts, 5PrimeV1 cov tsev qiv ntawv tau txais los ntawm 10x Genomics. Rau hashtagging, peb ua raws li "feature barcode" cov lus qhia los ntawm cov khw. Cov tsev qiv ntawv tau sib sau ua ke thiab ua tiav ntawm NovaSeq (Illumina Biosciences). FASTQ cov ntaub ntawv tau tsim thiab ua raws li tus nas siv genome mm10 nrog Cell Ranger 5.0.0 (10x Genomics) los tsim cov noob-cell thiab cell-antibody suav matrix.

scRNA-Seq cov ntaub ntawv ua haujlwm. Cov 10x cov ntaub ntawv nyoos los ntawm txhua tus qauv tau demultiplexed, thiab FASTQ cov ntaub ntawv tau tsim los ntawm "ceev" Cell Ranger pipeline (v5.0.0, 10 x Genomics). Cell Ranger "suav" tau siv los ua kom cov ntawv nyeem mus rau mm10 siv genome, thiab mRNA cov ntawv teev lus, thiab HTO cov cim cim molecular (UMI) cov lus tau tsim. Cov ntaub ntawv nyoos barcode matrix tsim los ntawm Cell Ranger pipeline tau siv ntxiv rau kev ntsuas qis qis siv Seurat pob (v4.0.0) (12) hauv R (v3.4.3).

Thawj tswj kev ua tau zoo thiab ua tiav. Cov hlwb uas qhia tsawg dua 200 cov noob, lossis nrog ntau dua 10 feem pua ​​​​ntawm UMIs uas tau teeb tsa rau mitochondrial DNA, raug lim tawm. Cov rooj HTO tau ntxiv rau cov ntaub ntawv teeb tsa thiab normalized los ntawm qhov chaw nruab nrab-log piv txoj kev siv "NormalizeData" muaj nuj nqi. Kev suav HTO ib txwm siv los txiav txim siab yog tias txhua lub gel hlaws-hauv-emulsion muaj ib lub xov tooj ntawm tes uas siv Seurat "MULTIseqDemux" muaj nuj nqi thiab phau ntawv tshuaj xyuas cov hlwb, qhov twg lub xovtooj tau suav tias yog ib qho singlet yog qhov qhia ntawm ib qho HTO suav nrog ntau dua. ntau dua 70 feem pua ​​​​ntawm tag nrho HTO qhia nyob rau hauv lub cell; txwv tsis pub, lub xovtooj ntawm tes tau suav tias yog ib qho doublet thiab tshem tawm. Gene qhia qhov muaj nuj nqis rau txhua lub xovtooj tau teev2 - normalized siv "NormalizeData" muaj nuj nqi, qhov twg cov kev qhia ntawm cov noob tau zoo li qub rau tag nrho cov kev qhia ntawm cov noob hauv lub cell thiab ntsuas los ntawm qhov ua tau ntawm 10,{{8 }}. UMI, mitochondrial cov ntsiab lus, thiab hemoglobulin noob thiab ribosomal gene cov ntsiab lus tau "regressed" siv Seurat's "ScaleData" muaj nuj nqi.

Dimensionality txo thiab pawg. Cov noob sib txawv tau raug kuaj pom siv "mean.var.plot" txoj hauv kev "FindVariableFeatures" muaj nuj nqi nrog kev txiav tawm, uas suav cov ntsiab lus qhia thiab dispersion (log[variance/mean]) rau ib noob, ua raws li kev faib cov ntaub ntawv rau hauv 20 bins. raws li lawv lub ntsiab lus qhia. Cov noob sib txawv tau raug xaiv raws li z-scored dispersion nyob rau hauv txhua lub bin. Cov noob sib txawv no tau siv rau kev txo qhov loj me raws li kev txheeb xyuas qhov tseem ceeb (PCA) siv "RunPCA" muaj nuj nqi. "ElbowPlot" tau siv los ntsuas thawj 50 lub hauv paus tseem ceeb, thiab cov khoom tseem ceeb uas suav nrog qhov sib txawv loj tshaj plaws hauv cov ntaub ntawv tau raug xaiv rau UMAP qhov kev txo qis thiab kev txheeb xyuas pawg ntxiv.

