Cov ntaub ntawv tshiab ntawm Homozygous Interferon Alpha / Beta Receptor Alpha Chain (IFNAR1) Deficiency Nrog Hemophagocytic Lymphohistiocytosis
Apr 17, 2023
(Saib Cov Lus Tshaj Tawm los ntawm Mogensen ntawm nplooj 140–3.)
Peb nthuav tawm ib rooj plaub ntawm qhov tsis txaus ntawm interferon-alpha / beta receptor alpha chain (IFNAR1) hauv tus menyuam uas muaj mob hnyav heev, pom tau tias yog qhov tshwm sim los ntawm kev txhaj tshuaj tiv thaiv kab mob nyob. Xws li pathologic hyperinflammation, ua kom tiav cov txheej txheem rau hemophagocytic lymphohistiocytosis, yog ib qho tshwm sim phenotype nrog inborn yuam kev ntawm hom I interferon tiv thaiv kab mob.
Hemophagocytic lymphohistiocytosis (HIVEL/T-LGL) yog ib hom kab mob tiv thaiv kab mob uas tsis tshua muaj feem cuam tshuam nrog kev tiv thaiv kab mob. Qhov tshwm sim ntawm HIVEL / T-LGL yog cuam tshuam nrog kev tsis sib haum xeeb ntawm lub cev tiv thaiv kab mob, uas yog tshwm sim los ntawm qhov txawv txav ntawm kev loj hlob thiab ua kom cov T cell. Qhov kev loj hlob txawv txav thiab kev ua kom tsis zoo no yuav ua rau T hlwb tawm tsam cov hlwb ib txwm nyob hauv lub cev, yog li ua rau kev ua haujlwm ntawm lub cev tsis muaj zog, yog li qhia qhov tseem ceeb ntawm kev tiv thaiv rau peb. Hauv peb lub neej niaj hnub, peb kuj yuav tsum tau saib xyuas kev txhim kho kev tiv thaiv. Cistanche tuaj yeem txhim kho kev tiv thaiv. Cov polysaccharides nyob rau hauv cov nqaij yuav tswj lub cev tiv thaiv kab mob ntawm tib neeg lub cev tiv thaiv kab mob, txhim kho cov kev nyuaj siab muaj peev xwm ntawm lub cev tiv thaiv kab mob, thiab txhim kho lub sterilization ntawm lub cev tiv thaiv kab mob.
Ntsiab lus.
IFNAR1; hom I interferon; HLH; inborn yuam kev ntawm kev tiv thaiv.
Hom I interferons (xws li IFN- thiab 13 IFN- subtypes) teeb liab los ntawm ib qho kev qhia ubiquitously qhia receptor uas muaj tsawg- thiab high-affinity subunits, IFNAR1 thiab IFNAR2. Hom I IFNs zoo nkaus li tseem ceeb rau kev tiv thaiv kab mob hauv mammalian, raws li kev tshawb fawb dav dav ntawm Ifnar1- cov nas tsis muaj peev xwm, tab sis lawv lub luag haujlwm meej hauv tib neeg yog tam sim no tsis paub tseeb [1].
Peb qhov kev tshawb pom ntawm kev ua tiav tib neeg IFNAR2 tsis muaj peev xwm nyob rau hauv tus menyuam uas muaj tus kab mob tuag taus thib ob rau kev txhaj tshuaj tiv thaiv kab mob measles thiab rubella (MMR) tau hais txog qhov tseem ceeb ntawm kev ua haujlwm tiv thaiv kab mob [2]. Txawm li cas los xij, nws tau tawm tsam tias qhov kev tshaj tawm tsis pom muaj tus kab mob kis tau yooj yim ua ntej MMR raug. Qhov phenotype ntawm tus kab mob no provoked los ntawm kev sib tw nrog kev txhaj tshuaj tiv thaiv kab mob hauv lub cev tau pom hauv 2 tus neeg mob uas tsis muaj IFNAR1, ob qho tib si zoo ib yam mus txog thaum txhaj tshuaj [3].
