Lub luag haujlwm ntawm Neutrophils hauv Non-tuberculous Mycobacterial Pulmonary Disease
Jun 08, 2023
Abstract
Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) yog ib qho kev paub txog kev noj qab haus huv thoob ntiaj teb. Cov kev tshawb fawb tau qhia tias neutrophils tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tswj hwm tus kab mob NTM thiab pab txhawb kev tiv thaiv kab mob hauv lub sijhawm ntxov ntawm kev kis kab mob. Txawm li cas los xij, cov hlwb no tseem cuam tshuam nrog cov kab mob kev loj hlob thiab exacerbation thiab tuaj yeem ua rau pathology, piv txwv li hauv kev loj hlob ntawm bronchiectasis. Hauv kev tshuaj xyuas no, peb tham txog cov kev tshawb pom tseem ceeb thiab cov pov thawj tseeb txog kev ua haujlwm sib txawv ntawm neutrophils hauv NTM kab mob.
Ua ntej, peb tsom mus rau cov kev tshawb fawb uas cuam tshuam cov neutrophils hauv cov lus teb thaum ntxov rau NTM tus kab mob thiab cov pov thawj qhia txog kev muaj peev xwm ntawm neutrophils tua NTM. Tom ntej no, peb nthuav qhia cov ntsiab lus ntawm qhov zoo thiab qhov tsis zoo uas ua rau muaj kev sib raug zoo ntawm kev sib raug zoo ntawm neutrophils thiab kev tiv thaiv kev tiv thaiv. Peb xav txog lub luag haujlwm pathological ntawm neutrophils hauv kev tsav tsheb phenotype ntawm NTM-PD suav nrog bronchiectasis. Thaum kawg, peb hais txog cov kev kho mob zoo tam sim no hauv kev txhim kho lub hom phiaj neutrophils hauv cov kab mob hauv txoj hlab ntsws. Xav paub ntau ntxiv txog lub luag haujlwm ntawm neutrophils hauv NTM-PD yog xav tau los qhia ob txoj kev tiv thaiv thiab kev tswj hwm tus tswv tsev rau cov kab mob tseem ceeb no.
Nontuberculous mycobacterial pulmonary disease (NTM) yog ib qho kab mob uas tshwm sim los ntawm cov kab mob uas tsis yog tuberculous mycobacteria, feem ntau hauv cov neeg muaj kev tiv thaiv kab mob. Yog li ntawd, nws yog ze ze rau kev tiv thaiv.
Immunocompromised pejxeem suav nrog cov neeg laus, cov neeg mob uas muaj kab mob ua pa xws li bronchitis thiab bronchiectasis, cov neeg mob uas muaj cov kab mob tiv thaiv kab mob xws li kab mob sib txuas, qog nqaij hlav, lossis hloov pauv hauv nruab nrog cev, thiab cov neeg uas tau siv tshuaj tiv thaiv kab mob xws li glucocorticoids ntev ntev. .
Kev tiv thaiv qis tuaj yeem ua rau lub cev tsis muaj zog tiv thaiv kab mob, tsis tuaj yeem tshem tawm cov kab mob uas tsis yog tuberculous mycobacteria, thiab yog li ua rau tsis muaj tuberculous mycobacterial pulmonary kab mob. Tsis tas li ntawd, kev tiv thaiv qis kuj tuaj yeem ua rau mob hnyav, thiab mob hnyav tuaj yeem ua rau muaj teeb meem xws li tuberculosis.
Yog li ntawd, rau cov neeg uas muaj kev tiv thaiv tsawg, nws yog ib qho tsim nyog yuav tsum tau txhim kho kev tiv thaiv tus kheej kom ntau li ntau tau, ntxiv dag zog rau txoj kev ua pa, thiab tiv thaiv qhov tshwm sim ntawm cov kab mob uas tsis yog tuberculous mycobacterial pulmonary. Yog tias muaj cov tsos mob tshwm sim, nrhiav kev kho mob raws sij hawm rau kev kuaj mob thiab kho kom raug. Los ntawm qhov no, peb tuaj yeem txiav txim siab qhov tseem ceeb ntawm kev tiv thaiv kab mob. Peb yuav tsum txhim kho peb txoj kev tiv thaiv. Cistanche tuaj yeem txhim kho kev tiv thaiv. Cistanche kuj muaj cov tshuaj tiv thaiv kab mob, tiv thaiv kab mob qog noj ntshav, thiab lwm yam teebmeem, thiab tuaj yeem ntxiv dag zog rau lub cev tiv thaiv kev sib ntaus sib tua thiab txhim kho lub cev tiv thaiv kab mob.
