Innate And Adaptive Immunity Thaum SARS-CoV-2 Infection: Biomolecular Cellular Markers And Mechanisms

Abstract

Tus kab mob coronavirus 2019 (COVID-19) kis thoob qhov txhia chaw yog tshwm sim los ntawm ib qho kev nkag siab zoo ib leeg-stranded RNA (ssRNA) mob hnyav ua pa nyuaj rau tus mob coronavirus 2 (SARS-CoV-2). Txawm li cas los xij, lwm tus neeg mob coronaviruses (hCoVs) muaj nyob. Cov kab mob kis thoob plaws keeb kwm suav nrog cov kab mob me me thiab kab mob khaub thuas, nrog cov kev kho mob zoo siv los txo cov kab mob tag nrho los ntawm kev tsom mus rau lub peev xwm lub cev tiv thaiv kab mob. Lub cev tiv thaiv kab mob yog tsim los ntawm thawj / theem nrab lymphoid cov qauv nrog thawj yim hom kab mob hauv lub cev, thiab ntau lwm yam subtypes, traversing cell membranes siv cell signaling cascades uas ua rau kom tshem tawm cov kab mob pathogenic. Lwm cov proteins uas tau tham txog muaj xws li pawg sib txawv (CD) cov cim, qhov loj histocompatibility complexes (MHC), pleiotropic interleukins (IL), thiab chemokines (CXC). Cov ntsiab lus keeb kwm ntawm kev tiv thaiv tus tswv tsev yog lub cev tsis muaj zog thiab yoog raws lub cev. Lub cev tiv thaiv kab mob adaptive yog sawv cev los ntawm T hlwb, B hlwb, thiab cov tshuaj tiv thaiv. Lub cev tiv thaiv kab mob hauv lub cev yog sawv cev los ntawm macrophages, neutrophils, dendritic cells, thiab cov kab ke ntxiv. Lwm cov kab mob tuaj yeem cuam tshuam thiab tswj kev hloov pauv ntawm lub cev, piv txwv li, hauv cov qog nqaij hlav uas suav nrog tib neeg papillomavirus (HPV: cervical carcinoma), Epstein-Barr virus (EBV: lymphoma), Kab mob siab B thiab C (HB / HC: hepatocellular carcinoma), thiab tib neeg. T cell Leukemia Virus -1 (T cell leukemia). Cov kab mob kab mob kuj ua rau muaj kev pheej hmoo ntawm kev mob qog noj ntshav (xws li Helicobacter pylori). Cov kab mob kis kab mob thiab kab mob tuaj yeem ua rau muaj kev mob nkeeg thiab kev tuag nrog rau kev sib kis hauv chaw kho mob thiab hauv zej zog los ntawm kev cuam tshuam rau tus tswv tsev tiv thaiv kab mob. Yog li ntawd, nws yog qhov tsim nyog los tsim cov ntsiab lus ntawm kev nce qib hauv ib leeg-cell sequencing nrog rau lwm yam kev kuaj sim uas tso cai rau kev nkag siab txog kev tiv thaiv kab mob hauv lub cev. Cov kev txhim kho no muab kev txhim kho kom pom tseeb thiab nkag siab tias sib tshooj nrog cov kab mob autoimmune uas tuaj yeem cuam tshuam los ntawm innate B hlwb (B1+ lossis marginal zone cells) lossis hloov T cell teb rau SARS-CoV-2 kab mob thiab lwm yam pathologies . Yog li, qhov kev tshuaj xyuas no pib nrog kev qhia txog kev tiv thaiv kab mob ua pa ua ntej tshuaj xyuas cov cellular messenger proteins uas muaj nuj nqis thiab tom qab ntawd cov cim tiv thaiv kab mob ntawm tus kheej.

Keywords: COVID-19; B-hlwb; neutrophils; dendritic hlwb; T-cells; NK-cells; monocytes; macrophages; nyob hauv; yoog raws; cytokines; tshuaj chemokines; adhesion molecules; tshuaj tiv thaiv; pawg ntawm kev sib txawv; receptors; cov protein; SARS-CoV-2; serology

cistanche ntxiv cov txiaj ntsig-nce kev tiv thaiv

1. Taw qhia

1.1. Txheej txheem cej luam

Lub causal virion SARS-CoV-2 ntawm COVID-19 kis thoob qhov txhia chaw muaj ntau tshaj plaub lub immunogenic proteins uas muaj xws li spike (S protein), nucleocapsid (N protein), hnab ntawv (E protein), thiab membrane (M protein) thiab cov subunits txuam nrog cov proteins ntxiv [1,2]. Kev txhim kho tam sim no tau tshwm sim ua ntej / tom qab Lub Peb Hlis 2020 thaum Lub Koom Haum Saib Xyuas Kev Noj Qab Haus Huv Ntiaj Teb (WHO) tshaj tawm tias muaj tus kabmob kis loj; SARS-CoV-2 paub tias kis tau ntawm cov tsiaj thiab nruab nrab tiam [3]. Nws tau xav tias nyob ib ncig ntawm 15% ntawm COVID{10}} tus kab mob tuag tuaj yeem yog vim mob ntsws lossis mob ua pa nyuaj (ARDS) [4]. Cov tshuaj tiv thaiv kab mob tam sim no tau tsim kho ntau yam ua ntej fusion S protein derivatives nrog cov neeg sib tw tshiab tau nce qib los ntawm kev sim tshuaj ntsuam xyuas nrog lub hom phiaj los txo cov kab mob COVID{13}} mob hnyav hauv cov pej xeem raws li kev tshawb fawb txuas ntxiv. SARS-CoV-2 genome yog kwv yees li 30 kilobases encoding 9860 amino acids thiab yog txhais los ntawm qhib kev nyeem ntawv (ORF) thiab cov protein uas tsis yog cov qauv (NSP) xav tau rau kev nthuav tawm cov kab mob hauv txhua hom tsiaj [5]. SARS-CoV-2 genome hosts 16 ORFs uas encode 29 proteins xav tau rau kev nthuav tawm cov kab mob thiab tiv thaiv kev tiv thaiv kab mob. Piv txwv li, ORF1a thiab ORF1ab encode polypeptides cleaved rau hauv 16 NSPs. Cov kev sim tshuaj molecular (piv txwv li, PCR) feem ntau yog siv cov cuab yeej kuaj mob uas tso cai rau kev tsom xam thiab nrhiav pom cov RNA tshwj xeeb hauv cov qauv. SARS-CoV-2 kis cov cell ntawm txoj kev ua pa thiab hom II pneumocytes (ATII) siv angiotensin-hloov enzyme 2 (ACE-2) ua cov receptor predominant rau nkag [6]. Kev cuam tshuam thiab kab mob ntawm ATII hlwb qhia ACE2 tshwm sim los ntawm phospholipid daim nyias nyias. Lwm cov receptors qhia ntawm tag nrho cov leukocytes, platelets, thiab endothelial hlwb suav nrog ntau pawg ntawm cov cim sib txawv (CD), piv txwv li, CD3, CD4, thiab CD19, thiab lwm yam. Qee qhov tam sim no tseem cuam tshuam rau thawj zaug SARS-CoV-2 cellular nkag uas suav nrog hom II transmembrane protease (TMPRSS2), asialoglycoprotein receptor-1 (ASGR1) thiab kringle uas muaj transmembrane protein 1 (KREMEN1), dipeptidyl peptidase 4. (DPP4), neuropilin (NRP1), CD147 thiab vimentin [7–12]. Yog li ntawd, vim hais tias ntawm cellular kab mob, lub cev tiv thaiv kab mob tswj thiab txhim kho nyob rau hauv lub hauv paus qog nqaij hlav hauv nruab nrog cev (xws li, pob txha pob txha thiab thymus), tab sis kuj los ntawm ib tug network ntawm cov qog nqaij hlav hauv nruab nrab (xws li, tonsils thiab lwm yam) siv cov qog nqaij hlav (LNs) thiab cellular membranes. uas tso cai rau cellular permeability thiab lymphocyte tsiv teb tsaws los ua cov kab mob sib kis kab mob ntawm txhua qhov teeb meem los ntawm lub paj hlwb, digestive, endocrine, ua pa, circulatory, muscular, thiab skeletal systems. Kev nce qib kev siv tshuab txij li xyoo 2017 kuj tau tso cai rau kev tshuaj xyuas phenotypic ntau dua thiab, yog li ntawd, tam sim no nws pom tseeb dua tias SARS-CoV-2 cov proteins muaj lub luag haujlwm sib txawv. Cov kev soj ntsuam tau lees paub tias M protein yog qhov tseem ceeb rau kev sib sau ua ke, S protein yog rau cov cellular receptor nkag, thiab N thiab E cov proteins tshwm sim los ua cov pore-forming proteins [13,14]. Ib leeg-cell RNA sequencing (scRNA-Seq), spectral flow cytometry (FACS), thiab huab hwm coj cytometry (CyTOF) tuaj yeem ntes cov cim ua kom muaj kev tshuaj xyuas phenotypic ntawm txhua lub cev tiv thaiv kab mob [15–18]. Nws yog ib qho tseem ceeb uas cov tshuaj tiv thaiv kab mob sib koom ua ke hauv kev sim rau SARS-CoV-2 kab mob muaj qhov sib txawv thiab cov tshuaj tiv thaiv tib neeg. Cov no yog ntsuas los ntawm kev kuaj mob monoclonal antibody uas muaj ntau qhov ntsuas uas tau lees paub los ntawm cov chaw tsim khoom. Piv txwv li, cov koom haum ntsuas cov concentration hauv sera siv ntau qhov kev ntsuam xyuas uas ntsuas cov tshuaj tiv thaiv kab mob (BAU / mL), lwm tus ntsuas cov tshuaj tiv thaiv kab mob tsis zoo (nAb hauv IU / mL), thiab lwm tus ntsuas qhov concentration (ng / mL) raws li kev tsim qauv tshwm sim los xyuas kom meej qhov sib xws ntawm ib thoob ntiaj teb teev (Cov Khoom Siv Ntxiv thiab Cov Ntaub Ntawv S1–S5) [19,20]. Yog li ntawd, hauv daim ntawv no, peb tshuaj xyuas cov chaw kuaj mob tam sim no thiab cov kev tshawb fawb soj ntsuam tam sim no uas tau ntsuas thiab piav qhia qhov tseem ceeb ntawm cov ntaub ntawv los qhia txog qhov hloov pauv ntawm lub cev tiv thaiv kab mob cellular maturation ib puag ncig, kom ntseeg tau tias muaj ntau yam kev mob tshwm sim pom nrog SARS-CoV-2 kab mob tuaj yeem. yuav dysregulated adaptive immune teb. Ntau yam kab mob, kab mob, thiab fungal pathologies muaj ob qho tib si kev tiv thaiv kab mob thiab cov caj ces hloov pauv tau cuam tshuam los ntawm kev tswj hwm lub voj voog ntawm tes thiab kev nthuav qhia antigen. Cov no cuam tshuam rau ntau yam pathologies, thiab kev pheej hmoo yog yog li cuam tshuam los ntawm cov tshuaj genetic susceptibility yam. Qhov no suav nrog cov noob uas encode cov protein uas tau hais tawm ntawm lub cev tiv thaiv kab mob, xws li tib neeg leukocyte antigens (HLA), hu ua qhov loj histocompatibility complex (MHC). Cov protein luv luv tam sim no (peptide) tawg rau lub cev tiv thaiv kab mob hlwb thiab cov cim hauv cheeb tsam uas cuam tshuam los ntawm lwm cov kab mob sib kis, raws li peb tham hauv qab no. Lub cev tiv thaiv kab mob sib tham nyob rau hauv daim ntawv no muab tag nrho cov ntsiab lus nrog ntxiv cell characterization los ntawm kev sib cuam tshuam ntawm B hlwb, T hlwb, thiab txhua lwm ntawm plaub cell subtypes uas tau tham hauv qab no, cais tshwj xeeb los ntawm pawg sib txawv (CD) cov proteins qhia nyob rau ntawm lub xov tooj ntawm tes reliant. ntawm cytokine thiab chemokines ua raws li lub cev tiv thaiv kab mob cov cim cuam tshuam los ntawm cov kab mob sab nraud.

1.2. Tam sim no SARS-CoV-2 Vaccine Immunogen Responses

Cov txiaj ntsig ntawm cistanche tubulosa- ua kom muaj zog tiv thaiv kab mob

Tam sim no cov tshuaj tiv thaiv antigens lossis viral antigens tseem ceeb rau lub cev tiv thaiv kab mob kom paub txog cov kab mob pathogenic ntawm epitopes uas tuaj yeem hloov pauv, yog li cuam tshuam rau lub cev tiv thaiv kab mob los ntawm B cell thiab T cell receptors (BCR / TCR). Kev tiv thaiv tus kab mob sib kis ntev -19 tus kab mob rau pre-Omicron variants tau kwv yees nyob rau hauv cov piv txwv ntawm cov tshuaj tiv thaiv tam sim no, tsim los ntawm Pfizer/BioNTech, Astra Zeneca, Sinopharm, thiab Novavax: BNT162b2: 95.3%, AZD1222: 70.4%, BBIBP -CorV: 79%. Immunogen development qhia NVX-CoV2373 ntawm 72% thaum kuaj pom Omicron BA.1 thiab BA4/BA5 [21]. Kev txo qis ntxiv ntawm tus kab mob COVID{18}} tau kwv yees li ntawm 86%. Cov kev tshawb fawb pej xeem qhia tau hais tias qhov sib txawv ntawm SARS-CoV-2 cov tshuaj tiv thaiv kab mob protein (76%: 24% teb / tsis teb). Kev kwv yees tsim cov tshuaj tiv thaiv kab mob rau S protein immunogens tam sim no ncua 6 lub hlis txog 1.5 xyoo. SARS-CoV-2 S protein mutations yog tam sim no muaj ntaub ntawv zoo nyob rau hauv lwm cov kev tshawb fawb kom paub tseeb tias muaj peev xwm epitopes uas cuam tshuam rau lub cev tiv thaiv kab mob [22]. Cov lus teb ua haujlwm ntawm tes T cell, tus pab (TH) lossis cytotoxic (TC), kuj yog qhia txog CD4+: CD8+ kev ua haujlwm tshwm sim hauv qhov piv ntawm 96%: 54% hauv COVID{{35} } kab mob [21]. Piv nrog rau lwm cov kab mob ua pa xws li mob npaws, SARS-CoV-2 S protein muaj qhov hloov pauv ntau dua nyob rau hauv qhov sib txuas / ACE2, thiab qhov tshwm sim ntawm Omicron variants txhawb qhov no, txhais los ntawm BA1, BA2, BA2.75, BA4, BA5, BQ1, thiab XBB [23]. Hmoov zoo, cov txheej txheem thev naus laus zis thiab kev kuaj sim muaj nyob uas ua kom yooj yim ntawm cov cell profileing thiab tso cai rau kev sib piv ntawm cov kab mob tiv thaiv kab mob. Yog li ntawd, nyob rau hauv daim ntawv no, peb yuav tham txog txoj kev ntawm tus kab mob, predominant cytokine thiab protein markers, thiab, thaum kawg, ib tug neeg cellular teb ntawm predominant immune cell kab mob nyob rau hauv kev txiav txim ntawm B hlwb, neutrophils, monocytes / macrophages / dendritic hlwb (DC), natural killer (NK cells), thiab T cell subtypes.