Txawm li cas los xij, kev txheeb xyuas tsis ntev los no ntawm IFNAR1 qhov sib txawv hauv 2 tus neeg mob uas muaj mob hnyav ua pa nyuaj ua pa mob coronavirus 2 (SARS-CoV-2) qhia txog qhov tseem ceeb ntxiv ntawm hom I IFNs hauv kev tiv thaiv kab mob rau ib txwm kis tau tus kab mob [4].
Hauv qhov kev tshawb fawb no, peb tau tshawb xyuas ib tus menyuam yaus hnub nyoog ib hlis uas tau mob hnyav tom qab txhaj tshuaj tiv thaiv MMR, suav nrog kev loj hlob zuj zus thiab thaum kawg tuag hyperinflammation ntsib kev kuaj mob rau hemophagocytic lymphohistiocytosis (HLH; saib cov ntaub ntawv xaus, Daim duab 1A, Ntxiv Table E1). Kev soj ntsuam cov ntshav (Sab Ntxiv Table E2) thiab cerebrospinal kua (Table Ntxiv E3) tsis tau ua pov thawj ntawm cov tshuaj tiv thaiv kab mob sib kis, thiab tsis yog lwm txoj kev kis kab mob etiology txheeb xyuas, uas tsis yog qib qis Epstein-Barr tus kab mob (EBV) reactivation. Cov ncauj lus kom ntxaws txog kev tiv thaiv kab mob phenotyping tau pom tias muaj monocytosis thiab T-cell lymphocytosis, nrog cov lej B hlwb tsawg thiab cDC1 (Cov Duab Ntxiv E1, Cov Lus Ntxiv E4).
Despite aggressive antiviral, immunomodulatory therapy, and intravenous immunoglobulins (IVIG), he developed encephalopathy with abnormal neuroimaging and succumbed suddenly approximately 6 months after presentation (Supplementary Figure E2–E4). Rapid diagnostic whole exome sequencing revealed a novel homozygous nonsense variant (c.922C>T) nyob rau hauv IFNAR1, qhia txog lub sij hawm ua ntej nres codon nyob rau hauv lub thib peb extracellular domain ntawm IFNAR1 protein (p.Gln308Ter, daim duab 1B).
Qhov kev hloov pauv no tsis tuaj ntawm GnomAD cov ntaub ntawv thiab kwv yees tias yuav raug tshem tawm los ntawm cov cuab yeej silico (Table Ntxiv E5). Tsis muaj cov khoom lag luam protein raug kuaj pom thaum soj ntsuam thawj dermal fibroblast lysates nrog N-terminal (Daim duab 1C) lossis C-terminal IFNAR1 antibody (Cov duab ntxiv E5), qhia tias ua tiav IFNAR1 tsis txaus. Kev tshuaj xyuas ntawm cov vaj huam sib luag dav ntawm cov noob txuas rau hauv yug me nyuam tsis raug ntawm kev tiv thaiv kab mob hauv tus neeg mob cov ntaub ntawv exome qhia tsis muaj tus neeg sib tw kab mob sib txawv ntxiv.
Raws li ligand binding, lub ternary complex ntawm IFNAR1-IFNIFNAR2 pib ib qho intracellular signaling cascade nyob rau hauv uas reciprocal transphosphorylation ntawm receptor-associated kinases JAK1 thiab TYK2 yog ua raws li phosphorylation ntawm lub teeb liab transducers thiab activators STAT1. Feem ntau ntawm cov lus teb rau IFN- yog tshwm sim los ntawm heterotrimer tsim los ntawm phosphorylated STAT1 thiab STAT2 ua ke nrog IRF9.