Txhawm rau txheeb xyuas cov pab pawg sib txawv ntawm cov hlwb, kev tsis saib xyuas pawg tau ua tiav siv "FindClusters" muaj nuj nqi, uas suav cov k-cov neeg nyob ze ze tshaj plaws raws li qhov sib txawv ntawm cov noob qhia hauv txhua lub hlwb, yog li tsim cov duab sib koom ze tshaj plaws hauv zej zog siv Louvain algorithm. Txhawm rau kom tsis txhob muaj pawg ntau dhau, peb tau sim cov kev daws teeb meem sib txawv ("res"), xws li los ntawm 0.1 mus rau 2 increments ntawm 0.1, thiab cov kev sib koom ua ke tau soj ntsuam thiab pom tau siv "Cluster " (v 0.4.3) (57). Qhov kev daws teeb meem zoo tshaj plaws tau txiav txim siab raws li kev sib cais txuas ntxiv ua ntej "over clustering" raws li pom los ntawm kev nce crossover ntawm pawg. Cov kev daws teeb meem qis qis tau raug txiav txim siab raws li kev tshuaj xyuas ntawm txhua lub hlwb nyob rau hauv tag nrho pawg, thaum lub siab daws teeb meem pawg tau txhais tias yog pawg ntawm cov neeg uas tau xaiv ua ntej, piv txwv li, CD4 ntxiv, CD8 ntxiv, lossis Treg hlwb yav dhau los tau txhais hauv peb qhov kev daws teeb meem qis. tsom xam. Raws li cov kev soj ntsuam no peb xaiv cov kev daws teeb meem 0.9, 1.4, {{20}}.6, thiab 0.9, ntsig txog, rau Main-Seq, CD4 ntxiv , CD4 ntxiv rau Treg sub, thiab CD8 ntxiv los ntawm pawg 1 thiab kev daws teeb meem 0.7 rau merged cohort CD8 ntxiv rau T hlwb. Cell pawg tau pom pom siv UMAP qhov seem txo cov phiaj xwm.

Qhov "FindAllMarkers" muaj nuj nqi nrog kev teeb tsa ua ntej tau siv los nrhiav DEGs hauv txhua pawg, piv nrog rau lwm pawg, siv Wilcoxon qeb-sum test nrog cov noob kuaj pom tsawg kawg ntawm 10 feem pua ​​​​ntawm cov hlwb, yam tsawg kawg nkaus ntawm 0.25 qhov nruab nrab lub log hloov pauv, thiab qhov tsawg kawg nkaus ntawm 0.01 Bonferroni-kho P tus nqi.

Kev txheeb xyuas kev sib raug zoo. Rau kev sib koom ua ke UMAP hauv daim duab 8, 3 tus neeg ua haujlwm ntawm nws tus kheej tau sib koom ua ke siv Harmony (58) nrog rau kev teeb tsa tsis raug.

Kev ntsuas lub voj voog ntawm tes. Qhov "CellCycleScoring" muaj nuj nqi hauv Seurat tau siv los suav cov G1, G2 / M, thiab S theem cim qhia cov qhab nia hauv txhua lub xov tooj siv cov qhab nia zoo uas tau piav qhia yav dhau los (59). Tus naj npawb ntawm cov hlwb txiav txim siab nyob rau hauv G1, G2 / M, lossis S theem tau suav nrog hauv ib pawg, thiab kev sib txawv ntawm kev faib tawm tag nrho raug ntsuas los ntawm χ2 tsom xam.

GSEA thiab nthuav qhia daim ntawv qhia. P qhov tseem ceeb rau GSEA tau txiav txim siab siv Wilcoxon xeem rau kev tshaj tawm cov noob npe kos npe raws li tau hais tseg hauv Cov Lus Ntxiv 1. Siv "ggplot2" hauv Seurat, –log10 P qhov tseem ceeb tau npaj rau hauv UMAPs.

Ntxiv analytics. Bar plots, dot plots, and PCA plots are builded using ggplot2 in R. Heatmaps are generated using the "heatmap" function in R.

TCR data analysis. TCR cov ntaub ntawv tau ua tiav siv cell ranger vdj nrog-reference {{{0}}} refdata-cellranger-vdj-GRCm38-alts-ensembl-3.1.0 los sib sau TCR thiab chains thiab txiav txim siab clonotypes . Cells nrog 1 tsim TCR (thiab ) tau khaws cia rau kev soj ntsuam ntxiv, thaum tsis muaj TCR chains raug cais tawm. Clonal T hlwb tau txhais tias yog cov hlwb uas qhia TCR- thiab - receptors nrog CDR3 zoo ib yam ntawm qib nucleotide.

Pseudotime trajectory tsom xam. Kev tsom xam kev siv cov Seurat-processed gene suav tau ua los ntawm Monocle 3 (version 0.1.3) rau qauv CD4 ntxiv rau T cell sib txawv. Cov duab rov qab embedding txoj kev DDRTree tau siv los txo qhov loj me, cov hlwb raug xaj raws ib txoj hauv kev siv "orderCells" muaj nuj nqi, thiab cov trajectory tau pom nyob rau hauv qhov chaw txo qis.