1.3. Ua pa microenvironment

Cov kab mob ua pa cuam tshuam yog lub qhov ntswg, caj pas, lub ntsws, trachea, bronchi, thiab lub ntsws raug rau sab nraud antigens uas tsim los ntawm cov txheej txheem epithelial cell. Ib tus neeg laus lub ntsws thaj chaw muaj kwv yees li 700 lab alveoli, nrog thaj tsam ntawm 70 m2 thiab txoj kab uas hla ntawm 200 µm thiab 500 µm, npog los ntawm capillaries. Nyob rau hauv cov txheej txheem alveolar no yog ciliated hom I pneumocytes (ATI) hlwb, nrog rau hom II pneumocyte (ATII) hlwb thiab alveolar Mφ (AMφ) uas tswj kev ua pa, tso tawm ntawm surfactant, thiab kev tswj lub cev tiv thaiv kab mob, raws li, nrog rau cov kab mob goblet, basal hlwb thiab lwm hom cell [24] Cov kev tshawb fawb thaum ntxov (n=7) nyob rau hauv mob SARS-CoV-2-induced kab mob qhia ncaj qha kis kab mob ntawm ATII hlwb los ntawm glycocalyx thiab surfactant txheej, yog li cuam tshuam homeostatic barriers thiab valve ua hauj lwm los ntawm kev nce siab ntawm inhaled O2 los yog exhaled. CO2 nyob rau hauv nanobubbles thoob plaws cell membranes qhov twg CO2 yog tsim los ntawm tricarboxylic acid (TCA) voj voog [25]. Cov txheej glycocalyx paub tias muaj ntau cov proteins uas cuam tshuam rau vascular function (xws li, syndecans) uas tuaj yeem degraded thiab cuam tshuam rau vasculature, xws li matrix metalloproteinases (MMP), heparanase, thiab hyaluronidase, los ntawm kev ua ntawm cytokines (IL{ {13}} thiab lwm yam) [26,27]. Cov txheej txheem ntawm kev ua pa no yog nyob ntawm daim nyias nyias thiab cov roj solubility ntawm O2, N2, thiab CO2 nanobubbles [28] (saib daim duab 1).

Figure 1. Overview of SARS-CoV-2 immune cell interactions.

1.4. Cytokine thiab Serum Proteins thaum SARS-CoV-2 Infection

Serum protein elevation, sau tseg tias yog "cytokine cua daj cua dub" uas nce siab lossis ua haujlwm tsis zoo hauv SARS-CoV-2-induced chronic COVID-19 kab mob, tshwm sim hauv ntau lwm yam pathologies [32]. Cytokines yog ib pab pawg ntawm cov proteins luv luv tso tawm los ntawm ntau lub hlwb ua haujlwm ua cov tub txib intercellular. Cytokine synthesis thiab secretory mechanisms muaj xws li tso tawm los ntawm lysosomes, los ntawm vesicles los ntawm plasma membranes, thiab tso tawm los ntawm plasma membranes. Ntau cov kev tshawb fawb sau cov no, uas tsis yog lub ntsiab lus tseem ceeb ntawm qhov kev tshuaj xyuas no. Hauv kev sib piv, kab mob khaub thuas (genus Influenza A/B/C/D), cytokines IL-1, IL-4, IL-5, IL-6, IL{ {9}}, IL-12, IL-13, TNF- , thiab IFN- muaj feem cuam tshuam rau lub cev tiv thaiv kab mob, raws li tau hais hauv qab no hauv cov duab. Thaum lub sij hawm SARS-CoV-2 kab mob-induced COVID{17}} kab mob, lwm cov proteins tau raug txiav txim siab, uas suav nrog kev hloov pauv thiab vascular endothelial cellular loj hlob yam (TGF- /VEGF) nrog rau cov MMPs tshwj xeeb (MMP2, MMP3 , MMP9) [33–36] ib. Cov no sawv cev rau cov ntaub so ntswg rov ua qauv ntawm cov proteins uas muaj cov tshuaj chemotactic tshwj xeeb kuj yuav tsum tau coj cov leukocyte chemotaxis ntawm cov kab mob hauv nruab nrab cov qog ntshav (GC) thiab thoob plaws hauv lub cev [34–36]. Cov tshuaj chemokines ntsig txog hauv qab no suav nrog CXCL10 (IP-10), CCL2 (MCP-1), CCL3 (MIP1-), thiab CCL11 [33–37]. Txawm li cas los xij, ua ntej xyoo 2020 muaj kev sib kis, hauv cov kab mob sib kis (MERS-CoV) ua rau Middle East Respiratory Syndrome (MERS), cytokine proteins IL-1 , IL-6 thiab IL-8 yog taw qhia tias yog tus yuam sij rau tus tswv teb, qhov twg, hauv kev kis kab mob, CXCL10 thiab lwm cov tshuaj pleiotropic tau tshawb xyuas ntxiv uas siv CXCR3 qhia ntawm Mφ, T cells, DCs, thiab ob lub NK / B hlwb [38–40]. Cov cytokines saum toj no thiab chemokines yog, yog li ntawd, tag nrho cov innate/adaptive regulators uas pab rau kev tswj kab mob thiab kev tswj nyob rau hauv cov ntshav cov ntshav. Cov kev tshawb fawb qhia tias COVID-19-sociated coagulopathy (CAC) yog qhov ua rau muaj kab mob ntev nrog cov complexes tsim ntawm lub cev tsis muaj zog tiv thaiv kab mob cuam tshuam rau coagulation thiab fibrinolytic txheej txheem los ntawm cov txheej txheem tsis paub. Categorization ntawm COVID-19 tau, yog li ntawd, tau tshwm sim hauv vascular endothelial cell dysfunction, hyper-inflammatory teb, thiab hypercoagulability, documenting no nam ntawm SARS-CoV-2 induced pathology nrog ua rau cov ntshav nce siab hauv plasma qib D. -dimer, C-reactive protein, P-selectin, thiab fibrinogen [41]. Tsis ntev los no, hauv kev tshuaj xyuas tseem tsis tau luam tawm ua ntej, 7315 cov proteins tau tshawb xyuas tshwj xeeb hauv tus kab mob COVID{59}}, hais txog cov protein ntxiv uas yog qhov tseem ceeb hauv txoj hauv kev coagulation; ntxiv rau C1q subcomponent subunits A, B, thiab C (C1QA, C1QB, thiab C1QC) feem ntau yog enriched hauv ntsws thiab LNs [42]. Ntxiv cov ntsiab lus C3, C5, C7, thiab C9, nyob rau hauv sib piv, feem ntau upregulated nyob rau hauv LNs thiab aorta / nkoj phab ntsa nrog downregulated SP-C hauv ATII hlwb [42]. Kev tshawb fawb qhia ob lwm cov proteins, cov receptor rau cov khoom siv qib siab glycation kawg (RAGE / AGER) thiab chloride intracellular channel (CLIC5), kuj cuam tshuam nrog ATI hlwb, tab sis hais tias ib qho SP-C-txog cov protein tau downregulated tshwj xeeb rau ATII hlwb, raws li. saum toj no [42]. Qhov zoo siab, cov kws sau ntawv tau sau tseg qhov txo qis hauv IL-12 ntau lawm hauv LN uas tuaj yeem cuam tshuam rau DC maturation, raws li tau tham hauv qab no. Ntau lub voj voog ntawm kev tswj hwm cov protein tau raug ntsuas, xws li cyclin-dependent kinase (CDK2), tab sis kuj tseem muaj keeb kwm replication complex (ORC) thiab nucleoporins (NUC), uas tau pom tias yuav tsum tau tswj hwm hauv LNs. Tsis tas li ntawd, ntau qhov kev hloov pauv protein tau raug sau tseg tias yog txuam nrog cov ntaub so ntswg hloov pauv hauv cov glycocalyx. Nyob rau hauv ib tug zoo xws li cov ntaub ntawv-tswj kev tshawb fawb saib ntawm biomarkers nyob rau hauv cov tib neeg seropositive (n=400), tseem ceeb hloov tau tshwm sim rau E-selectin (CD62) thiab cathepsin B, thiab cov tsos mob tsis tu ncua tej zaum yuav txuam nrog hlau-sulfur pawg co- chaperone protein (HSCB), heat shock protein HSP 90-beta (HSP90AB1), amyloid-beta precursor protein (APP), phospholipase D Family Member 3 (PLD3), cystatin-C (CST3), thiab calprotectin (S{ {93}}A9) [43].

1.5. Ua ntej -2022 Laboratory Research Context

Txij li xyoo 2015, cov kev tshawb fawb kev tshawb fawb tau qhia meej tias SP tuaj yeem hloov kho lub cev tiv thaiv kab mob hauv lub ntsws thiab, yog li ntawd, tej zaum yuav yog lub hom phiaj kho mob thaum muaj kev tsis haum tshuaj pom nyob rau hauv tus kab mob COVID-19 mob [44]. Muaj kev tsis sib haum xeeb hauv cov ntaub ntawv, thiab qhov no tej zaum yuav raug saib tsis taus thaum tus mob khaub thuas 2009 H1N1 muaj thoob qhov txhia chaw [44]. Raws li ntau daim ntawv tshaj tawm (n=10) qhia meej, nrog SARS-CoV-2 kab mob, muaj kev puas tsuaj ntau ntawm alveolar nrog kev raug mob endothelial ntawm cell membranes, vascular thrombosis, occlusion ntawm alveolar capillaries, edema nrog angiogenic hlab ntsha loj hlob, thiab lymphocyte tsiv teb tsaws [44]. Cov txiaj ntsig tau tswj hwm kev tswj hwm cytokine tshwm sim ntawm tag nrho cov leukocytes nrog cov lus nug ntawm lub cev tiv thaiv kab mob thiab cov interleukins (IL), kev loj hlob (GF), chemokines (CXC), thiab cov receptors lossis ligands (xws li, CXCR3 thiab / lossis CXCR4) uas yuav tsum tau. kev qhia ntxiv hauv qab no [45]. SARS-CoV-2 pathogenesis pib nrog cuam tshuam cov membrane homeostasis nrog qhov tshwm sim syncytia tsim, cell fusion, thiab multinucleate hlwb nrog rau lub cev tiv thaiv kab mob dysregulation [46–48]. Qhov kev tsim ntawm syncytia tuaj yeem pib los ntawm cov proteins transmembrane (xws li, TMEM16) uas tswj cov phospholipid-nplua nuj cell membranes nrog rau phosphatidylserine (PS) [49–51]. Braga et al. siv cell fusion inhibition assays (CFIA) thiab nyob rau hauv qhov chaw ntsuas ntawm tus kab mob RNA assays (n=41) kev tshawb fawb hauv cov tib neeg cuam tshuam los qhia meej tias SARS-CoV-2 cov tib neeg kis tau fused cell syncytia tseem ceeb uas muaj cov ntaub so ntswg, uas ua SP-B ntau rau ATII hlwb [50]. Lawv tau sau tseg tias, los ntawm kev tswj hwm cov ion channel nyob ntawm calcium thiab ib qho scramblase enzyme uas tswj PS, S protein kom meej meej pom los ua kom cov protein ntau (TMEM) ntawm lub cell membrane nto los yog hauv organelle membranes [49]. Piv txwv li, ib qho ntawm cov TMEM16 no yog ib feem ntawm tsev neeg cov protein uas muaj cov calcium-dependent ion channels lub luag haujlwm rau PS kev tswj hwm hauv cov txheej txheem calcium- thiab arginine-nplua nuj [49]. Tam sim no, tam sim no paub tias SARS-CoV-2 ORF3a tuaj yeem cuam tshuam rau calcium-regulated ion channel, TMEM16F, tswj los ntawm PS, uas tuaj yeem txhawb kev ua haujlwm ntawm procoagulant los ntawm tenase thiab prothrombinase complexes, uas yog cov tswj tseem ceeb ntawm txoj kev coagulation. [50–52]. Yog li ntawd, xws li kev hloov pauv hauv cheeb tsam infer txoj hauv kev ntawm SARS-CoV-2 nkag mus rau hauv epithelial microenvironment. Qhov tseeb, cov carbohydrate-nplua nuj glycocalyx txheej npog cov mucosal epithelial hlwb kuj muaj cov sib xyaw ntawm mucin (MUC) glycoproteins, glycosaminoglycans, thiab lwm yam glycoproteins, uas txuas ntxiv thiab ncig cilia thiab nquag ua haujlwm kom tshem tawm cov kab mob loj dua. Kev tshawb fawb nthuav dav tsis ntev los no tau tshaj tawm tias cilia, microvilli, thiab cov hnoos qeev ua haujlwm tseem ceeb rau SARS-CoV-2 adhesion thiab receptor-mediated nkag mus rau hauv cov hlwb epithelial, uas tshwm sim ua cov nplaum. MUC proteins yog cov proteins uas hnyav molecular uas tsim cov mucus pawg. Hauv COVID-19 tus kab mob, thawj zaug (n=16) ob hom mucins tau tshawb xyuas ntau, ntawm cov membrane-tethered MUC1 thiab cov gel-forming MUC5AC tshwm sim nyob rau theem siab. Yog li ntawd, kev tshem tawm cov kab mob ib txwm muaj los ntawm mucin proteins tuaj yeem cuam tshuam, ua kom yooj yim rau SARS-CoV-2 nkag mus kom tso cai rau tus kab mob mus ntev [53–56]. Qhov tseem ceeb, lwm yam kev tshawb fawb qhia tias, ntxiv rau ORF3a, lwm yam SARS-CoV-2 cov proteins suav nrog E thiab ORF8 tuaj yeem ua rau sib sau ua ke thiab tsim cov kab mob ion lom [57,58].

cistanche tubulosa- txhim kho lub cev 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