Nyem qhov txiaj ntsig kev noj qab haus huv ntawm cistanche
Ntsiab lus
Neutrophils, Granulocytes, Tsis-tuberculous mycobacteria, Tsis-tuberculous mycobacterial pulmonary kab mob, Bronchiectasis.
Taw qhia
Cov kab mob uas tsis yog tuberculous mycobacterial pulmonary disease (NTM-PD) yog ib qho mob hnyav zuj zus thiab nyuaj rau kev kis kab mob uas ua rau muaj kev mob hnyav, kev siv kho mob, thiab kev tuag [1].
Txawm hais tias muaj ntau tshaj 170 NTM hom, feem ntau NTMPD tshwm sim los ntawm ib tug me me ntawm cov kab mob ib puag ncig, uas ua raws li tib neeg opportunistic pathogens [2] tab sis txawv nyob rau hauv lawv pathogenicity thiab teb rau kev kho mob [3, 4]. Hom kab mob uas ua rau NTM-PD yog Mycobacterium avium complex (MAC), (feem ntau yog cov qeeb qeeb-loj hlob M. avium, M. intracellular, thiab M. chimaera hom), M. kansasii, thiab M. xenopi, thiab tseem ceev- Grower M. abscessus complex (MABC) [5, 6]. Tsis zoo li tuberculosis, uas feem ntau cuam tshuam rau cov neeg hluas yam tsis muaj lwm yam kab mob sib kis, kab mob NTM mob ntsws feem ntau tshwm sim rau cov neeg muaj hnub nyoog tsib caug xyoo lossis siab dua, uas tej zaum yuav muaj lwm yam mob, xws li bronchiectasis, mob ntsws obstructive pulmonary (COPD) thiab cystic fibrosis ( ZPO) [7–9].
Qhov kev txiav txim siab kho tsis yog ncaj nraim: qee cov neeg mob zoo li tshem tawm tus kab mob sai sai thiab lwm tus neeg nyob hauv tsev kho mob tsis muaj kev kho mob ntev [9]. Tsis tas li ntawd, kev kho tshuaj tiv thaiv kab mob feem ntau ntev tuaj yeem ua rau tsis zoo [10], thiab tsis tas yuav ua haujlwm zoo.
Kev tshawb fawb ntawm tus tswv teb lub cev tiv thaiv kab mob rau NTM feem ntau tsom rau T hlwb, 'T pab-1' cytokines, thiab mononuclear phagocytes [11]. Txawm hais tias cov no tseem ceeb hauv kev tiv thaiv NTM [12], lawv lub luag haujlwm hauv kev ua lossis tiv thaiv lub ntsws puas tsawg dua.
Feem ntau, cov kws tshaj lij phagocytes (neutrophils, macrophages, thiab dendritic cells) yog suav tias yog thawj kab tiv thaiv kab mob. Neutrophil polymorphonuclear granulocytes yog hom cell uas tseem ceeb tshaj plaws nyob rau hauv lub bronchial lumen thiab tau txais sai sai rau qhov chaw ntawm tus kab mob thaum lawv hnov cov teeb meem los ntawm cov tshuaj chemoattractants xws li Interleukin -8 (IL-8) tsim los ntawm cov cell. Tom qab kev tsiv teb tsaws chaw (chemotaxis) lawv cuab thiab tua cov kab mob invading. Neutrophils paub tias yog qhov tseem ceeb rau kev tiv thaiv kab mob extracellular [13]. Txawm li cas los xij, lub luag haujlwm ntawm cov lus teb neutrophil hauv NTM-PD tseem tsis to taub tag nrho. Cov kev tshawb fawb tsis ntev los no tau qhia tias neutrophils tuaj yeem pab tswj tus kab mob NTM [14, 15]; Txawm hais tias lawv tuaj yeem pab txhawb rau NTM-txo cov kab mob pathology, piv txwv li hauv kev txhim kho bronchiectasis [14, 16]. Hauv kev tshuaj xyuas no, peb tham txog lub luag haujlwm ntawm neutrophils hauv cov kab mob uas tsis yog tuberculous mycobacterial pulmonary disease (NTM-PD) thiab tshawb nrhiav qhov tsis sib haum xeeb ntawm neutrophils hauv tus kab mob no.