Qhov no complex, hu ua interferon-stimulated gene factor 3 (ISGF3), translocates mus rau lub nucleus qhov twg nws cuam tshuam nrog interferon-rhiab lus teb cov ntsiab lus (ISREs) los qhib cov transcription ntawm ib tug loj tus naj npawb ntawm interferon-stimulated noob (ISGs). Ib feem ntawm phosphoSTAT1 es tsis txhob homodimerizes los tsim IFN- activation factor (GAF), agonizing ib tug txawv tab sis overlapping txheej ntawm noob bearing IFN- activation sites (GAS), feem ntau yog txuam nrog hom II IFN (IFN- ) signaling. Qhov kev kwv yees tshwm sim ntawm IFNAR1 tsis txaus yog los tiv thaiv kev taw qhia thiab nqes dej ua haujlwm cov lus teb rau IFN- tab sis tawm cov lus teb tsis zoo rau IFN- .
Daim duab 1. A, Pedigree. B, Sanger sequencing kev pom zoo ntawm kev sib txawv nrog IFNAR1 protein domains. C, IFNAR1 deficiency (immunoblot). D, Kev taw qhia los ntawm IFN- 2b lossis IFN- (1000 IU/mL, 30 m, immunoblot). E, ISG induction los ntawm IFN- 2b lossis IFN- (1000 IU/mL, 16 h, immunoblot). F, EMCV cytopathic tiv thaiv kev soj ntsuam. G, ZIKV hnab ntawv (ENV), ISG15, RSAD2, thiab MX1 qhia (immunoblot) hauv fibroblasts (H) ZIKV cytopathic assay. Kev tiv thaiv ZIKV los ntawm IFN- 2b lossis IFN- (MOI 1.0, 1000 IU/mL, 24 h) los ntawm (I) immunoblot thiab (J) viability assay. Ua kom tiav nrog IFNAR1 tab sis tsis khoob vector (VEC) rov qab (K) ISG induction los ntawm IFN- 2b (1000 IU/mL, 16 h, immunoblot) thiab (L) IFN- 2b-mediated tiv thaiv tiv thaiv EMCV. Txhua qhov kev sim rov ua dua n = 3 zaug hauv II: 1 thiab tswj thawj fibroblasts. Txhais ± SD. **** P< .001, 2-way ANOVA with Tukey's post-test. *nonspecific band. Abbreviations: ANOVA, analysis of variance; EMCV, encephalomyocarditis virus; IFN, interferon; IFNAR1, interferon alpha/beta receptor alpha chain; ISG, interferon-stimulated gene; MOI, the multiplicity of infection; ZIKV, Zika virus.
Raws li qhov kev kwv yees no, phosphorylation ntawm JAK1 thiab nws lub hom phiaj nqes hav STAT1 thiab STAT2 tsis tuaj yeem kuaj pom hauv IFNAR1-cov neeg mob tsis muaj fibroblasts raug rau IFN 2b rau 30 feeb, raws li qhia los ntawm kev tiv thaiv ntawm tag nrho cov cell lysates, whereas phosphorylation ntawm JAK1 thiab T. thaum raug IFN- tau khaws cia (Daim duab 1D). Cov qauv tib yam tau pom los ntawm kev tsom xam ntawm STAT1 phosphorylation hauv cov neeg mob lymphocytes thiab monocytes los ntawm phospho-flow cytometry (Cov duab ntxiv E6). Yog li, immunoblotting qhia qhov ua tsis tiav los txhawb ISG cov khoom lag luam protein hauv IFNAR1- cov neeg mob tsis muaj zog fibroblasts nthuav tawm hmo ntuj rau IFN- 2b txawm tias tsis muaj cov lus teb rau IFN- (Daim duab 1E).