1.6. Lub luag hauj lwm ntawm Tus Xov Tooj Zoo Li Tus Txais (TLR) lossis TLR-Induced IFN Dysregulation

Txhawm rau txhim kho cov lus teb los tiv thaiv kab mob, feem ntau hom I IFN yog tsim [59]. Cov kev tshawb fawb tam sim no cuam tshuam qhov no, raws li hom I IFN ntau lawm nthuav tawm tias muaj txiaj ntsig zoo thiab cuam tshuam rau COVID-19 kab mob; Txawm li cas los xij, kev tshawb fawb soj ntsuam Middle Eastern respiratory syndrome (MERS) thiab tus kab mob ua pa syncytial (RSV) qhia tias lub sijhawm ntawm hom I IFN ntau lawm cuam tshuam rau cov lus teb ntawm tes [59,60]. Cov kev txiav txim siab ntxiv yog qhov saum npoo thiab cytosol pattern recognition receptors (PRRs) uas pib downstream signaling cascades siv NF-kB, hom I IFN, thiab inflammasome txoj kev [43–46,61]. Cov no suav nrog kev puas tsuaj cuam tshuam nrog cov proteins molecular (DAMP) uas suav nrog ntau ntau cov proteins nyob ib puag ncig thiab hauv cov chaw nuclear thiab cov chaw sab nraud uas suav nrog kaum tus neeg hu xov tooj zoo li receptors (TLRs), retinoic acid-inducible gene-I-(RIG-I)-zoo li receptors, Nod-zoo li receptors (NLRs), AIM2-zoo li receptors, thiab intracellular DNA thiab RNA sensors, uas ua rau tsim cov pro-inflammatory lossis anti-viral cytokines tsim nyog rau antigen tshwj xeeb adaptive teb [61,62 ]. Piv txwv li, IL-1RA yog DAMP receptor, uas, ib zaug tso tawm intracellularly, khi rau thiab pib IL-1 tso tawm, uas tau txhawb nqa los ntawm cov ntaub ntawv tshawb fawb (n=71) uas qhia qhov no yog qhov xwm txheej ntawm tus kab mob COVID{26}} ua ke nrog IL-10, uas yog cov tshuaj tiv thaiv kab mob loj heev [63,64]. Nws paub tias SARS-CoV-2 cov proteins raug lees paub los ntawm cov cellular sensors thiab, yog li ntawd, lub luag haujlwm ntawm TLR3/4/7 yog qhov txaus siab rau cov kab mob hauv lub cev uas qhia cov no. TLR3 muaj ntau dua hauv NK hlwb, thaum TLR4 muaj ntau dua hauv Mφ. Hu xov tooj zoo li receptors (TLRs) hloov cov teeb liab ntawm MyD88 thiab TRIF. Feem ntau TLRs siv MyD88 los ua kom muaj cov kab mob cytokine ntau lawm; TLR3 yog qhov tshwj xeeb thiab cov cim tshwj xeeb los ntawm TRIF, thaum TLR4 yog qhov tshwj xeeb hauv qhov uas nws tuaj yeem khi thiab teeb liab los ntawm MyD88 lossis TRIF rau nuclear transcription yam. Cov kev tshawb fawb yav dhau los hauv vitro qhia tias TLR3/7 tuaj yeem cuam tshuam nrog IL-1 , IL-1 , IL-4, thiab IL-6 tso tawm [65]. Yog li, lwm cov kev tshawb fawb tau tshawb xyuas qhov xwm txheej ntawm TLR7 raws li qhov muaj feem cuam tshuam rau COVID{51}} kab mob hnyav [66]. Lub luag haujlwm ntawm TLRs hauv lub cev tiv thaiv kab mob yog qhov tsis meej, thiab yuav xav tau kev tshawb fawb ntxiv, tab sis cuam tshuam rau T-cell signaling [67]. TLR4 nthuav tawm ntawm monocytes, Mφ, thiab DCs, thiab hauv qee lub cev tsis muaj zog, xws li cov hlwb endothelial, thiab muaj lub luag haujlwm hauv LPS-induced Gram-negative bacterial CD14 immune cell trafficking, thiab, interestingly, tej zaum yuav tswj ROR t + Kev tswj hwm T cell teb hauv colitis [68–70]. Kev sim tshuaj ntsuam xyuas txog cov kev kho tshiab tshiab uas cuam tshuam rau TLR tab tom ua tsis tu ncua (NCT05089110, NCT04526977, thiab NCT05293236) hauv ob qho tib si COVID thiab HIV pathologies uas yuav qhia meej txog qhov no ntxiv (saib Cov Khoom Siv Ntxiv). Lub luag hauj lwm ntawm SP-A, raws li tau hais los saum no, yog nyob rau hauv kev tshawb fawb, thiab nws yog plausible hais tias TLR4 qhia muaj qhov sib txawv los nyob rau hauv cov kev xaiv ntawm lub cev nyob rau hauv lub activation, raws li pom nyob rau hauv neonates, qhov twg TLR2/4 activation tau pom los txhawb downstream extracellular teeb liab. tswj kinase (ERK) thiab protein kinase B (AKT) nrog IL-6 txoj hauv kev tsis hloov ntawm cov menyuam yaus thiab cov neeg laus [71]. Kev nthuav qhia ntawm ob qho tib si platelets thiab alveolar Mφ tuaj yeem cuam tshuam thrombotic thiab kev tiv thaiv kab mob ib txhij nrog kev txo qis ntawm ATII hlwb, thiab kev pom zoo hauv kev tshawb fawb tsiaj, uas tsis ntev los no tau pom tias txuas TLR4 rau plab hnyuv cytokine mRNA qhia [72–74]. TLR4 kom meej meej muaj kev cuam tshuam rau platelets los ntawm kev sib sau ua ke thiab P-selectin qhia, thiab tsim cov sib xyaw ua ke ntawm platelets thiab neutrophils, thiab hauv microbes nrog LPS ua rau synthesis thiab / lossis tso tawm ntawm von Willebrand factor (vWF), platelet factor 4 (CXCR4). ), thiab thromboxaneA2 (TXA2), nrog rau NETosis nrog CD11b upregulation thiab lwm yam adhesion molecules (Cov ntaub ntawv ntxiv S1) [75,76]. Keeb kwm pom nyob rau hauv 1957 los ntawm Isaacs thiab Lindemann, IFNs tau pom nyob rau hauv secretions inhibit viral thiab qog loj hlob. Tam sim no lawv tau muab faib ua peb pawg thiab ib tus neeg subtypes: Hom I, II, thiab III. Hom I IFNs suav nrog IFN- thiab IFN- (tseem IFN-δ, IFN-ε, IFN-κ, IFN-τ, IFN-ω, thiab IFN-ζ) tab sis kuj nyob rau hauv Hom II yog IFN-, thaum hom III IFNs encompasses IFN-λ [77]. Hais txog SARS-CoV-2 rhiab heev rau IFN, cov ntaub ntawv tshawb fawb thaum ntxov qhia tias SARS-CoV-2 rhiab heev rau IFN- thiab IFN- hauv vitro, txawm li cas los xij, kev tshawb fawb cov ntaub so ntswg tsis ntev los no qhia tias IFN- thiab IFN - cov lus teb tuaj yeem pab txhawb kev kis tus kab mob los ntawm kev ua pa epithelium mus rau vasculature los ntawm cov kab mob endothelial ncaj qha [78,79]. Tsis ntev los no, hom III IFN-λ tau raug tshawb xyuas thiab nyob rau hauv kev tshawb fawb soj ntsuam tom qab kev tshawb fawb ua ntej (n=257) uas cov ntaub ntawv txo IFN- λ2 thaum lub sij hawm tus kab mob COVID{111}} mob [80]. Lub cellular qhov chaw ntawm SARS-CoV-2 kab mob-induced IFN ntau lawm yog tsis paub tam sim no, raws li IFN receptors nyob rau hauv B hlwb, monocytes, Mφ, T lymphocytes, glial hlwb, neurons, thiab plasmacytoid dendritic cells (pDCs) , ntawm lwm tus [60,61]. Interestingly, epithelial teb nyob rau hauv vitro kev tshawb fawb qhia tau hais tias IFN- tuaj yeem txhawb SARS-CoV{120}} kab mob hauv cell kab lis kev cai los txhim kho kev sib txawv ntawm tes hauv enterocytes hauv vitro [81]. IFN-λ tau pom tias tau ua haujlwm los ntawm cov kab mob, suav nrog Staphylococcus aureus [82]. Nws yog ib qho tseem ceeb uas hom II IFN thiab hom III IFN tuaj yeem zais los ntawm NK thiab T hlwb, thiab ob peb cov ntaub ntawv tshawb fawb seb hom III IFN cuam tshuam rau cov chav kawm antibody witching. Yog li, raws li tus neeg sawv cev tseem ceeb ntawm cov lus teb los tiv thaiv kab mob hauv lub ntsws, tam sim no tau pom tias IFNA2 thiab IFNG gene qhia nyob rau hauv txoj kev ua pa yog nrog los ntawm kev nce hauv IFNB1, thiab kuj nrog txo qis thaum ntxov IFNA2, tab sis qhov no IFN teb. zoo li tshwm sim hauv sera es tsis yog cov ntaub so ntswg [83–85].

2. Innate Immune Systems and SARS-CoV-2 Research

2.1. B Cell Development Dependency ntawm T cell Ua kom

B lymphocytes sawv cev 10% ntawm cov qe ntshav dawb (leukocytes). Central rau innate lub cev tiv thaiv kab mob raws li pathogen sensors, cov no tsim nyob rau hauv cov kab mob chaw zov me nyuam (GC) thiab ces muab faib thoob plaws hauv lub lymphatic system network los ntawm secretion ntawm immunoglobulins (Ig), txiav txim siab nrhiav thiab neutralization ntawm antigens los ntawm cellular txoj kev loj hlob txheej txheem [86 ]. B hlwb teb rau cov antigens uas tsis yog-tus tswv tsev nyob ntawm cov receptors uas muaj cov tshuaj tiv thaiv los ntawm lub xov tooj ntawm tes (piv txwv li, IgM, CD79a, thiab CD79b) (saib daim duab 2).

Daim duab 2. B cell thiab T cell sib cuam tshuam

B cell kev loj hlob los ntawm hematopoietic precursor cells (HPSC) tshwm sim nyob rau hauv theem ntawm pro-B hlwb, pre-B hlwb, tsis paub tab B hlwb, thiab loj hlob mus rau hauv mature B hlwb nyob rau hauv lub fetal daim siab thiab ces nyob rau hauv cov pob txha pob txha. Cov lus teb B cell yog txhais los ntawm CD cov cim hloov mus rau cov neeg laus B cell subpopulations, xws li B-1, B-2, thiab kev tswj hwm B hlwb [87,88]. Kev tshawb fawb txog B cell subtypes tshiab uas txhais los ntawm lwm cov phenotypic CD cim nrog ib leeg-cell sequencing tau tshwm sim txij li 2017. Remarkably, B lymphocytes synthesize mus txog 1011 antibodies, los yog B cell receptors (BCR), nyob rau hauv ib tug tswv tsev uas undergoes clonal xaiv thiab somatic hypermutation (SHM) ua rau qhov tshwj xeeb ntawm antigenic epitope protein paub. BCR muaj ib ntu transmembrane txuas mus rau cytoplasm nrog cov protein ntau uas nyob ntawm kev sib koom tes lossis kev txhawb nqa los ntawm lwm cov proteins kom qhib B hlwb. Lwm cov CD molecules txhais tau tias B cell kev loj hlob lossis kab mob (xws li CD19, CD21). Cov no muaj feem xyuam rau qhov chaw nyob ntawm tes, theem kev loj hlob, kev loj hlob, thiab kev ua kom lub xeev. CD10 qhia tau tshwm sim rau thawj theem B cell kab mob (piv txwv li, pro-B, pre-B cell, thiab GC) thiab tuaj yeem hloov pauv mus rau kev loj hlob nrog lwm tus (saib daim duab 3) [89]. Ntxiv mus, CD27 tsuas yog nyob hauv lub cim xeeb B plasma hlwb, thaum CD5 cim B-1 hlwb thiab DCs (saib daim duab 3). B cell receptor (BCR) complexes nrog lwm cov T cell markers (TCR) cuam tshuam rau kev loj hlob thiab kev nthuav qhia antigen tshwm sim hauv pre-GC nco B hlwb (pre-GC MBCs) thiab luv-lived plasma cells (SLPCs) uas tsim cov tshuaj tiv thaiv qis thaum ntxov. . Lwm cov B hlwb mus txog GC, qhov twg antibody affinity thiab kev xaiv tuaj yeem tshwm sim los ntawm kev xaiv clonal / SHM, hloov cov qauv protein ntawm chav kawm-switching recombination (CSR), uas ua rau cov ntshav nyob ntev (LLPCs) thiab nco B hlwb (MBCs) nrog. Cov tshuaj tiv thaiv kab mob tshwj xeeb, tab sis kuj plasmablasts (PB) uas tsim Ig ntawm tsib lub ntsiab isotypes uas tshwm sim raws li cov protein ntau (IgM, IgG, IgA, IgE, thiab IgD) hauv ib txwm muaj cov tshuaj tiv thaiv kab mob. Cov no tau qhia nyob rau hauv cov kab no hauv sera IgG: 80%, IgA: 15%, IgM: 5%, thiab IgD: 0.2%, nrog cov lej ntawm IgE (saib Table 1) [90].

Daim duab 3. B cell phenotypes thaum loj hlob tuaj.

Table 1. Antibody isotypes concentrations nyob rau hauv sera thiab complement activation muaj peev xwm [83].

2.3. Lub luag haujlwm ntawm B Cell Markers hauv Kev Tshawb Fawb Tam Sim No

CD19 tau ntev tau siv los ua B cell biomarker [104]. Nyob rau hauv xyoo tas los no, qhov no tau nthuav dav mus rau hauv tus cwj pwm, raws li hauv qab no, ntawm B hlwb los ntawm cov receptors qhia nyob rau theem sib txawv thoob plaws hauv B cell, uas suav nrog B hlwb tsis hloov, tsis hloov lub cim xeeb B hlwb, hloov lub cim xeeb B hlwb, thiab ob-tsis zoo (DN. ) B hlwb, tab sis kuj, nrog rau qhov no, chemokine receptors lub luag hauj lwm rau cov kab mob lymphatic kev taw qhia. Qee qhov kev tshawb fawb qhia tias tsis muaj kev pom zoo ntawm DN B hlwb; Txawm li cas los xij, tsis ntev los no cov cim DN B cellular cov cim qhia tau pom tseeb dua (saib Daim duab 3 lossis Cov Ntaub Ntawv Ntxiv S2). Ntxiv DN B cell tsom xam ntawm CD11c tau ua kom zoo dua cov no rau hauv cov subsets qhia CXCR5 kev xav kom tawm los ntawm kev ua kom tsis zoo B cell sab nraum GC [105]. Cov kws tshawb fawb tau nthuav tawm qhov no tsis ntev los no rau ob hom subtypes, DN3 thiab DN4 B hlwb (saib daim duab 3). Enrichment nyob rau hauv tej yam DN B cell subsets tau tham los ua lub luag hauj lwm tseem ceeb nyob rau hauv lwm yam comparatively zoo autoimmune kab mob (ntau yam sclerosis (MS), systemic lupus erythematosus (SLE), myasthenia gravis (MG), thiab rheumatoid mob caj dab (RA) [ 105–107]. Piv txwv li, CD27+ IgD+ tau raug qhia kom muaj kev cuam tshuam cov noob caj ces hauv RA txog VH3-23D rau VH1-8, cuam tshuam rau kev tsim khoom lossis, theej, txo BCR ntau haiv neeg. Thaum xaiv [108]. Yog li, cov subtypes tsis ntev los no tau tshuaj xyuas DN CD11c B cell phenotype (n=18) los qhia cov no hauv autoimmune pathologies piv rau kev tswj kev noj qab haus huv (SLE, Sjøgren's syndrome). Tsis tas li ntawd, B hlwb (CD19) qhia CD11c+ nrog rau qib siab ntawm CD69, Ki-67, CD45RO, thiab CD45RA, raws li cov cim metabolic thiab B cell nco phenotype markers, nrog rau qhov tsis muaj DN cell markers CD21, tuaj yeem khiav tawm ntawm lub cev tiv thaiv kab mob ib txwm muaj [109,110 Yog li ntawd, qhov depletion ntawm B cell subsets kuj tau soj ntsuam nyob rau hauv lub hnub nyoog, hu ua lub hnub nyoog-associated B hlwb (ABCs), hais txog kev cuam tshuam rau zus tau tej cov autoantibodies [111–118].