Ua qauv CD8 ntxiv rau T cell sib txawv, peb siv Slingshot nrog "pib. clubs" teem ua B6 / naive pawg. Cov hlwb raug txiav txim los ntawm Slingshot pseudo lub sij hawm thiab pab pawg raws li Seurat pawg los npaj cov pawg neeg txoj hauv kev. Lub Slingshot trajectory kab mob tshwm sim tau npaj rau ntawm CD8 ntxiv rau ntawm tes Seurat UMAP.

TF regulatory network tsom xam. SCENIC v.1.1.2 workflow tau siv nyob rau hauv R los txheeb xyuas cov kev cai siv Seurat-ua tiav suav thiab pawg raws li kev kawm dhau los (60). Heatmaps tau tsim raws li tau piav qhia saum toj no.

Histologic qhab nia. Lub raum histology npaj thiab ntsuas tau ua raws li tau hais tseg dhau los (61).

Cov ntaub ntawv thiab cov ntaub ntawv muaj. Tag nrho cov kev soj ntsuam thiab kev pom pom tau ua tiav hauv R. Cov txheej txheem tshwj xeeb thiab kev tshuaj xyuas uas siv cov kev pab cuam Seurat luam tawm tau piav qhia hauv Cov Txheej Txheem Tshooj. Cov ntaub ntawv, metadata, thiab kev txheeb xyuas cov txiaj ntsig xws li kev txheeb xyuas pawg tau muab tso rau hauv National Center for Biotechnology Information's Gene Expression Omnibus (GSE197339).

Kev txheeb cais. Cov txheeb cais tau suav hauv R raws li tau teev tseg hauv cov ntu tshwj xeeb lossis GraphPad Prism los ntawm 1- txoj kev ANOVA nrog Tukey qhov kev sim rau ntau qhov kev sib piv, 2- txoj kev ANOVA nrog rov ntsuas dua, lossis χ2 tsom xam raws li tau hais tseg hauv cov lus dab neeg, nrog P tus nqi sawv cev yog *P < 0.05, **P < 0.{{10}}1, ***P < 0.001, ****P <0.0001. P <0.05 tau suav tias yog qhov tseem ceeb.

Kev pom zoo kawm. Txhua txoj haujlwm tau pom zoo los ntawm University of Pittsburgh's lossis Yale University's Institutional Animal Care and Use Committee.

Sau cov nyiaj pab

JST thiab MJS tau tsim txoj kev kawm. SS, MC, JST, thiab MJS tsim cov txheej txheem. JST thiab SS tau tshawb xyuas. JST thiab SS pom cov ntaub ntawv. JST thiab MJS tau txais nyiaj txiag. JST thiab MJS muab kev tswj xyuas qhov project. JST thiab MJS muab kev saib xyuas. JST thiab MJS tau sau cov qauv qub. JST, MJS, SS, thiab MC tau tshuaj xyuas thiab kho cov qauv.

Kev lees paub

Peb xav ua tsaug rau Minjung Kim rau nws txoj kev mob siab rau hauv chav kuaj, tso cai rau txoj haujlwm no ua tiav, thiab lees paub qhov kev pom tseem ceeb ntawm txoj haujlwm los ntawm Kevin Nickerson, Rachael Gordon, thiab Peter Lipsky thiab kev tshuaj xyuas tseem ceeb ntawm txoj haujlwm no los ntawm Fadi Lakkis thiab Warren. Shlomchik. Tsis tas li ntawd, peb xav ua tsaug rau University of Pittsburgh Single Cell Core thiab tshwj xeeb Tracy Tabib, uas tau pab ua tiav kev npaj tsev qiv ntawv thiab 10x Genomics thev naus laus zis.

Cov nyiaj tau txais los ntawm Lupus Research Alliance, Novel Research Grant (rau JST); NIH/National Institute of Arthritis thiab Musculoskeletal and Skin Diseases pub K08AR075056 (rau JST); thiab NIH/National Institute of Allergy and Infectious Diseases muab R01 AI137132 (rau MJS).

Chaw nyob sau ntawv mus rau:Jeremy S. Tilstra, 3500 Terrace Street, BST S705A, Pittsburgh, Pennsylvania 15261, USA. Xov tooj: 412.383.8861; Lossis mus rau Mark J. Shlomchik, W1052 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, Pennsylvania 15261, USA. Xov tooj: 412.648.8771.

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