Neutrophils thiab tiv thaiv kab mob
Neutrophils 'cov tshuaj tua kab mob muaj xws li phagocytosis (kev noj tshuaj), degranulation (tso tawm cov tshuaj tua kab mob soluble mus rau hauv phagosome lossis extracellularly), thiab tso tawm cov khoom siv nuclear hauv daim ntawv ntawm neutrophil extracellular ntxiab (NETs) [17, 18]. Kev pib ntawm neutrophil phagocytosis yog qhov ua tau zoo dua los ntawm opsonization ntawm cov kab mob uas yog opsonins, piv txwv li, ntxiv cov khoom xyaw thiab cov tshuaj immunoglobulins (Igs), cov kab mob, thiab tau lees paub los ntawm cov chaw tshwj xeeb ntawm cov neutrophils ua rau avid khi thiab ua rau muaj kev noj qab haus huv.
Feem ntau, ib zaug phagocytosis tau pib los ntawm kev koom tes ntawm opsonic receptors, internalization ntawm cov kab mob hauv phagosomes hauv cov neutrophil tshwm sim hauv vib nas this [19].
Tom qab ntawd, phagosomal maturation nrog intracellular granule fusion tshwm sim thiab muab cov neutrophils tshwj xeeb zoo dua lwm cov phagocytes vim cov granules muaj cov kab mob bactericidal muaj zog. Plaub pawg ntawm granules muaj nyob rau hauv neutrophils: azurophil (primary), muaj enzymes xws li neutrophil elastase (NE) thiab antibacterial molecules xws li leukocidin thiab tib neeg neutrophil peptides (HNP) 1-3, tshwj xeeb granules (secondary), gelatinase granules thiab gelatinase granules. vesicles, txhua lub luag haujlwm tshwj xeeb thaum lub sij hawm teb rau tus kab mob [20]. Qee qhov no tau tham txog ntau yam hauv qab no.
NADPH oxidase nyob rau hauv cov phab ntsa ntawm cov granules theem pib pib oxidative tawg, ua rau zus tau tej cov antimicrobial reactive oxygen intermediates (superoxide, hydrogen peroxide, hypochlorous acid). Txawm li cas los xij, neutrophil influx kuj tseem cuam tshuam nrog pathology los ntawm kev tso tawm cov ntsiab lus cytotoxic; thiab yog tias neutrophils cuam tshuam cov txheej txheem no yuav ua rau muaj kev puas tsuaj rau cov hlwb nyob sib ze thiab cov ntaub so ntswg raug mob [21, 22].
Neutrophils kuj yog cov kab mob ua haujlwm tiv thaiv kab mob. Hu xov tooj zoo li receptors (TLRs) yog ib hom qauv lees paub receptor (PRR) uas ua rau lub cev tiv thaiv kab mob hauv lub cev los ntawm kev hnov cov qauv molecular thiab tso cai rau kev tiv thaiv kab mob thaum ntxov [23].
Cov tshuaj tiv thaiv kab mob neutrophil ceev ceev no muab lub sijhawm tiv thaiv kab mob txaus los tsim cov kab mob tshwj xeeb tiv thaiv kab mob, txawm hais tias, raws li tau tham tom qab, tus cwj pwm neutrophil tuaj yeem cuam tshuam rau lub cev tiv thaiv kab mob.
Neutrophil teb rau NTM
Innate phagocytic immune cells, suav nrog mononuclear phagocytes xws li macrophages, tshem tawm cov kab mob mycobacteria sai heev los ntawm phagocytosis thiab intracellular tua, thiab kev puas tsuaj hauv cov txheej txheem no tuaj yeem ua rau muaj kev txhim kho ntawm mycobacterial kab mob [24, 25]. Txawm hais tias cov lus teb neutrophil rau NTM tau kawm tsis zoo, kev ua haujlwm yav dhau los tau hais tias granulocytes yog cov koom nrog tseem ceeb hauv kev tiv thaiv tus tswv ntawm mycobacteria [26, 27] thiab cov hlwb no tuaj yeem tua ntau hom mycobacteria [28]. Txawm li cas los xij, lawv kuj tseem cuam tshuam rau hauv cov kab mob ntawm cov kab mob mycobacterial xws li tuberculosis [16, 29] qhov chaw uas lawv yog cov tswv cuab tseem ceeb ntawm cov kab mob hauv cov hnoos qeev, bronchoalveolar lavage (BAL) kua, thiab cov kab noj hniav hauv cov neeg mob ntsws TB [ 14] ib. Txawm hais tias nws yog qhov yooj yim los txhais cov txiaj ntsig hauv Mycobacterium tuberculosis (Mtb)-raws li kev sim rau NTM, cov ntaub ntawv meej ntawm NTM feem ntau tsis muaj thiab hauv qhov kev tshuaj xyuas no yog qhov tsim nyog, peb tau tham txog cov ntaub ntawv muaj rau Mtb. Qhov no qhia txog qhov xav tau ceev nrooj rau kev tshawb fawb ntxiv ntawm NTM (thiab tshwj xeeb tshaj yog cov tsiaj uas ua rau tib neeg mob feem ntau).