2.4. B Cell Antibody Responses thaum muaj kab mob ua pa

IgG1 thiab IgG3 tau pib cuam tshuam nrog cov kab mob hnyav hauv cov neeg laus nrog COVID-19 (n=123) kab mob thiab nrog rau qhov tsis sib xws hauv kev tsis sib haum xeeb ntawm cov tshuaj tiv thaiv kab mob (nAbs), chemokines, thiab T cell teb, uas yog qhov tsis zoo xws li IgG3 yav dhau los tau xav tias yuav muab cov kab mob ua kom zoo dua qub [91,119,120]. Txawm li cas los xij, IgG deficiency tau pom tias muaj feem cuam tshuam nrog kev pheej hmoo tuag ntau ntxiv hauv cov neeg mob Chronic Obstructive Pulmonary Disease (COPD) (n=489) ​​hauv cov piv txwv no: 56% IgG1: 27%: IgG2: 24% IgG3: 31% IgG4 [120]. Ib txoj kev tshawb fawb yav dhau los (n=105) piv serology of hCoV-229E, hCoV-OC43, hCoV-NL63, and hCoV-HKU1 elucidated tias cov neeg koom qhia hauv lwm cov lus teb hCoV antibody hais txog IgG uas yog 99 %: 100%: 98%: 91%, nrog IgA hauv kev kuaj qhov ntswg, kuaj pom ntawm 8% thiab 31% ntawm cov neeg koom [121]. Cov kab mob qis dua hCoVs sawv cev rau 15-30% ntawm cov kab mob khaub thuas ua pa rau tib neeg txhua xyoo, nrog rau cov seropositivity kwv yees li ntawm 90% hauv cov neeg laus, qhia tias T cell lub luag hauj lwm xav tau kev qhia ntxiv [122]. Kev sib piv cov tshuaj tiv thaiv tsis yog tus kabmob coronavirus yuav yog tus kab mob khaub thuas uas qhia txog haemagglutinin (HA) thiab neuraminidase (NA) cov proteins uas tshwm sim raws caij nyoog. Hauv cov xwm txheej no, kev tshawb fawb qhia txog kev nce hauv cov ntshav IgM-specific HA cov tshuaj tiv thaiv kab mob thaum xyoo 2009 H1N1 muaj thoob qhov txhia chaw hauv cov piv txwv no: IgM (86–94%), IgG (100%), thiab IgA (76 txog 96%) [ 123, 124] ib.

2.5. B Cells and Antibody Responses to SARS-CoV-2 Infection

Thaum xaus 2020, Plume et al. tau ua ib txoj kev tshawb fawb tshwj xeeb (hauv luv luv, saib Table 2) tshuaj xyuas SARS-CoV-2 cov protein antigen fragments, tshuaj xyuas cov tshuaj tiv thaiv kab mob isotypes tawm tsam feem ntau ntawm cov kab mob antigens, thiab lawv tau qhia tias seroconversion nyob rau hnub 20 yuav ua rau muaj teeb meem, raws li 97.3% reacted tawm tsam tus xaiv epitopes ntawm SARS-CoV-2, tab sis E protein tsis tau soj ntsuam nyob rau hauv txoj kev tshawb no [125–127]. Tag nrho cov zaus ntawm cov tshuaj tiv thaiv ib tus neeg hauv cov tib neeg (n=103) hauv txoj kev tshawb no, uas tau ua thaum lub Plaub Hlis 2020 txog Lub Ib Hlis 2021, tau qhia (saib Table 2). Kev sib txawv ntawm cov tshuaj tiv thaiv kab mob polyclonal feem ntau yuav tshwm sim thaum lub cev tsis muaj zog tiv thaiv kab mob sib txawv antigens. Yog li ntawd, qhov zaus ntawm cov tib neeg tsim cov tshuaj tiv thaiv polyclonal tiv thaiv subtypes ntawm SARS-CoV-2 S protein (S1, S2), M protein, thiab N protein antigens hauv kev kuaj ua ntej Lub Ib Hlis 2021. Qhov no suav nrog IgG tseem ceeb tiv thaiv RBD, S1, thiab M cov protein ntau hauv 100% ntawm lawv cov qauv hauv cov kab mob nruab nrab mus rau qhov hnyav (saib Cov Ntaub Ntawv Ntxiv S3). Qhov zaus ntawm IgA cov neeg teb tau pom tias yog 24.7-35.6%, reacting tawm tsam tag nrho S protein domains, RBD, S1, S2, M, thiab N protein domains, nrog rau qhov kawg tsis muaj qhov hnyav heev. Nws yog ib qho tseem ceeb uas qhov kev tshawb fawb no tau lees paub cov kev txwv ntawm IgE kev soj ntsuam rhiab heev ntawm qhov kev sib tshuam, thiab yuav tsim nyog rau kev tshawb nrhiav ntxiv hauv cov kev tshawb fawb sib piv [126,127].

Table 2. Frequency of Individual Serological Response during SARS-CoV-2 Infection (%) [127]. Kev tso cai txwv tsis pub xa mus rau cov ntawv sau thiab/lossis Cov Ntaub Ntawv Ntxiv.

B cell nco thiab zus tau tej cov S-protein-specific Ig tau raug ntsuas, thiab tam sim no nws yuav pom tau hais tias ib tug putative lub luag hauj lwm rau B cell subtypes tsis paub, xws li DN2 B hlwb downregulating CXCR5, los yog lwm yam kev taw qhia tshwj xeeb receptors xws li CD62L ( L selectin) uas feem ntau qhia, tuaj yeem cuam tshuam rau lub cev tiv thaiv kab mob [125]. CD19+ CD24+ CD27+ CD38+ B cells qhia tias cov tshuaj tiv thaiv kab mob rau SARS-CoV-2 S protein-specific B cells tau nce, txawm tias ntxiv lawm Cov ntsiab lus tuaj yeem pom tau hais txog ob qho kev hloov pauv B hlwb (saib Cov Ntaub Ntawv Ntxiv S2) [107,126]. Hauv kev sib piv nrog lwm cov kev tshawb fawb, nws tau pom tias 32 amino acid peptide (V551–L582) hauv daim ntawv qhia RBD tam sim no tuaj yeem yog cov tshuaj tiv thaiv kab mob B cell epitope, sib npaug rau 58.7% ntawm cov qauv IgG kuaj [127]. Txawm li cas los xij, kev ntsuam xyuas E protein tau ua nyob rau hauv cov kev tshawb fawb ib txhij uas tsis tshwm sim, hauv keeb kwm kev tshuaj ntsuam, kom muaj cov kab mob sib kis zoo sib xws ua ntej-2020, qhia tias kev kis ua ntej yuav tsis tshwm sim vim tias epitopes txawv ntawm cov kab mob antigens. Thawj qhov kev soj ntsuam ntawm cov plaque neutralization qhia tau hais tias qhov ntau txaus ntawm nAbs tuaj yeem tshwm sim rau S1, RBD, thiab muaj feem cuam tshuam rau N protein SARS-CoV-2 domains nrog cov lus teb feem ntau ntawm IgG. Raws li saum toj no, naïve B hlwb qhia IgD + CD19+CD27− (saib daim duab 3, Table 3, thiab Cov Ntaub Ntawv Ntxiv S2) tuaj yeem yog ib qho kev kwv yees ntawm cov tshuaj tiv thaiv titration piv rau cov pab pawg tswj hwm uas muaj qhov tseem ceeb (p {{33}) }.009) [128].

Table 3. B cell phenotypes (adapted from Li et al.) [107]. Kev tso cai tso cai yog hais txog cov ntawv sau thiab/lossis Cov Ntaub Ntawv Ntxiv S2, kuj saib daim duab 3.

Txawm li cas los xij, cov neeg mob tus kab mob COVID-19 mob uas muaj DN (IgD− CD27−) B hlwb tau pom tias muaj cov kab mob hnyav zuj zus thiab muaj teeb meem. Lub DN1 subset yog qhov tseem ceeb rau kev tuav lub peev xwm rau cov hlwb ua haujlwm thaum ntxov, thaum DN2 hlwb suav nrog cov tshuaj tiv thaiv kab mob PB-PB-secreting hlwb uas tau ua ntej ua ntej; Txawm li cas los xij, nws tseem tsis paub meej tias qhov cuam tshuam dab tsi rau txhua DN B cell subtype thiab cov cuab yeej cuab tam muaj rau kev daws teeb meem kab mob [129]. Interestingly, ua ntej muaj kev sib kis, qhov xwm txheej ntawm SARS-CoV-2 S2 domain antibody teb tau qhia tias nws tau sib piv cov tshuaj tiv thaiv kab mob, txhawb nqa IgA thiab IgG. Raws li kev txheeb cais, yim caum-rau feem pua ​​(86%) ntawm cov tib neeg tau pom tias muaj cov tshuaj tiv thaiv kab mob tiv thaiv qhov chaw khaws cia S2 no, nrog ntau cov tshuaj tiv thaiv uas tsim tawm tawm tsam S2 domain dua li RBD domain [130]. SARS-CoV-2 tuaj yeem suav hais tias yog qhov tshiab los ntawm kev tsis eliciting qib siab ntawm secretory IgA, xws li ob qho tib si ua npaws thiab qis dua cov kab mob hCoVs. Qhov tseeb, tus kab mob COVID{16}} mob ntev tau ua kom muaj qib siab ntawm tsib hom tshuaj tiv thaiv kab mob ntawm IgM, IgG1, IgA1, IgG2, thiab IgG3 [131–133]. Nws tau tshwm sim nyob rau hauv tus kab mob COVID-19 uas muaj ntau dua IgG1, IgG2, thiab IgG3 tshwm sim nyob rau hnub 3 nrog rau kev nce siab hauv IgA1, ploj mus los ntawm hnub 7; qhov cuam tshuam ntawm qhov no tsis meej, ib yam li cov xovtooj ntawm tes uas cuam tshuam rau qhov no, tab sis kev tshawb fawb tsis tu ncua. Ib qho kev tshawb fawb tam sim no kuj tau lees paub tias IgM–IgA1, IgM–IgG1, thiab IgM–IgG2 tau ua kom muaj txiaj ntsig zoo hauv tus kab mob SARS-CoV-2, ua rau pom qhov pib lub cev tiv thaiv kab mob [84]. Yog li ntawd, raws li cov kab no, IgA qhov sib txawv tau raug tshawb xyuas hauv sera los txiav txim siab cellular phenotypes, suav nrog FACS kev tshuaj ntsuam (n=135) ntawm PB B hlwb los qhia txog tus kab mob hnyav uas IgM thiab IgG tau zais ntawm 10 thiab 15 hnub tom qab kis kab mob. , hauv cov piv txwv no: IgM: 10.5% (ntau 4.2–54.1), IgG: 27.9% (ntau 7.4–64.8). Yog li ntawd, B plasma cells (PBs) uas tsim IgA tau ntxiv kom muaj nuj nqis los ntawm kev qhia cov cim kev loj hlob thiab B cell markers Ki67+CD19loCD27hiCD38hi los tsim IgA: 61.4% (ntau 18.1–87.6) tshwm sim hauv cov tshuaj tiv thaiv kab mob no, IgA1: 66%. Txawm li cas los xij, cov tib neeg uas muaj cov lus teb IgA tseem ceeb tau pom tias muaj feem cuam tshuam txog kev tuag ntawm tus kab mob COVID-19 hnyav, raws li hauv qab no, uas tau ntsib cov lus teb tsis zoo ntawm myelopoietic. High IgA mus rau qis IgG titrations tuaj yeem ua rau muaj qhov tshwm sim hauv tus tswv tsev, cuam tshuam nrog kev txo qis ntawm cov kab mob phagocytosis, nce cellular apoptosis, thiab nce NETosis, raws li tau tshaj tawm nyob rau hauv cov kab mob late-stage fatal COVID-19. Cov tib neeg uas muaj qhov siab IgG rau IgA piv tau nce inflammatory dampening los ntawm lub cev tiv thaiv kab mob, ua rau muaj kev cia siab zoo dua thiab daws teeb meem kab mob thaum ntxov. Cov ntaub ntawv txwv tsis pub muaj los qhia tias yog vim li cas SARS-CoV-2-induced COVID-19 kab mob nthuav tawm xws li cov tshuaj tiv thaiv kab mob tshiab txog cov lus teb ntawm IgG1/IgA1. Nws raug suav hais tias kev hloov pauv rau Ig qauv tuaj yeem tsim teeb meem, xws li kev kis kab mob ntau ntxiv lossis kev tiv thaiv kab mob thiab lwm yam kab mob xws li dengue antibody-dependent enhancement (ADE), IgG antibody qauv raug tshuaj xyuas. Cov kev hloov pauv no suav nrog glycosylation (glycan lossis carbohydrate nyob ib sab hydroxyl lossis lwm pab pawg ua haujlwm) thiab fucosylation (hloov cov piam thaj fucose los ntawm GDP-fucose mus rau lwm cov proteins lossis glycans), thiab, yog li ntawd, qhov no tuaj yeem cuam tshuam rau leukocyte extravasation thiab selectin-mediated binding los ntawm cellular. daim nyias nyias, uas tau lees paub tias yog qhov tseem ceeb hauv kev kho mob qog noj ntshav [135,136]. Yog li ntawd, cov kev tshawb fawb thaum lub sij hawm muaj kev sib kis (n=33) tau tshuaj xyuas qhov no hauv tus kab mob COVID-19 mob ntev kom paub meej tias IgG, tawm tsam SARS-CoV-2 RBD protein, tuaj yeem cuam tshuam rau Mφ tso tawm IL -1 , IL-6, IL-8, and TNF [137]. Txawm li cas los xij, IgG3 thiab IgM tau suav tias yog lub luag haujlwm rau 80% ntawm qhov nruab nrab ntawm SARS-CoV-2, nrog cov lus qhia tias IgG3 glycosylation cuam tshuam rau SARS-CoV-2 khi tshwj xeeb rau S protein [132,138]. Raws li tau hais ua ntej, glycosylation tuaj yeem tshwm sim qhov twg N-N-txuas glycan cov ntaub ntawv hauv cheeb tsam IgG-Fc. Raws li kev tshuaj xyuas IgG subtypes, ib txoj kev tshawb fawb tsis ntev los no los ntawm Brazil tau tshuaj xyuas cov avidity ntawm IgG (n=47) rau SARS-CoV{105}} cov proteins kom pom qhov nce ntawm IgG1 thiab IgG3 qib ntawm hnub 8, thiab IgG4 qib concentration tau pom tsawg dua thaum lub sijhawm kawm. Kev tuag ntawm 8-21 hnub tau pom tias muaj ntau dua los tiv thaiv RBD IgG4 qib hauv kev sib piv nrog cov rov qab los, uas cuam tshuam lwm cov kev tshawb fawb thiab tsis paub txog kev tshawb fawb txog IgG4 pathology [139]. Initial screens of N/S/E SARS-CoV{116}} proteins in me cohorts (n=320)) qhia tias anti-N IgG thiab anti-N IgA raug tsim los teb rau SARS-CoV{{121 } }, thiab IgG cov tshuaj tiv thaiv tau tsim rau S1 thiab E cov proteins, tab sis kuj hais tias cov tshuaj tiv thaiv-E cov tshuaj tiv thaiv kab mob E-protein evoked tsis tau siab dua, uas yog qhov qhia txog cov tshuaj tiv thaiv tam sim no hauv kev sim tshuaj thiab cov uas siv rau hauv kev ntsuam xyuas lateral flow [140]. Tam sim no, hauv vitro, nws tau txiav txim siab tias lub cim xeeb B hlwb raug tsim tawm mus txog 6 lub hlis, piv rau S protein, nrog IgG ntsuas ntawm 66% thiab IgM ntawm 100%, uas yuav zoo ib yam nrog kev kis kab mob lossis kev txhaj tshuaj [ 126] ​​ib.