Txhawm rau hais txog qhov cuam tshuam rau kev ua haujlwm, peb tau tawm tsam cov hlwb nrog tus kab mob picornavirus encephalomyocarditis virus (EMCV). Hauv qhov kev sim no, fibroblasts tau pretreated nrog IFN- 2b lossis IFN- hmo ntuj ua ntej kis kab mob, ntawm ib koob tshuaj uas tau txiav txim siab yav dhau los los tiv thaiv cytopathic effect (CPE) hauv cov hlwb tswj, thiab tom qab ntawd tshuaj xyuas tom qab 24 teev tom qab kis kab mob. IFNAR1-cov hlwb tsis muaj peev xwm raug cuam tshuam rau CPE txawm tias IFN- 2b raug tab sis raug cawm los ntawm IFN- kev kho mob, lees paub qhov tsis xws luag ntawm IFN- -kev tiv thaiv kab mob sib kis (Daim duab 1F).
Txhawm rau txuas ntxiv thiab lees paub cov kev tshawb pom no, peb kis kab mob nrog tus kab mob flavivirus Zika (ZIKV) ntawm ntau qhov sib txawv ntawm kev kis kab mob, tshuaj xyuas cov kab mob ntawm lub hnab ntawv protein thiab ISGs los ntawm immunoblot ntawm 48 teev tom qab kis kab mob (Daim duab 1G). Hauv cov neeg mob hlwb, peb pom cov kab mob kis tau ntau dhau (Cov Duab Ntxiv E7), nrog rau qhov tsis ua haujlwm los txhawb kev qhia ntawm ISG15, RSAD2, thiab MX1, qhia txog qhov tsis xws luag ntawm IFNAR-mediated antiviral resistance thiab correlated nrog susceptibility rau viral cytotoxicity (Daim duab 1H. ). Kev kho mob ntawm cov neeg mob hlwb nrog exogenous IFN- tab sis tsis yog IFN- 2b tiv thaiv kab mob ZIKV (Daim duab 1I) thiab CPE (Daim duab 1J).
Txhawm rau ua pov thawj tseeb tias qhov poob ntawm IFNAR1 yog lub luag haujlwm, peb tau ua tiav cov neeg mob fibroblast hlwb nrog cov tib neeg ntev IFNAR1 xa los ntawm lentiviral transduction. Lentiviral transduction ntawm IFNAR1 nyob rau hauv cov neeg mob fibroblasts, tab sis tsis yog khoob vector, rov qab induction ntawm ISGs (Daim duab 1K) thiab tsim cov tshuaj tiv thaiv kab mob hauv teb rau IFN- 2b (Daim duab 1L), yog li lees paub lub koom haum genotype-phenotype.
Peb tshaj tawm cov ntaub ntawv tshiab ntawm kev ua tiav IFNAR1 tsis txaus, ua tiav daim ntawv tshaj tawm tsis ntev los no ntawm homozygous IFNAR1 deficiency hauv 2 tus menyuam tsis muaj feem cuam tshuam [3]. Hauv tag nrho 3 ntawm cov xwm txheej no thiab zoo ib yam li IFNAR2- cov neeg mob tsis txaus [2], kev kis tus kab mob kis tau tshwm sim tsuas yog tom qab inoculation nrog cov tshuaj tiv thaiv kab mob nyob. Thaum xub thawj pom, qhov no sib piv nrog qhov dav dav ntawm STAT2- lossis IRF9- cov neeg mob tsis txaus [5–7] rau cov kab mob tshwm sim nyob rau ntawm qhov chaw mucosal, uas tej zaum yuav piav qhia txog kev ua haujlwm rov ua haujlwm ntawm hom Kuv thiab hom III IFNs ntawm mucosa [1].