Siv Mtb, Jones et al. thiab Majeed et al. pom muaj kev ua tau zoo ntawm mycobacterial phagocytosis los ntawm neutrophils los ntawm kev sib ntxiv-mediated opsonization [30, 31]. Txawm li cas los xij, cov txiaj ntsig ntawm kev tshawb fawb hauv vitro los ntawm Irina li al. thiab Lenhart-Pendergrass li al. taw qhia qhov tsis muaj peev xwm ntawm neutrophils rau phagocytose uas tsis yog-opsonized M. smegmatis thiab M. avium feem [32, 33]. Sib sau ua ke, cov ntaub ntawv no qhia tias neutrophils muaj peev xwm ntawm phagocytosing mycobacteria tab sis qhov no yuav xav tau opsonization los ntawm kev ntxiv lossis immunoglobulins thiab tuaj yeem sib txawv ntawm hom [33].
TLR-2 cov nas uas tsis muaj M. avium kis tau pom qhov tsis zoo neutrophil muaj nuj nqi thiab kev ua haujlwm tsis zoo tom qab hauv kev tswj tus kab mob hauv nws cov theem pib [34, 35], qhia txog lub luag haujlwm tseem ceeb rau neutrophils hauv kev tiv thaiv tus tswv teb rau NTM. Hloov pauv, nws tau pom tias neutrophils tuaj yeem ua rau muaj kev sib kis ntawm cov kab mob ntau dua li kev tshem tawm ntxov ntawm cov nas uas muaj kab mob, txawm tias qhov no tau nyob ntawm cov kab mob mycobacterial (tshwm sim nrog M. avium tab sis tsis yog Mtb [36]). Tshwj xeeb, nws tau raug pom tias neutrophils tuaj yeem nqa mycobacteria mus rau hauv lub ntsws [14].
Faldt et al. tau tshaj tawm tias NTM (M. avium thiab M. smegmatis) ua rau muaj kev tso tawm ntau dua ntawm TNF , IL-6, thiab IL-8 los ntawm cov kab mob activated neutrophils dua li Mtb uas yuav qhia tau tias cov tsiaj no evoke lub cev tiv thaiv kab mob uas tuaj yeem ua rau muaj txiaj ntsig zoo ntawm mycobacteria. [37].
Table 1 piav qhia cov kev tshawb fawb nas qhia txog lub luag haujlwm tseem ceeb rau cov neutrophils hauv cov lus teb thaum ntxov rau NTM tus kab mob, qee qhov kev tshawb fawb ntxiv hauv ntu tom ntej.
Cov qauv tsiaj thiab tib neeg kev tshawb fawb caj ces cuam tshuam rau neutrophils hauv tus tswv teb rau tus kab mob mycobacterial
Tshaj li 35 xyoo dhau los, Brown thiab cov npoj yaig tau sau txog kev sib cuam tshuam ntawm neutrophils thiab mycobacteria [42]. Appelberg et al. Tom qab ntawd tau ua pov thawj qhov kev koom tes loj ntawm neutrophils los tiv thaiv cov kab mob hauv cov kab mob mycobacterial intravenously thaum siv granulocyte-depleting monoclonal antibody (MAb) RB6- 8C5 kev kho mob, lawv tau sau tseg cov kab mob loj dua [38]. Petrofsky thiab Bermudez tau siv cov txheej txheem zoo sib xws rau neutrophil depletion thiab tseem xaus lus tias neutrophils muab qee qhov kev tiv thaiv M. avium thaum ntxov ntawm kev kis tus kabmob [35]. Hauv qhov sib piv, Saunders thiab Cheers tsis tau txheeb xyuas lub luag haujlwm tiv thaiv meej rau nas lub ntsws neutrophils tom qab nqus tau cov nyom nrog M. avium, txawm tias siv cov kev sim zoo sib xws [43].