cistanche ntxiv cov txiaj ntsig-yuav ua li cas ntxiv dag zog rau lub cev

2.6. Lub luag haujlwm ntawm B Cell Markers thaum SARS-CoV-2 Kab mob thiab Lwm yam mob

Antibody cov lus teb rau SARS-CoV-2 immunogens tuaj yeem nkag rau hauv cov tib neeg ntawm kev kho tshuaj tiv thaiv CD20 los ntawm qhov pib ntawm B cell repopulation [150]. Thaum tsis muaj B hlwb, txawm li cas los xij cov lus teb T cell muaj zog tau tsim, uas tuaj yeem pab tiv thaiv tus kab mob SARS-CoV-2-induced COVID-19 kab mob hauv cov neeg muaj kev pheej hmoo siab no [150]. Yog li ntawd, nws yog ib qho tseem ceeb kom nkag siab qhov xwm txheej ntawm cov lus teb no. Cov kws tshawb fawb xyoo 2020 pom, ua ntej muaj kev sib kis, uas nyob rau hauv tus kab mob COVID{11}} mob ntev (n=52), cuam tshuam rau tib neeg lub cev tag nrho ntawm B hlwb tsis hloov pauv loj. Txawm li cas los xij, piv rau cov tib neeg noj qab haus huv, DN1 B hlwb txo qis nrog qhov hnyav, nrog kev nce hauv DN2 B hlwb pom ntawm nruab nrab mus rau cov kab mob ntev, tab sis nco ntsoov qhov nce ntxiv hauv cov neeg mob thaum muaj kab mob hnyav ntawm DN3 hlwb, tab sis tsis muaj kev hloov pauv hauv DN4. B hlwb. Lwm cov B cell subsets yog li ntawd tau tshawb xyuas kom pom cov tshiab subset ntawm B hlwb hu ua "transitional B cells lossis TR" uas yuav cuam tshuam nrog cov txiaj ntsig kho mob raws li ntsuas los ntawm B hlwb qhia ntau CD24 tshaj CD21 [129]. Qhov no yog qhov kev tshawb pom nthuav vim hais tias CD24 qhia tau paub tias cuam tshuam rau cell migration, ntxeem tau, thiab kev loj hlob, thaum qhia lossis tsis muaj CD21 cuam tshuam nrog B cell hloov thiab nco nrog ntxiv cov proteins. CD21 kuj tau hais tawm ntawm cov hlwb follicular dendritic thiab paub tias yog koom nrog ua ke nrog cov protein ntau ntxiv (C3dg, C3d, thiab tsis muaj zog C3b) ntawm qhov chaw antigen, ua ke nrog CD19 / CD81 [115,129,151]. Qhov zoo siab, nce TR hlwb tau cuam tshuam nrog COVID-19 kab mob niaj hnub siv cov ntshav protein cov cim kuaj pom, suav nrog neutrophil/lymphocyte piv, mob theem proteins, qib ferritin, D-dimer, thiab lwm yam. Qhov tseeb ntawm DN B hlwb yuav tsum tau qhia meej ntxiv, raws li cov subsets cuam tshuam nrog SLE [152]. Raws li yav dhau los, B cell DN1 txo qis / DN2 nce hauv cov kab mob sib kis ntev -19 tau nrog cov qib siab ntawm CD69 thiab CD89 hauv DN2 hlwb, nrog rau qhov zoo li DN2 xaiv ntawm IgG, tab sis kuj qhia tias DN3 hlwb tuaj yeem tsim VH4-34 IgG autoreactive antibodies, qee qhov tuaj yeem tiv thaiv [118]. Muaj cov lus qhia thawj zaug uas germline Ig kuj sib txawv ntawm cov saw hnyav VH4-34 tau pom cov SHM zaus tsawg, uas yuav cuam tshuam rau B cell Ig maturation los ntawm cov txheej txheem SHM [153]. Unswitched nco B hlwb (CD27+ IgD+), keeb kwm, yog ib feem ntawm lub cev thiab cov kab mob tiv thaiv kab mob nrog txo tag nrho IgM-secreting B hlwb. Piv txwv li, nyob rau hauv RA, unswitched B hlwb yog xav tias yuav tshwm sim vim gene recombination, pab rau antibody xaiv los ntawm VH3-23D rau VH1-8 [108]. Interestingly, BCR repertoire ntawm cov hlwb tau hloov pauv hauv RA, nthuav tawm qee cov cim zoo ib yam li DN2 hlwb, xws li CD11c, FcRL5, thiab cov khoom siv hloov pauv (T-bet) [154,155]. Thaum cov tshuaj tiv thaiv tsim los ntawm B hlwb muaj keeb kwm zoo, nws tsis paub meej tias yog vim li cas SARS-CoV-2 tsim cov tshuaj tiv thaiv kab mob siab rau hauv qhov mob hnyav thiab tsis yog mob hnyav. Lub sijhawm ntawm cov tshuaj tiv thaiv kab mob yog qhov tseem ceeb hauv kev kho tshuaj tiv thaiv kab mob, vim tias kev siv tshuaj cuam tshuam rau tus neeg mob cov txiaj ntsig [156,157]. Naïve B hlwb tau qhib nrog kev pab ntawm follicular T (TFH) hlwb [158]. Yog li ntawd, qhov tshiab tshuaj tiv thaiv kab mob no tshwm sim los ntawm SARS-CoV-2- kis tau tus kab mob kis tau tus kab mob COVID-19 tau pom tias yog peb hom tshuaj tiv thaiv kab mob thiab isotypes, suav nrog IgM, IgG1, IgA1, IgG2, thiab IgG3, uas yuav tsum tau soj ntsuam ntxiv. Tsis ntev los no tsom xam ntawm SARS-CoV-2 S protein immunogens qhia Ig qhia los ntawm spike-specific B hlwb ntawm rau lub hlis tau tsim nyob rau hauv cov kab no: IgG: 61.33–77.46%, nrog concurrent IgA: 3.04–7.37%, thiab IgM : 12.30–24.97%, kom nco ntsoov qhov txo qis hauv IgG / IgA nrog kev nce ntxiv hauv B cell-specific IgM ntawm rau lub hlis [159,160]. Raws li tau tham ua ntej lawm, B hlwb tsim nyob rau hauv GCs thiab, los ntawm kev kawm me me (n=15), lub luag haujlwm rau kev nthuav tawm TFH hlwb tau piav qhia los qhia S-protein-specific B hlwb tsim los ntawm SHM. Nyob rau tsib lub hlis, 66% ntawm pawg neeg no muaj B nco hlwb los txhaj tshuaj tiv thaiv kab mob, thiab qhov kev tshawb fawb no tau pom tias muaj qhov nce me ntsis hauv nAb [160–163]. Concurrently nrog rau lwm yam kev tshawb fawb, unsurprisingly me me sib txawv nyob rau hauv lub cim xeeb-hloov hlwb raws li cov pej xeem tseem ceeb tau sawv cev (qhov nruab nrab: 59.92%) [163]. Lawv qhov kev tshuaj ntsuam xyuas SARS-CoV-2– cov cim tshwj xeeb B cell, CD27 thiab CD38, uas tau nrog kev nce ntxiv hauv CD27hiCD38hi PBs. Qhov no tau tshwm sim hauv cov tib neeg zoo li qub piv rau cov neeg tsis muaj kab mob ntawm rau lub hlis, nrog IgD+CD{105}} thiab IgD− CD{106}} B hlwb uas tau txo qis hauv cov mob SARS-CoV{108}} mob [161,163 ]. Cov lus teb ntxiv follicular tseem nyob rau hauv kev tshawb nrhiav thiab Woodruff li al., hauv kev tshawb fawb sib koom ua ke, qhia tias DN2 / DN1 B cell piv yuav ua rau muaj qee qhov kev tsis sib haum xeeb hauv COVID-19 kab mob hnyav nrog CXCR5 downregulated thiab CXCR3 upregulated. CXCR5 yog cov tshuaj chemokine uas tau hais qhia tshwj xeeb rau B hlwb thiab TFH hlwb ua lub luag haujlwm coj B hlwb mus rau GCs, thaum CXCR3 muaj ntau lub ligands, suav nrog CXCL8/9/10, tab sis nyiam tshaj tawm ntawm TH1 hlwb thiab feem ntau ntawm cov neeg T cell, DCs, thiab nco B hlwb. Cov ntaub ntawv pov thawj tau tshwm sim tias kev txhim kho lossis kev hloov pauv hauv cov tshuaj no thiab lwm yam tshuaj lom neeg (CXCR3, CXCR5, CCR7) hauv kev kis mob hnyav thiab kev txo qis hauv qhov hnyav yuav yog qhov qhia ntxiv ntsig txog kev loj hlob ntawm DCs [162,163]. Kev txheeb cais tseem ceeb tau pom meej ntawm cov tshuaj tiv thaiv kab mob zais cia ntawm tes (ASC) nthuav dav nrog cov qib siab ntawm CD21-B hlwb ywj pheej ntawm lub sijhawm kis kab mob [164,165]. B hlwb tswj cov tshuaj tiv thaiv kab mob, thiab cov ntawv ceeb toom qhia tias IL-10 thiab IL-21 yog lub luag haujlwm rau B cell class-hloov mus rau IgG1, IFN- chav kawm-hloov mus rau IgG2, thiab TGF- hloov ntawm IgA1 rau IgA2 lus teb [133]. Kev tshawb fawb qhia tau hais tias IgG1 thiab IgG3 (n=123) sib cuam tshuam nyob rau hauv chronic SARS-CoV-2 qhov hnyav nrog cytokine IL-1 teb [119]. IgG2 xav tias muaj feem cuam tshuam rau cov kab mob cov lus teb rau capsular polysaccharide antigens. Concurrent in vitro studies kuj qhia tau hais tias SARS-CoV{151}} IgA1 thiab IgG3 tej zaum yuav muaj kev tiv thaiv tsis zoo hauv SARS-CoV{155}} tus kab mob [164,165]. Kev tshawb fawb ntxiv yuav tsum tau ua kom paub meej qhov kev thov no. Lwm cov kev tshawb fawb (n=82) paub meej tias nyob rau hauv mob SARS-CoV{160}} tus kab mob, nyob rau hauv xya hnub, cov tshuaj tiv thaiv kab mob hauv cov ntshav yog 60% IgA, 53.3% IgM, thiab 46.7% IgG, nrog IgG ncav cuag 100 % los ntawm hnub 2 [166,167]. Yog li ntawd, ib leeg-cell transcriptomic kawm tsom xam ntawm tus kab mob hnyav COVID{171}} hauv kev nthuav dav qhia tias DN1 hlwb qhia IgA2 cov noob, thiab tuaj yeem ua rau muaj peev xwm zais IgA2, thaum DN3 B hlwb tau pom los qhia IgM noob tsis nyob hauv DN2 hlwb, nrog DN4 hlwb muaj cov noob IgE thiab coj Fc receptor noob (saib daim duab 3) [118]. Qhov txaus siab, qhov no ua rau muaj peev xwm muaj qhov sib txawv ntawm T cell-yooj yim thiab T cell-dependent txoj hauv kev hauv B hlwb thaum muaj tus kab mob COVID{182}}, uas tam sim no tau qhia hauv lwm qhov kev tshawb fawb. IgE, yog li ntawd, tuaj yeem tsim los ntawm DN4 B hlwb, tab sis serology los ntawm COVID{184}} cov neeg mob tsis tau txiav txim siab tias muaj feem cuam tshuam rau cov cellular subset [118,129,168,169]. IgE paub tias ua rau mast cell degranulation los ntawm ntau dua affinity FcεRI receptor, thiab assay rhiab heev yuav tsum tau validation thiab kev loj hlob rau cov tshuaj tiv thaiv no ib txwm pom nyob rau hauv kev tsis haum tshuaj nrog cov lus teb ntawm IgG predominant thaum kis kab mob. Nws yog ib qho tseem ceeb uas H2 receptor, tam sim no nyob rau hauv plab hnyuv mucosa, hlwb, thiab mast hlwb, tau tsom siv ib tug antagonist famotidine nyob rau hauv kev sim, thiab tau pom tias muaj ib co cuam tshuam nyob rau hauv modulating SARS-CoV-2-cov tsos mob tshwm sim nrog synergism nrog macrophage TH2 cytokines [170–172].