Txawm li cas los xij, qhov kev tshawb pom tsis ntev los no ntawm 2 qhov xwm txheej ntxiv ntawm IFNAR1 tsis txaus ntawm cov neeg muaj tus kab mob coronavirus hnyav 2019 (COVID-19) txhais tau tias, rau SARS-CoV-2 tsawg kawg, hom I IFNs tuaj yeem ua lub luag haujlwm txhais nyob rau hauv tus tswv teb rau tej yam ntuj tso pathogens [4]. Qhov kev txiav txim siab no tau txais kev txhawb ntxiv los ntawm kev tshawb pom ntawm cov tshuaj tiv thaiv kab mob tiv thaiv hom I tab sis tsis yog hom III IFNs hauv 10 feem pua ntawm cov mob hnyav COVID-19 [4], nrog rau cov teeb liab sib txuas genome-wide nrog IFNAR2 hauv pawg neeg ywj pheej [8].
Peb cov ntaub ntawv nthuav dav phenotypic spectrum ntawm IFNAR1 deficiency kom suav nrog HLH-zoo li hyperinflammation, yav dhau los tau sau tseg hauv IFNAR2 tsis muaj peev xwm thiab tau lees paub ntau ntxiv hauv lwm qhov tsis xws luag ntawm IFNAR- kev tiv thaiv xws li STAT2 lossis IRF9 tsis xws [7, 9]. Txhais cov pathomechanism ntawm hyperinflamation nyob rau hauv cov ntsiab lus no, tshwj xeeb tshaj yog nws txoj kev sib raug zoo rau dysregulated inflammatory signaling thiab / los yog kab mob replication yog ib qho tseem ceeb cheeb tsam rau yav tom ntej ua hauj lwm. Txawm hais tias muaj kev koom tes nrog kev txhaj tshuaj tiv thaiv ib ntus, peb cov ntaub ntawv tseem ceeb heev rau qhov tsis tuaj yeem kuaj pom cov tshuaj tiv thaiv kab mob sib kis. Ib daim duab zoo sib xws tau pom nyob rau hauv qee qhov STAT1- thiab STAT2-cov neeg mob tsis muaj mob hyperinflammation [12, 11].
Txawm hais tias peb tsis tuaj yeem tshem tawm qhov kev koom tes ntawm qib qis EBV rov ua haujlwm, tsis muaj mob autoinflammation tau tshwm sim los ua ib qho kev kho mob tshwj xeeb hauv qhov tsis xws luag ntawm IFN- signaling [7]. Qhov no qhia txog ib txoj hauv kev nyuaj uas cuam tshuam nrog kev poob ntawm IFN- kev tswj hwm [1]. Ntawm lub ntsej muag ntawm nws, qhov no yog paradoxical vim tias tsis muaj kev tswj hwm IFN- teeb liab yog nws tus kheej cuam tshuam nrog HLH zoo li tsis muaj mob o [12]. Txawm li cas los xij IFN- kuj tseem tswj tsis tau ntau yam cytokine txoj hauv kev, suav nrog interleukin (IL) -1 [13] thiab IL-17 [14]. Immunomodulatory zog ntawm IFN- yog siv los kho cov kab mob tiv thaiv kab mob xws li ntau yam sclerosis. Cov lus teb ib nrab ntawm kev kho mob rau corticosteroids thiab IL-1 thaiv hauv peb cov ntaub ntawv qiv qee qhov kev txhawb nqa rau qhov kev xav tias kev poob ntawm IFN- teeb liab ua rau muaj kev cuam tshuam hauv lub cev tiv thaiv kab mob. Nyob rau hauv cov ntsiab lus ntawm tus kab mob kis, nws zoo nkaus li tias qhov raug ntsuas IFN- teb yog tsim nyog los tiv thaiv immunopathology. Qhov no yog "Goldilocks" hauv paus ntsiab lus ntawm kev tiv thaiv homeostasis, qhov twg ob qho tib si tsis txaus thiab kev ua haujlwm ntau dhau los ua rau muaj kab mob.