Kev tshawb fawb los ntawm Goncalves thiab Appelberg tau qhia tias CXC receptor 2 (CXCR2) tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev nrhiav neeg ua haujlwm neutrophil tom qab kis kab mob mycobacterial. Hauv kev sib piv los tswj cov nas, CXCR2 knockout nas muaj ntau dua neutrophils nyob rau hauv kab noj hniav peritoneal thoob plaws hauv 15-hnub intraperitoneal kab mob nrog M. avium. Txawm li cas los xij, qhov kev hloov pauv CXCR2 tsis cuam tshuam rau kev ua haujlwm neutrophil rau lub ntsws thaum muaj tus kab mob atherogenic M. avium thoob plaws hauv 60-hnub sim - qhia tias qhov no yuav yog qhov tshwm sim ntawm cov ntaub so ntswg [39].
Tag Nrho Cov Ntshav Gene Expression tau ua los tshawb xyuas tus tswv tsev tiv thaiv kab mob rau NTM-PD. Ib txoj kev tshawb fawb tsis ntev los no suav nrog 25 tus neeg mob uas muaj NTM-PD thiab 27 tus tswj hwm uas tsis muaj kab mob tab sis muaj kab mob ua pa. Kev tsom xam Microarray qhia tias NTMPD cov pej xeem tau txo qis kev qhia ntawm 213 cov noob cuam tshuam nrog T-cell signaling, suav nrog IFN-g. Lub hauv siab CT qhov mob hnyav, lub ntsws tsis ua haujlwm, thiab lwm yam cim ntawm cov kab mob hnyav nrog rau kev suav neutrophil siab tau cuam tshuam nrog kev txo qis IFN-g qhia [44].
Sib sau ua ke, cov pov thawj kev sim no qhia tias cov neutrophils ua lub luag haujlwm tseem ceeb hauv tus tswv teb rau tus kab mob NTM tab sis tsis tau txhais tias qhov no yuav yog dab tsi, lossis seb nws yog kev tiv thaiv lossis kev tsav tsheb.
Puas tuaj yeem neutrophils tua NTM?
Ntau qhov kev tshawb fawb hauv vitro (cov ntsiab lus hauv Table 2) tau hais txog lub peev xwm ntawm tib neeg neutrophils los tua NTM hom nrog kev pom zoo tias neutrophils tuaj yeem tshem tawm-lossis tsawg kawg txwv kev loj hlob ntawm-kho qhov tseem ceeb NTM.
Muaj qee cov pov thawj kho mob qhia txog NTM kev raug mob hauv cov neeg mob neutropenic lossis cov neeg muaj kab mob neutrophil [44]. Txawm li cas los xij, neutropenia tau cuam tshuam nrog kev tshaj tawm NTM (txawm tias tsis yog pulmonary NTM) hauv cov neeg mob hematological malignancy [45].
Ib txoj hauv kev uas cov neutrophils tuaj yeem tua cov kab mob mycobacteria yog los ntawm tib neeg neutrophil peptides (HNP) 1, 2, thiab 3. Cov no yog ib tsev neeg ntawm endogenous cationic antimicrobial thiab cytotoxic peptides (defensins) nyob rau hauv azurophilic granules. HNP kuj ua haujlwm raws li kev tiv thaiv kab mob molecule uas cuam tshuam rau cytokine ntau lawm nrog rau cov tshuaj tiv thaiv kab mob thiab kev tiv thaiv kab mob [46]. Lub peev xwm ntawm HNP-1 los tua M. tuberculosis tau kawm hauv vitro los ntawm Miyakawa li al., [47], Sharma et al., [48], Kalita et al., [49], thiab Martineau et ib., [50]. Cov kev tshawb fawb no tau qhia tias cov neutrophils tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob hauv lub cev tiv thaiv kab mob TB los ntawm kev ua haujlwm ntawm HNP thiab cov molecules no tuaj yeem yog lub hauv paus ntawm kev kho tshiab.
Txawm li cas los xij, lwm txoj kev tshawb fawb tau pom tias muaj ntau ntau ntawm HNP raug kuaj pom hauv ob qho tib si cystic fibrosis (CF) thiab tsis yog-CF bronchiectasis airways thiab tias cov no inhibit PMN kev ua haujlwm ntawm kev cuam tshuam nrog phagocytosis [51, 52].
Neutrophils ncaj qha cuam tshuam rau kev txhim kho ntawm kev tiv thaiv kab mob tiv thaiv kab mob rau NTM
Neutrophils tuaj yeem txhim kho kev tiv thaiv kab mob thiab txuas cov kab mob hauv lub cev thiab yoog raws [58, 59].