3. Inflammatory Cells thiab Phagocytes

3.1. Neutrophil Taw Qhia

Polymorphonuclear neutrophils (PMN) yog granular thiab trilobed, yog cov feem ntau circulating leukocyte, sawv cev ntawm 40% thiab 80% ntawm leukocytes nyob rau hauv ib txwm neeg laus. Neutrophil infiltration nyob rau hauv cov ntaub so ntswg ua pa yog yam ntxwv ntawm ntau yam kab mob in-inflammatory [173]. Neutrophils yog granular, ua tawm tsam antigens los ntawm dispersing azurophilic cytoplasmic granules siv cov kev ua ntawm proteolytic enzymes (xws li, myeloperoxidase, elastases, thiab proteinase-3) tab sis kuj lactotransferrin, lysozyme, los yog reactive oxygen hom (ROS), uas kuj yog anti-microbial hom. , rau tshem tawm cov kab mob [174,175]. Pathogenic stimuli ua rau cellular calcium tso tawm ntawm endoplasmic reticulum (ER), ua rau ua kom cov protein kinase C (PKC) thiab sib dhos ntawm NADPH oxidase complex generating ROS. Neutrophils tsim cov kab mob hematopoietic stem cells (HPSCs) hauv cov pob txha pob txha thiab luv luv, nyob nruab nrab ntawm 1 thiab 7 hnub, thiab hla cov cell membranes los ntawm selectin-dependent capture thiab integrin-mediated adhesion (saib Cov Ntaub Ntawv Ntxiv S1), tom qab ntawd tsiv mus rau cov ntaub so ntswg. tshwm sim, thiab lawv muaj sia nyob rau 1-2 hnub thaum ncig thiab tshem tawm los ntawm phagocytosing Mφ. Kev loj hlob ntawm neutrophils tshwm sim hauv pob txha pob txha los ntawm progenitor neutrophils thiab tuaj yeem faib dav dav raws li cov cim CD raws li CD81+CD43+CD15+CD63+CD66b+, uas txawv rau qhov tsis paub tab. neutrophils qhia CD11b+CD66b+CD101+/-CD10-CD{25}}/- ua ntej maturing nyob rau hauv cov pob txha pob txha qhia CD11b+CD66b+CD101+CD10+CD16 [ 176] ib. CD16 yog sib koom ua ke ntawm lwm cov hlwb suav nrog NK hlwb, monocytes, Mφ, thiab qee lub T hlwb [176]. CD16 (Fc RIII) muaj cov subtypes xws li CD16a thiab CD16b (Fc RIIIa/Fc RIIIb), thaum CD11 thiab, tshwj xeeb, CD11b raug cais raws li qhov cuam tshuam rau kev tsiv teb tsaws thiab mob ntsws [177–179]. Nws yog ib qho tseem ceeb uas CXCR2 thiab CXCR4 zoo li yog cov tswj hwm tseem ceeb hauv lub xov tooj ntawm tes uas cuam tshuam rau hauv lub ntsws fibrosis, tab sis cov no kuj hloov kho cellular mitochondrial kev ua, neutrophil tsiv teb tsaws, thiab neutrophil homing siv adhesion receptors uas suav nrog CD62L [180–184]. Txawm li cas los xij, tsis ntev los no, CD11b thiab CD18, uas tau nthuav tawm thoob plaws, tam sim no xav tias yuav tsum tau CD47 hauv kev hloov pauv hauv epithelial [185,186]. Interestingly, Alberca et al. tshuaj xyuas ib lub xovtooj tshiab subtype, txhais tau tias yog myeloid-derived suppressor (MDSC) hlwb, nyob rau hauv cov ntaub ntawv tshawb fawb: CD33+CD11b+HLA-DR-CD14-CD66b+ thiab CD33+CD11b+HLA- DR- CD14+CD66b-cells. Hauv cov ntshav peripheral cov cim ntawm tus kab mob COVID-19 ntev, qhov no tau pom tias muaj feem cuam tshuam txog M-MDSC thiab polymorphonuclear P-MDSC, uas tau txuas rau kev mob ntev [186]. Cov MDSC-txhais hlwb no tau piav qhia thawj zaug hauv kev mob qog noj ntshav, HCV, thiab HIV los cuam tshuam rau T cell proliferation. Cov lus qhia tsis ntev los no ntawm putative phenotypes tshwm sim raws li M-MDSC (CD11bloD14+CD15-HLA-DR-) thiab P-MDSC li CD11bloCD14-CD15+ HLA-DR- tau raug qhia kom cuam tshuam TREGS raws li hauv qab no los ntawm TGF- cuam tshuam tag nrho qhov sib npaug ntawm TREGS thiab tus kheej-tolerant DCs [187].

cistanche ntxiv cov txiaj ntsig-yuav ua li cas ntxiv dag zog rau lub cev

3.2. Neutrophil Cellular Markers after Host SARS-CoV-2 Infection during COVID-19 Disease

Thaum muaj tus kab mob COVID-19, nws ntseeg tau tias neutrophils tsim neutrophil extracellular ntxiab (NETs), raws li peb tau tham saum toj no, qhov twg lub xov tooj ntawm tes taw qhia nyob rau hauv raug cuam tshuam, ua rau active degranulation los yog "NETosis/neutrophil apoptosis" [188]. Cov txheej txheem tseeb ntawm NETosis kev koom tes tseem tsis paub [189]. Yog li, cov ntaub ntawv tshawb fawb tsis ntev los no (n=64) tau tsom mus rau kev txheeb xyuas cov neutrophils 'cellular markers ntxiv. Thaum lub sij hawm COVID-19 kab mob, qee qhov tshwm sim los txwv kev txhawb nqa ntawm IFN- ntau lawm nrog cov xov tooj ntawm tes tsis paub uas txhawb nqa T cell proliferation tab sis ua tsis tau T cells [190]. Ntau tus kws sau ntawv qhia tias tus tswv tsev uas muaj lub cev tiv thaiv kab mob yog qhov ua rau tsis muaj kev tsim tawm ntawm hom I thiab III interferons ua ke nrog cov tshuaj chemokines siab, thiab IL-6 yog qhov ua rau muaj tus kabmob coronavirus [191,192]. Txawm hais tias IL-6 tuaj yeem yog qhov tseem ceeb tshaj plaws cytokine regulator ntawm NETosis, lwm cov cim cov protein tau pom meej dua, cov uas yog extracellular DNA (cDNA), neutrophil elastase (NE) kev ua, los yog myeloperoxidase-DNA (MPO-DNA), thiab cov correlates nrog cov kab mob hnyav, ntsuas hauv neutrophils los ntawm cov cim CD33loCD16+CD11b+ [193]. Cov kws tshawb fawb tsis ntev los no pom (n=155) tias NE, histone-DNA, MPO-DNA, thiab dawb ob-stranded DNA (dsDNA) tau nce nrog DNase txo qis thiab exacerbation ntawm neutrophil stimulation tshwm sim ntawm IL-8 , CXCR2, thiab DAMPs nrog kev puas tsuaj ntawm NETs ntawm DNase 1 thiab DNase 11L3, uas tau pom zoo los ua tus tswj hwm ntawm neutrophil DNA metabolism [194]. Cov lus piav qhia tsis ntev los no kuj txhais tau tias muaj kev sib raug zoo ntawm cov no thiab cov membrane-bound lossis soluble CD13 [195]. Kev tsom xam neutrophil (n=384) siv ib leeg-cell tsom xam cais rau lub xeev cell txhais los ntawm inflammatory gene kos npe (IGS) los qhia tias concordant IgA1: IgG1 piv tau nce siab hauv cov kab mob coronavirus tuag, nrog IgG qhia txog cov tshuaj tiv thaiv kab mob. neutrophil phagocytosis thiab IgA2 inducing apoptosis [133]. Interestingly, neutrophils qhia tau nce qib thaum lub sij hawm loj hlob ntawm CD32 (Fc RII), CD16b (Fc RIIIb), thiab CD89 (Fc R), lub ntsiab Ig receptors uas muaj feem ligands ntawm B hlwb, saum toj no. Tsis muaj kev tshawb fawb paub tam sim no muaj txuas rau hom III IFN nrog qhov hloov pauv isotype. Ib qho kev tshawb nrhiav zoo sib xws rau IgA2 (n=97) tau lees paub tias cov tshuaj tiv thaiv SARS-CoV-2 IgA2 hauv cov kab mob COVID-19 hnyav cuam tshuam nrog cDNA [131]. Syncytia tsim thiab NETosis muaj feem cuam tshuam rau kev tsim cov tshuaj tiv thaiv kab mob raws li qhov tsis txaus ntseeg vim los yog tshwm sim los ntawm coagulopathy thiab immunothrombosis [131,193]. Cov kab mob endothelial nyob rau hauv ob qho tib si tsiaj thiab tib neeg kev tshawb fawb pom tias cov kab mob endothelial tuaj yeem kis ncaj qha; Txawm li cas los xij, cov kev tshawb fawb pom tias colocalization nrog CD31 nyob rau hauv ib qho kev cuam tshuam ntawm cov kab mob endothelial, raws li pom meej los ntawm kev txhim kho ntawm ntau cov adhesion molecules (piv txwv li, P-selectin) thiab chemotactic factor tso tawm ntawm CXCL10 nrog rau IL-6 (saib Cov Ntaub Ntawv Ntxiv S4) [ 196, 197] ib. Lwm yam tseem ceeb uas cuam tshuam nrog platelet coagulation yog vWF, nrog nce P-selectin thiab E-selectin upregulation, pom nyob rau hauv cov neeg mob tus kab mob COVID-19, uas yog tag nrho cov koom nrog endothelial dysfunction [76,198]. Tshawb nrhiav qhov no ntxiv, Kuchroo et al. tau ua ib txoj kev tshawb nrhiav ib leeg-hlwb (n=168) ntawm tus kab mob SARS-CoV-2 cov neeg mob uas sib txawv ntawm cov neeg neutrophil thiab monocyte nrog cov cim monocyte (CD16hiCD66b/CD14-CD16hiHLA-DRlo) txhawm rau nrhiav T tus pab 17 (TH17) cell teb generated IFN- thiab granzyme B [199]. Hauv qhov kev tshawb pom tseem ceeb no, CD14-CD16hi monocytes tau ua kom muaj kab mob hnyav, thiab nws tau lees paub tias HLA-DR upregulation cuam tshuam nrog qhov hnyav. Xyoo 2020, nws tau tshwm sim hauv cov neeg mob COVID-19 mob ntev uas IL-2, IL-4, IL-6, IL-10, TNF- , thiab IFN - nrog C-reactive protein (CRP) correlated nrog IL-10 [34]. IL-1 yog ib qho tseem ceeb cytokine cuam tshuam nrog kev ua haujlwm ntawm neutrophil, uas qhia txog homology thiab cov haujlwm zoo sib xws nrog cov tsev neeg TLR tau hais tseg [64,200]. IL-1 thiab IL-1 tau cuam tshuam rau COVID-19 kab mob hauv lwm qhov kev tshawb fawb. Yog li ntawd, cov txheej txheem tseeb ntawm kev tswj hwm enzyme glycosyltransferase, -1, 6-fucosyltransferase (FUT8) tau raug tshuaj xyuas, tsuas yog nrhiav kev cuam tshuam me me nrog cov kab mob prognosis, tab sis nws tau pom tias cov lus qhia receptor yog upregulated nyob rau hauv lwm yam myeloid. monocyte compartments uas qhia CD16a (Fc RIIIa), kuj suav nrog classical (CD14hi/+, CD16−−) thiab nruab nrab (CD14hi/+, CD16lo/+), thiab non-classical (CD14−−/lo, CD{108} } ) cov cim uas tseem suav nrog CD11c DCs uas kuj yog HLA-DR + myeloid hlwb [146,201–204]. Kev sim tshuaj kho mob tseem txuas ntxiv mus ntxiv kom paub meej cytokines IL-1 , IL-6, IL-8, TNF- , TGF- , IFN- , IL-17, IL{{122} }, IL-22, IL-23, thiab IL{125}}, thiab ROS ntau lawm hauv COVID pneumonia, nrog cov txiaj ntsig tos (Cov Ntaub Ntawv Ntxiv) (NCT04930757, NCT04434157, thiab NCT05520918). Raws li saum toj no, neutrophil proteins cuam tshuam thaum NETosis ib txwm yuav cuam tshuam rau cov ions extracellular thiab, tshwj xeeb tshaj yog, calcium homeostasis xav tau los ntawm lwm cov cytoskeletal proteins nrog intracellular enzymes, tsis tas yuav degraded, uas muaj MPO, histones, thiab lwm yam proteases nyob rau hauv no cytokine thiab lub cev tiv thaiv kab mob ib puag ncig [205 ].

3.3. Monocyte Cellular Development

Txij li thaum lub advent ntawm FACS thiab nrhiav pom ntawm monocytes los ntawm Ehrlich thiab Metchnikoff, tam sim no txheeb xyuas cov monocyte subsets yog dav txhais los ntawm classical (CD14hi / +, CD16−), nruab nrab (CD14hi / +, CD16lo / +), thiab tsis classical (CD14). −/lo, CD16+ ) markers [203,206,207]. Monocytes sawv cev ib ncig ntawm 10% ntawm cov neeg leukocytes, thiab lawv nyob luv luv (1-2 hnub) thaum ncig hauv cov ntshav, pob txha pob txha, thiab tus po (saib daim duab 4).