Hyperinflammation yog lub hauv paus rau kev mob tshwm sim ntawm qhov mob hnyav COVID-19, raws li tau pom los ntawm kev kho mob zoo ntawm corticosteroids. Peb cov ntaub ntawv tshiab ntawm IFNAR1 tsis txaus qhia txog lub luag haujlwm muaj peev xwm rau IFN- hauv kev tiv thaiv hyperinflammation, tsis yog los ntawm kev tswj ncaj qha ntawm tus kab mob replication [2, 3] tab sis tej zaum kuj los ntawm nws txoj kev tiv thaiv kab mob rau lwm yam cytokines. Kev poob ntawm ob qho tib si ntawm IFN- ua haujlwm tuaj yeem ua rau muaj kev cuam tshuam rau cov neeg mob uas muaj IFNAR1 qhov tsis xws luag rau COVID hnyav-19 [4, 9]. Nkag siab txog kev sib txuas ntawm cellular thiab molecular ntawm qhov tsis xws luag IFN- signaling thiab pathogenic o yuav yog qhov tseem ceeb hauv kev coj noj coj ua rau tus kab mob viral hnyav.,
Cov ntaub ntawv ntxiv
Cov ntaub ntawv ntxiv muaj nyob rau ntawm Chaw Kho Mob Kab Mob Sib Kis hauv online. Raws li cov ntaub ntawv muab los ntawm cov kws sau ntawv kom muaj txiaj ntsig zoo rau tus nyeem ntawv, cov ntaub ntawv tshaj tawm tsis tau luam tawm thiab yog lub luag haujlwm ntawm tus sau ntawv, yog li cov lus nug lossis cov lus pom yuav tsum tau hais rau tus neeg sau ntawv.
Nco tseg
Muaj peev xwm tsis sib haum xeeb ntawm kev txaus siab. F. G. tau txais nyiaj los ntawm Deutsche Forschungsgemeinschaft (GO2955/1-1) nrog rau Bubble Foundation. C. FH tau txais nyiaj los ntawm Pawg Saib Xyuas Kev Tshawb Fawb Kev Kho Mob (MRC) cov tub ntxhais kawm (MR/ N013840/1). V. K., E. F., thiab M. F. yog nyiaj txiag los ntawm Ministry of Health ntawm Czech koom pheej (NV19-05-00332). S. H. thiab C. JA D. tau txais nyiaj los ntawm Wellcome Trust (207556/Z/17/Z thiab 211153/Z/18/Z, raws li).
Tag nrho lwm tus neeg sau ntawv tsis muaj qhov tsis sib haum xeeb. Txhua tus kws sau ntawv tau xa daim ntawv foos ICMJE rau Kev Tshaj Tawm Txog Kev Muaj Peev Xwm Tsis Txaus Siab. Cov kev tsis sib haum xeeb uas cov neeg kho txiav txim siab muaj feem xyuam rau cov ntsiab lus ntawm cov ntawv sau tau raug nthuav tawm.
Cov ntaub ntawv
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Florian Gothe, 1,2, Catherine F. Hatton, 1, Linh Truong, 1 Zofia Klimova, 3 Veronika Kanderova, 4 Martina Fejtkova, 4 Angela Grainger, 1 Venetia Bigley, 1,5 Joanna Perthen, 6 Dipayan Mitra, 6 Ales Janda, 7 Eva Fronkova, 4 Dusana Moravcikova, 3 Sophie Hambleton, 8, thiab Christopher J. A. Duncan 1,9.
1 Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK, 2 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany, 3 Banská Bystrica Children's University Hospital, Banská Bystrica, Slovakia, 4 Department of Pediatric Hematology thiab Oncology, 2nd Kws Qhia Ntawv ntawm Tshuaj, Charles University thiab University Hospital Motol, Prague, Czech koom pheej, 5 Northern Center for Bone Marrow Transplant, Freeman Hospital, Newcastle upon Tyne Tsev Kho Mob NHS Foundation Trust, Newcastle upon Tyne, UK, 6 Department of Neuroradiology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK, 7 Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany, 8 Children's Immunology Service, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK, and 9 Infection and Tropical Medicine, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
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