Daim duab 4. Antigen-presenting cell roles in SARS-CoV-2 infection

3.4. Monocyte Cellular Markers thaum Host SARS-CoV-2 Infection

Hauv COVID-19 tus kab mob, nws tau hais tias classical CD14++CD16−− monocytes yog qhov chaw ntawm cov tshuaj kho mob CCR2, nrog rau cov tshuaj neutrophil chemoattractant IL-8 (CXCL8) thiab TNF- nrog. upregulated gene qhia thiab synthesis ntawm IL-1 thiab IL-18 nrog tsawg dua CD{9}}CD16++ monocytes. Ntxiv mus, kev txo qis ntawm HLA-DR hauv cov neeg mob hnyav (n=12) tau pom tias cuam tshuam rau tag nrho cov kab mob antigen nthuav qhia [201,211,212]. Cov neeg ntawm cov cellular no ntxiv tus cwj pwm los ntawm CD195 (CCR5), nrog rau TNF- receptors CD120a / CD120b (TNFR1/2). Ob leeg ntawm cov receptors no tau pom nyob rau hauv cov ntshav ntshav thiab kev tswj hwm nrog ADAM17, paub tias cuam tshuam L-selectin (CD62) shedding, nrog ADAM17, ib qho TNF- convertase, kuj upregulated hauv inflammatory plob tsis so tswj kab mob (IBD) [213,214]. Lwm cov tshuaj tiv thaiv kab mob hauv lub cev tiv thaiv kab mob tau ntsuas hauv sera (sCD14 thiab sCD163), thiab, txawm hais tias tsis cuam tshuam txog kev mob hnyav, lawv cuam tshuam nrog cov txheej txheem ntshav sera proteins (mob theem protein, ferritin, LDH, CRP, thiab procalcitonin) [215]. Tsis tas li ntawd, CCR5 inhibition kev tshawb fawb, thaum lub sij hawm ntev SARS-CoV{36}} kab mob thiab kab mob, pom tau hais tias hloov mus rau CD14/CD16 subsets tshwm sim, cuam tshuam rau pro-inflammatory cytokines ib sab CD4+/CD8+ T cell txo. Cov kws tshawb fawb no tau pom tias IL-2, IL-4, CCL3, IL-6, IL-10, IFN- , thiab VEGF tau nce siab thiab, tsis tas li ntawd, TREG hlwb poob nrog concurrent GM-CSF txo, cuam tshuam kev loj hlob ntawm monocyte [216]. FACS tsom xam tau siv rau NK cell tsom xam thiab sib txawv CD14hi/+, CD16−−monocytes los ntawm CD16 marker kom pom tshwm sim los ntawm inflammasome activation (NLRP3) pov thawj los ntawm caspase-1 kev ua ub no nyob rau hauv mob hnyav COVID-19. Qhov no tau pom zoo nrog dysregulation ntawm mitochondrial superoxide thiab lipid peroxidation cov cim ntawm oxidative kev nyuaj siab. Cov kev tshawb pom no tom qab tau lees paub thaum lub sij hawm kev tshawb fawb gasdermin D cleavage [217]. Gasdermin D (GSDMD) yog lub npe hu ua pore-forming protein ntau pom tau tias tau qhib los ntawm SARS-CoV-2 kab mob ntawm neutrophils, raws li ntsuas los ntawm caspase 1/3 ua kom muaj peev xwm NETosis thiab pyroptosis stimulator [218,219]. Tsis tas li ntawd, 6% ntawm SARS-CoV-2 cov kab mob monocytes tau pom tias muaj lwm cov cim pyroptotic thaum ntsuas GSDMD, IL-1 , IL-1RA, IL-18, thiab LDH, nrog rau peb qhov tseem ceeb chemokines: CCL7, CXCL9, thiab CXCL10 (saib daim duab 5) [220]. Cov kev tshawb fawb hauv vitro tau pom tias qhov no tuaj yeem ua rau IL-1 zais cia los ntawm SARS-CoV-2-exposed monocytes [221]. Tshwj xeeb, cov naj npawb ntawm cov kab mob sib xyaw ua ke (CD14hi / +, CD16−) tau ntxiv nrog kev txo qis ntawm CCR2 thiab HLA-DR, tab sis cov lej nruab nrab (CD14hi / +, CD16lo / +) thiab tsis yog classical (CD14− / lo. , CD16+ ) monocytes nce [222]. Alternative transcriptomic analysis tau lees paub tias nruab nrab CD14hi/+CD16lo/+ muaj ib lub sijhawm interferon-stimulated gene kos npe (ISG) hauv tus kab mob SARS-CoV-2 (IRF7, IFI44L, IFIT1, thiab IFIT3). Kev tshuaj ntsuam kuj, zoo kawg li, qhia tau hais tias IL-8 (CXCL8) thiab IL-1 ua ke nrog CCL3 tau raug kho kom zoo yam tsis muaj induction ntawm pro-inflammatory cytokine noob xws li TNF, IL-6, IL -1, CCL3, CCL4, lossis CXCL2 hauv cov hlwb uas muaj qhov txo qis HLA-DR qhia thiab txo cov peev xwm nthuav tawm antigen [223]. Ntawm qhov tod tes, tsis ntev los no, hauv kev tshawb fawb SARS-CoV{117}} case-control (n=37), nws tau qhia meej tias muaj qhov pib nce hauv cov monocytes classical (CD14hi/+, CD16. −−) nrog kev txo qis hauv nruab nrab (CD14hi/+, CD16lo/+) thiab maj mam normalization ntawm non-classical monocytes (CD14−/lo, CD16+) 6-7 lub hlis tom qab ua raws, nrog kev hloov rau lwm cov cell subtypes hauv qab no [203,204,207,224].

3.5. Macrophages Metabolism thiab Function

Nyob rau hauv 1950-1970, macrophage (Mφ) metabolic cycles tau soj ntsuam zoo nyob rau hauv dab tsi yog ces hu ua Warburg nyhuv, qhov Mφ nyob rau hauv cov qog pom tau hloov metabolic profiles. Tseeb, kev tshawb fawb tsis ntev los no qhia tau hais tias kev ua kom Mφ lossis DCs nrog ntau yam stimuli (LPS, TLR3 ligand poly (I: C), hom I IFN) induces ib tug metabolic hloov. Metabolic profiles yog li hloov los ntawm oxidative phosphorylation (OXPHOS) mus rau glycolysis nrog ib tug txo nyob rau hauv lub TCA voj voog, thaum lactate ntau lawm drives Mφ metabolism thiab fluxes upwardly los ntawm pentose phosphate txoj kev [225]. Mφ yog hom tshuaj tiv thaiv kab mob ntau tshaj plaws hauv lub ntsws, cais raws li alveolar φ (AMφ) lossis interstitial (iMφ). Macrophages (Mφ) pib los ntawm cov ntshav monocytes uas tsiv ntawm cov ntaub so ntswg vascular nrog morphology lees paub TLRs, kab mob sib txuas nrog cov qauv (PAMP), thiab cov kab mob antigens. Cov lus xaus yog qhov nyuaj rau kos nrog siv Mφ kev cuam tshuam nrog B / T hlwb, raws li tau piav qhia hauv qab no (saib daim duab 6).

Daim duab 5. Monocyte cell phenotypes.

3.6. Macrophage Classification

Cov ntaub ntawv tsawg dua tau txhais tau hais tias interstitial macrophages (iMφ), piv rau alveolar macrophages (AMφ) tau txhais tau zoo raws li kev tswj hwm ntawm lub ntsws pulmonary immune re sponses. AMφ thiab iMφ yog ob qho tib si cov ntaub so ntswg phagocytic hlwb uas tseem suav nrog lub hlwb microglia, lub siab Kupffer hlwb, thiab lwm yam. Yog li ntawd, AMφ yog qhov txawv ntawm lawv lub peev xwm los ntxias thiab cuam tshuam cov lus teb rau cov kab mob tshwm sim, thiab hloov pauv cov cim ntawm lub xov tooj ntawm tes siv cov khoom siv ntxiv rau opsonization receptors thiab lwm cov qauv kev paub txog cov molecules, raws li saum toj no, uas pab txhawb phagocytosis ntawm cov khib nyiab lossis cov kab mob [226]. Mφ tus cwj pwm tom qab xoob sib txawv ntawm qhov sib txawv ntawm cov phenotypes, feem ntau hu ua M0 (tsis ua haujlwm), M1 (pro-inflammatory), thiab M2 (anti-inflammatory) los ntawm polarization thiab cytokine secreted tab sis tam sim no tsis tau txhais. los ntawm CD nomenclature [227,228]. Raws li M-CSF thiab GM-CSF ua rau muaj kev sib txawv, nws tau pom tias Mφ tau muab faib ua M1φ zais cytokines IL1- , IL-6, IL-12, thiab TNF- , nrog M{ {18}}zoo li zais TGF- , IL-10, IL-4, thiab IL-13 (saib daim duab 7) [229].

Daim duab 6. Macrophage txheej txheem thiab lub luag haujlwm ntawm kev kis kab mob.

Daim duab 7. Macrophage phenotypes thaum lub sij hawm polarization.

3.7. Macrophage Metabolism Role thaum lub sij hawm Polarization thiab SARS-CoV-2 Infection

Macrophage polarization yog tus txheej txheem uas Mφ hloov zuj zus los ntawm kev loj hlob thiab txais kev ua haujlwm sib txawv thiab cov kev pabcuam zais cia hauv cov lus teb rau cov teeb liab los ntawm microenvironment uas lawv nyob ntawm ib qho chaw hauv lub sijhawm. Qhov no ob lub innate thiab adaptive peev xwm muaj feem xyuam rau ntau lub luag hauj lwm nyob rau hauv tag nrho cov kab mob raws li effector hlwb koom nyob rau hauv lub hauv paus ntawm feem ntau cov txheej txheem lom. Tshwj xeeb tshaj yog, lawv tau koom nrog hauv kev tshem tawm cov khib nyiab ntawm tes, cov kab mob, kev loj hlob ntawm embryonic, thiab cov ntaub so ntswg kho siv cov kab mob hauv lub cev uas muaj xws li B lymphocytes, DCs, TH1, TH2, NK hlwb, thiab lwm yam, hauv qab no (saib Daim duab 1 — 12) [232]. Nws yog ib qho tseem ceeb uas IFN- tau xav tias polarize M1φ, ua rau muaj kev tswj hwm ntawm cov kab mob cytokines thaum kis kab mob thaum inhibiting kev loj hlob thiab txhim kho apoptosis ntawm lub ntsws hlwb hauv vitro [233]. Dysregulation ntawm AMφ polarity yog li yuav tsum tau txiav txim siab nyob rau hauv cov ntsiab lus nrog rau lwm yam nyob rau hauv vitro los yog nyob rau hauv vivo kev tshawb fawb txog kev ua pa qhov twg ob leeg fibrosis thiab o tuaj yeem tshwm sim (xws li, silicosis) [234]. M1φ thiab M2φ, nrog rau cov cim noob caj noob ces nyob rau hauv bronchoalveolar lavage kua (BALF), yog ib txoj hauv kev los xyuas qhov kev hloov pauv ntawm lub xeev polarity cuam tshuam nrog tus kab mob. Cellular staining txoj kev xws li hematoxylin / eosin thiab trichrome staining ntawm lub ntsws tuaj yeem siv tau. M1φ / M2φ phenotypes tshwm sim rau kev hloov pauv phenotype sib txawv cuam tshuam rau T hlwb thiab qhov tshwm sim Ig chav kawm hloov pauv, nrog rau kev nthuav qhia sib txawv antigen nrog rau cov tshuaj chemokine thiab cytokine tso tawm hauv ob qho tib si ua pa thiab mucosal compartments, uas cuam tshuam los ntawm cov hauv qab no. M1φ tuaj yeem tsim nitric oxide synthase (iNOS), uas siv L-arginine los tsim nitric oxide (NO) thaum M2φ siv arginase 1 (ARG1), uas hydrolyses L-arginine rau L-ornithine rau collagen synthesis. Yog li ntawd, thaum lub sij hawm kis kab mob thiab / los yog phagocytosis ntawm Mφ, kev hloov nyob rau hauv extracellular metabolites yuav tshwm sim, cuam tshuam polarization thiab hloov oxidative phosphorylation tshuav nyob ntawm cov amino acid noj. Tsis tas li ntawd, nws muaj peev xwm hais tias M1φ metabolizing extracellular arginine rau hauv NO thiab L-citrulline nrog nce glycolysis, fatty acid synthesis, thiab ATP metabolism tuaj yeem hloov cov theem ntawm metabolites. Hauv kev sib piv, M2φ qhia txog kev txhim kho OXPHOS thiab glutamine metabolism yog li sawv cev rau kev hloov pauv ntawm cov cellular uas tuaj yeem tshwm sim zoo sib xws [235–237]. Kev tshawb fawb tsis meej txog seb qhov kev ua kom M2φ yog glycolysis nyob ntawm. Yog li ntawd, cov metabolism hauv COVID-19- cov tib neeg cuam tshuam yog qhov tseem ceeb rau lub cev tiv thaiv kab mob uas cov neeg mob txo qis tryptophan tau pom nrog qhov nce hauv L-kynurenine, uas feem ntau nce nrog hnub nyoog [238]. Tryptophan yog ib qho tseem ceeb amino acid tswj los ntawm enzymes indoleamine 2, 3-dioxygenase-1 (IDO-1) los yog indoleamine 2,3-dioxygenase-2 (IDO-2), thaum kawg ua rau tsim kynurenine. Cov kws tshawb fawb tau qhia meej txog IDO-2 hauv kev tshawb fawb txog kev tswj xyuas cov ntaub ntawv (n=21) nrog cov kab mob zoo sib xws kom paub meej tias ob qho tib si IDO-1 thiab IDO-2 tshwm sim muaj ntau nyob hauv thiab sab nraud AT1, AT2 hlwb, interstitial, thiab endothelial hlwb, nrog IDO-2 tau nyob rau hauv lub ntsws ntau dua li cov ntaub so ntswg. Xaiv cov kab mob tiv thaiv kab mob (Mφ, DCs, thiab neutrophils) tsiv mus nyob rau hauv cov pa ua pa hauv SARS-CoV-2- kis tau tus kab mob COVID-19 [238,239]. Yog li ntawd, qhov kev lees paub pom tseeb tias IDO tau hais tawm hauv tus kabmob, nrog rau qhov muaj tsawg ntawm lwm cov kev tshawb fawb, qhia tias paub xaiv M2φ cov cim IL-10/CXCR4 tuaj yeem nce ntxiv, thaum T cell homing receptors CCR7 thiab IL{{56 }}A (IL-12p35) tau paub tias txo qis hauv lwm cov mob fibrotic [240]. M1φ thiab M2φ phenotypes pom tseeb dua nrog rau lwm yam hauv vivo cov kab mob thiab cov kab mob kis [241,242]. Fibrosis tshwm sim nyob ib puag ncig cov hlab ntsha thiab hauv cov txheej txheem endothelial thiab nkag siab txuas rau COVID-19 kab mob thiab cov kab mob mus sij hawm ntev uas cov ntaub so ntswg txhav, nrog rau kev txo qis oxygenation thiab lub ntsws ua haujlwm tsis zoo. Piv txwv li, Galectin -3, raws li cov carbohydrates-binding protein, yog tsim nyob rau hauv lub ntsws los ntawm AMφ thiab epithelial hlwb. M2φ tso tawm ntawm TGF- lossis IL-10 tuaj yeem ua rau muaj qhov tso tawm ntawm cov ntaub so ntswg-modeling proteins lossis tswj TREG hlwb hauv mob ntsws mob. TGF- yog suav tias yog ua synergistically nrog -AMφ nyob rau hauv lub secretion ntawm retinal dehydrogenase (RALDH), ib tug enzyme uas catalyzes lub retinal rau retinoic acid hloov dua siab tshiab nyob rau hauv lub cell, uas yog ib qho tseem ceeb rau lub transcription factor retinoic acid-txog menyuam ntsuag receptor gamma t ( ROV t) [235,243,244]. Cov ntaub ntawv tsis ntev los no qhia tias M2φ yog nyob ntawm kev tsim hluav taws xob ntau dua [235,236,244]. Yog li ntawd, raws li tau hais los saum toj no, tsuas yog lwm yam kev tiv thaiv kab mob hlwb, cov hlwb mast, basophils, thiab eosinophils, tau tham txog lwm qhov tab sis tau tshawb xyuas hauv 2021.

Daim duab 8. Muaj ntau hom kev ua haujlwm ntawm cov hlwb dendritic hauv kev loj hlob

Daim duab 9. Dendritic cell phenotypes

Daim duab 10. Ntuj killer cell phenotype ntau haiv neeg thiab maturation

 Daim duab 11. T-Cell phenotype muaj ntau haiv neeg thiab kev loj hlob ntawm tes

Daim duab 12. T cell phenotype ntau haiv neeg thiab kev loj hlob cellular cim

3.8. Macrophage Phenotypes, Cytokines thiab Chemokines thaum SARS-CoV-2 Infection

SARS-CoV-2-mob Mφ nyob rau hauv vitro tau pom los ua colocalize ntawm endothelial cell membranes, qhia CD31 (PECAM-1) nrog rau cov endothelial cell endosomes thiab tseem qhia cov cim ua rau exosomes qhia mRNA rau IL{{4} } , caspase 1, thiab NLRP3 los ntawm cov neeg mob [249]. Nws yog ib qho tseem ceeb uas ua kom tiav opsonization receptors suav nrog CR1 / CR2, tab sis kuj exosomes CR3 thiab CR4 (2 integrin), nrog rau CD11b / CD18 (M 2) qhia ntawm neutrophils uas tuaj yeem khi iC3b ua phagocyte receptor zoo, txawm hais tias muaj ntau cov integrin subunits. kuj raug tswj hwm (saib Cov Ntaub Ntawv Ntxiv S1). Yog li HLA-DR (encoded ntawm chromosome 6p21.31), tau pom los nthuav qhia S protein antigens thiab kev sib xyaw peptide units ntawm S1 / S2 / RBD, yog li qhov no tau sawv cev rau qhov tseem ceeb pom tias kev nthuav qhia antigen tau tshwm sim [233]. Qhov zoo siab, ob qho tib si Mφ thiab MDSC nthuav qhia CD68 thiab CD163, uas tau tshawb xyuas hauv 2018 hauv cov ntsiab lus ntawm thrombocytopenia (ITP) los sim thiab qhia meej MDSCs phenotypes ntxiv. Thawj qhov qhia tau hais tias chemokine receptors thiab ligands qhia leukocyte tsiv teb tsaws tau tshwm sim nrog CCL2 / CCL3 thiab eotaxin. Nws kuj tau qhia tias IL-1 tuaj yeem nthuav dav ob hom cell no hauv ITP cov neeg mob ua ntej [250]. Tsis tas li ntawd, ib leeg-hlwb sequencing ntawm SARS-CoV-2 nyob rau hauv lwm yam kab mob inflammatory (RA/CD/UC) qhia meej tias, hauv BALF cov qauv thaum lub sij hawm tus kab mob COVID-19, qhov kev nyiam tshaj tawm tshwm sim ntawm CXCL10, CXCL9, CCL2 , CCL3, thiab IL-1 (tseem GBP1, STAT1 noob proteins). Cov no kuj tau raug ntxias los ntawm IFN- thiab TNF-, yog li qhia meej tias M1φ yog qhov ua rau mob rau COVID-19 kab mob. Txawm li cas los xij, Mφ subpopulations ntxiv tus cwj pwm los ntawm HLA-DR, CD195 (CCR5), thiab TNFR1 / TNFR2 qhia, uas tseem siab dua ntawm nruab nrab monocytes, ua raws li classical thiab tom qab ntawd tsis yog classical monocytes nrog rau Mφ [251]. Daim ntawv sau ua ntej tsis ntev los no qhia tias, nyob rau hauv mob SARS-CoV-2 kab mob, monocytes hloov IGS los ntawm lub cev tiv thaiv kab mob ua haujlwm raws li CD14+ monocytes txhim kho mus rau pro-thrombotic, qhia qhov sib txawv ntawm kev sib txawv ntawm MHC II nrog rau MHC I downregulation ( HLA-DR/HLA-ABC), nrog rau cov noob caj dab kos npe downregulated uas yuav cuam tshuam rau IFN ntau lawm (piv txwv li, IFNA1, IFNA2), tab sis kuj TLR7 thiab AIM2, cuam tshuam rau kev nthuav qhia txoj hauv kev koom nrog hemostasis thiab immunothrom bosis [207]. Hauv qhov sib piv, TNFR2 yog qhia nyob rau theem siab hauv cov monocytes uas tsis yog classical, ua raws li nruab nrab, thiab tom qab ntawd qhov qis tshaj plaws yog nyob rau hauv classical monocytes [252]. Enlarged monocytes nrog M2φ cov yam ntxwv tseem zais IL-6, IL-10, thiab TNF- , thiab nthuav qhia qhov chaw receptors CD11b+ , CD14+ , CD16+ , CD{{77} } , CD80+ , CD163+ , thiab CD206+/CD14hi/+ . CD14hiCD16− Mφ tau pom los ua kom pom kev ua kom mob plab, raws li pov thawj los ntawm caspase-1/ASC-speck tsim nyob rau hauv tus kab mob COVID-19 hnyav thaum piv rau kev tswj mob me lossis kev noj qab haus huv [221]. Nws tau tsim tias M2φ yog TH2-zoo li thiab tuaj yeem tsim cov cytokines tsis haum, uas muaj feem xyuam rau kev kho cov ntaub so ntswg thiab kab mob uas suav nrog IL-4/IL-13. Txawm li cas los xij, histamine H1 Mφ receptor thiab eosinophil H4 kuj qhia lub luag haujlwm no [171,253]. CD68 thiab CD163 nce hauv qhov hnyav nrog CD163 thiab TREGS. Nws yog tau hais tias M2φ, ua ke nrog suppressor TREGS, txhawb qhov kev tiv thaiv ib puag ncig. Txawm li cas los xij, nws tseem ceeb heev uas lwm cov kev tshawb fawb pom tau tias ob qho tib si M1φ / M2φ phenotypes tuaj yeem txhim kho CD{103}} CD{104}} hauv kab mob, uas tuaj yeem ua rau DCs thiab naïve T hlwb [254]. Ntxiv mus, nws tau qhia meej los ntawm kev txheeb xyuas cov noob caj noob ces tias qhov sib txawv M1φ lossis M2φ polarization tuaj yeem ua rau hauv vitro nrog M1φ qhia IL-6, TLR4, CXCL9, CXCL10, thiab CXCL11, thaum M2φ qhia CD206, CCL17, thiab CCL22 (nrog rau gene markers STAT6, IRF4) [233,255]. Qhov no yog qhov kev tshawb pom nthuav dav, vim tias TLR4 yog keeb kwm ua haujlwm los ntawm cov kab mob antigens, thaum CCL17 thiab CCL22 zoo li cuam tshuam li DC thiab Mφ chemokines. Yog li ntawd, ntawm Mφ, nws zoo nkaus li tias, ib sab ntawm M1φ zais IL-1 , IL-8 thiab IL{128}}, ntxiv chemokines tau nthuav tawm, xws li CXCL16 ua ke nrog CCL2, thaum tiv thaiv kab mob. M2φ qhia txog transglutaminase 2 (TGM2), apolipoprotein E (APOE), 2-macroglobulin (A2M), CCL13, thiab CCL26. Interestingly, lub luag hauj lwm rau ib tug triggering receptor qhia nyob rau hauv myeloid hlwb 2 (TREM2) protein nyob rau hauv lub peev xwm toxicity ntawm M1φ hlwb uas tuav ib tug affinity rau CXCR3 receptor zoo li clearer dua ua ntej. TREM2 tau pom tias tau nthuav tawm ntawm Mφ qhov sib txawv tshiab, ua tus sensor thiab activator ntawm T cell teb hauv SARS-CoV-2 kab mob. Cov ntawv sau tseem ceeb tsis ntev los no tau lees paub lub luag haujlwm ntawm TREM2 thiab iMφ hauv kev ua pa ua pa [256–258].

4. Dendritic Cells

4.1. Dendritic Cell Txheej txheem cej luam

Dendritic hlwb tau raug txheeb xyuas nyob rau hauv 1873 (Langerhans hlwb), thiab Steinman thiab Cohn nyob rau hauv 1973 nyob rau hauv vivo nyob rau hauv tus po, raws li cov cim morphology, nrog ib tug finite lifespan ntawm hnub, txawv lawv los ntawm Mφ, thiab lawv yog replenished los ntawm hematopoiesis los ntawm precursor. HPSC [265]. Thaum xub thawj pom tias yog cov muaj zog stimulators ntawm cov tshuaj tiv thaiv lymphocyte sib xyaw, qhov no tau piav qhia lawv lub luag haujlwm ua lub hauv paus rau kev nthuav qhia antigen los ntawm kev qhia txog qib siab ntawm MHC class II molecules thiab integrin CD11c [202]. Yog li ntawd, ua ke nrog kev muaj peev xwm tsiv teb tsaws chaw ntawm cov kab mob uas tsis yog lymphoid thiab lymphoid, lawv tuav ib qho tseem ceeb nrog lub peev xwm zoo tshaj plaws los cuam tshuam rau T cell txoj kev loj hlob thiab kev ua haujlwm. DCs tuaj yeem txhais tau los ntawm kev tsiv teb tsaws mus rau cov ntaub so ntswg lymphoid thiab priming TN (naïve) hlwb ua ke nrog Mφ hauv cov kab mob hauv lub cev. Xyoo 1994, kev txhim kho tseem ceeb tuaj hauv kev tshawb fawb piav qhia txog kab lis kev cai hauv vitro cell kab lis kev cai rau kev tsim DC-zoo li cov hlwb los ntawm monocytes siv GM-CSF thiab IL-4 [266,267]. Piv rau lwm cov APCs, xws li Mφ thiab B hlwb, cov no suav hais tias yog qhov ua tau zoo tshaj plaws APC priming T hlwb ntawm ob qho tib si MHC chav kawm I/II molecules thiab xa cov antigens rau CD4+ thiab CD8+ T hlwb. DCs tau tsim los ntawm kev tsis zoo mus rau kev loj hlob los ntawm kev sib koom ua ke monocyte / DC pas dej ua ke uas tau xav tias yog CD103+ DCs uas tuaj yeem ua cov kab mob khaub thuas hauv LN tes hauj lwm los ntawm kev nthuav qhia thiab yog cov muaj zog stimulators ntawm CD8+ T hlwb [268]. DCs yog tsim los ntawm cov pej xeem heterogeneous ntawm cov pob txha-pob txha tsim cov hlwb cais raws li plasmacytoid DC (pDCs), hom 1 pa DCs (cDC1), hom 2 (cDC2), myeloid DCs (mDCs), thiab Langerhans hlwb, tab sis kuj monocytic DCs. (MoDC) nrog CD14 subtypes saum toj no uas hloov zuj zus los ntawm hematopoietic qia progenitor cells (HPSC) (saib Table 4).

5. Kev sib tham

SARS-CoV-2 thiab lwm yam kab mob tau hloov zuj zus raws li kev kis tus kab mob zoonotic uas tuaj yeem hla cov tsiaj txhu. Nws yog ib qho tsim nyog los txiav txim siab tias, tsis hais txog lub hauv paus chiv keeb ntawm SARS-CoV-2, muaj cov noob caj noob ces ntawm 96.5% nrog Homophilus affinis, thiab cov xwm txheej cellular recombination yog tsim nyog rau ob qho tib si tiv thaiv kab mob thiab txuas ntxiv kis kab mob hauv tsiaj. tus tswv. Tam sim no, cov ntaub ntawv sib txawv ntawm kev soj ntsuam ntawm SARS-CoV-2 qhov txawv ntawm lwm cov tsiaj muaj xws li kev saib xyuas hauv cov tsiaj sib txawv xws li mink (1320) thiab bats (8), nrog rau kev saib xyuas tsawg dua hauv cov tsiaj thiab tsiaj txhu (saib Cov Ntaub Ntawv Ntxiv) . Cov ntaub ntawv qhia tias tsuas yog ob tus kab mob tau raug tshem tawm ntau hauv tib neeg thiab tsiaj txhu, uas yog kab mob me me (ib qho Orthopoxviridae variola) thiab rinderpest (ib Paramyxoviridae morbillivirus), feem [421]. Yog li ntawd, kev txiav txim siab ntxiv txog kev soj ntsuam tam sim no nyob rau hauv thiab thoob plaws cov tsiaj txhu tshwm sim txhawm rau saib xyuas lwm yam kab mob coronaviruses (xws li, kis kab mob ntsws hauv cov noog, porcine delta coronavirus, thiab feline coronavirus) los tiv thaiv cov kab mob zoonotic uas tshwm sim yav tom ntej. Kev sim tshawb fawb nyob nruab nrab ntawm 16th thiab 18th centuries thoob plaws ntiaj teb, pib los ntawm Edward Jenner nyob rau hauv lub lig 1700s ntawm tus kab mob cowpox, nws thiaj li coj mus rau niaj hnub kev txhais lus thiab siv lo lus "cov tshuaj tiv thaiv," hais txog cov tshuaj tau muab los ntawm tshuaj tiv thaiv (cowpox). ). Cov kab mob me me tshwm sim los ntawm tus kab mob variola thaum kawg tau tshaj tawm tias tshem tawm xyoo 1980 los ntawm Lub Koom Haum Saib Xyuas Kev Noj Qab Haus Huv Ntiaj Teb, los ntawm kev tshawb fawb kev tshawb fawb siv qee qhov yuav xav txog cov tshuaj tiv thaiv kab mob pioneering los ntawm cov qauv ntsuas. Ntau lwm yam tshuaj tiv thaiv kab mob tam sim no muaj nyob, nrog rau kev tshawb fawb kev txhim kho cov ntsiab lus ntawm no uas qhia txog lub hom phiaj thiab kev tshawb fawb ntawm ntau txhiab tus neeg thoob plaws ntiaj teb. Kev kwv yees ntawm kev tiv thaiv kab mob me me yog nyob ib puag ncig 50 xyoo, feem ntau yog vim cov pioneers nyob rau hauv daim teb no uas kuj muaj xws li Ehrlich, Medawar, thiab Edelman, thiab ntau lwm tus neeg uas nws tshawb fawb rau syphilis, nquag tau txais kev kam rau siab, thiab cov qauv ntawm cov tshuaj tiv thaiv molecules nteg lub hauv paus rau Kohler. thiab Milstein qhov kev tshawb pom ntawm yuav ua li cas los tsim cov tshuaj tiv thaiv kab mob monoclonal.

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

6. Cov lus xaus

Tom qab kev tshawb fawb dav dav, peb tau txheeb xyuas thiab piav qhia txog qhov xwm txheej tam sim no cov receptors tshwj xeeb thiab cov proteins cuam tshuam rau cov chaw kuaj mob thiab kev tshawb fawb kho mob los ntawm kev sau cov kab mob hauv lub cev thiab hloov pauv lub cev tsis muaj zog nyob rau hauv cov ntaub ntawv tiv thaiv kab mob coronavirus tam sim no thiab lwm yam pathologies rau hnub tim. B cell tiam ntawm cov tshuaj tiv thaiv kab mob, ua raws li cov neutrophils hauv pathophysiology, tso tawm thawj cytokines thiab sib txheeb uas nyob ntawm cov tshuaj tiv thaiv kab mob ntawm monocyte, macrophage, thiab dendritic cell kab mob. Txawm li cas los xij, txhua qhov no cuam tshuam rau cov kab mob T cell. Muaj cov pov thawj nce ntxiv hauv tsis tsuas yog S protein immunogen cov lus teb tab sis kuj nyob rau hauv N thiab M cov proteins. Hauv tsab xov xwm no, peb suav tias yog cov cim ntawm tes raws li cov ntaub ntawv tiv thaiv kab mob tam sim no thiab cov lus hais los ntawm cov kws tshaj lij hauv thaj chaw. Ntau tus kws tshawb fawb laus thaum lub Plaub Hlis thiab Lub Cuaj Hli 2020 tau sau ntawv hauv qhov no (saib Cov Khoom Siv Ntxiv) uas pom tau tias tag nrho cov kab mob tiv thaiv kab mob zoo ntawm 23% (NY), 18% (London), thiab 11% (Madrid) yog nyob ntawm lwm 10 lossis ntau T cell subtypes ua txhua yam kev tswj hwm ntawm lub cev tiv thaiv kab mob, uas yog qhov tseem ceeb tshaj plaws hauv txhua yam kab mob [427-445].