Cytokine tes hauj lwm ua si lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob hauv lub cev rau cov kab mob NTM. T cell teb tawm tsam NTM yog tswj los ntawm kev tsim cov IL-12 tom qab endocytosis ntawm mycobacteria los ntawm innate mononuclear phagocytes (xws li dendritic cells (DC) thiab macrophages). Nyob rau hauv lem, qhib CD4 ntxiv rau T hlwb (T-helper 1) thiab CD8 ntxiv rau T hlwb tso tawm IFN uas txhim khu kev tua los ntawm mononuclear phagocytes thiab yog ib qho tseem ceeb rau tus tswv tsev tiv thaiv mycobacteria [60, 61]. Yog li, NTM tus kab mob uas kov yeej cov txheej txheem hauv lub cev tuaj yeem tswj tau los ntawm T1 cov lus teb tau zoo los ntawm IL-12 thiab IFN [62].
Kev hloov pauv caj ces hauv IL-12-IFN txoj hauv kev ua rau muaj kev cuam tshuam rau NTM, piv txwv li; IFN-R1 thiab IFN-R2 deficiencies (ob leeg autosomal recessive thiab dominant daim ntawv), IL12 thiab IL12R 1 deficencies, transcription factor STAT1 deficiency, RAR-related Orphan Receptor C (RORC) deficiency, interferon-stimulated gene 15 (ISG15) deficiency regulatory factor 8 (IRF8) deficiency, thiab tyrosine kinase 2 (TYK2) deficiency [63–66].
Tshwj xeeb, Nws tau tshaj tawm tias qhov tsis xws luag hauv IL-12 thiab IFN txoj hauv kev tuaj yeem ua rau muaj kab mob ntsws NTM [67]. Qhov tseem ceeb, interleukin -12-induced IFN ntau lawm los ntawm T hlwb kuj activates neutrophils rau phagocytose thiab/los yog tua NTM [68]. Tsis tas li ntawd, IL-17, IL-21, thiab IL-22 tsim los ntawm T-helper 17 CD4 ntxiv rau T hlwb induce neutrophil influx mus rau hauv cov kab mob o uas yuav pab ntes qhov kev loj hlob ntawm NTM kab mob los ntawm direct tua [69–71].
Txawm li cas los xij, kev nrhiav neeg ua haujlwm neutrophil tuaj yeem ua rau muaj kev cuam tshuam tsis zoo rau lub cev tiv thaiv kab mob. Ib txoj kev tshawb fawb siv tus qauv nas ntawm MAC kab mob pom tau tias thaum T1 kev tiv thaiv tsis zoo, T17 ntxiv rau cov hlwb provoked neutrophil recruitment uas tshwm sim ua rau muaj kev cuam tshuam rau MAC kab mob [69]. Tej zaum yuav muaj qhov tsis zoo tshwj xeeb ntawm cov neutrophils tuag. Hauv cov qauv ntshav tag nrho nrog Mtb, necrotic neutrophils cuam tshuam tus tswv tswj kev loj hlob ntawm mycobacterial thiab nce kev tiv thaiv kab mob IL-10 nrog rau kev loj hlob thiab chemokines [72]. Qhov no tuaj yeem ua rau muaj kev sib txuas ntxiv ntawm neutrophil ntawm qhov chaw ntawm tus kab mob: lub voj voog kab mob uas tuaj yeem ua rau muaj kev cuam tshuam tsis zoo ntawm neutrophils ntawm tus tswv tsev tau txais txiaj ntsig [16, 73].
'Frustrated' neutrophils uas tso tawm cov ntsiab lus granule extracellularly tuaj yeem tsav cov ntaub so ntswg puas thiab ua rau muaj kev cuam tshuam loj heev ntawm T cell sib txawv thiab kev loj hlob [74–76]. Tseeb tiag, granule constituents los yog zus tau tej cov chemokines los ntawm neutrophils tuaj yeem kho cov nyhuv suppressive ncaj qha los yog tsis ncaj nraim ntawm T-cell cov lus teb, inactivating T-cell stimulating cytokines, xws li IL-2 thiab IL{5}}, thiab ceev cov tshem tawm ntawm IL-2 thiab IL-6 cytokine receptors ntawm T-cells [58, 77–79].
Raws li ib qho piv txwv, neutrophil elastase xaiv cleaves IL-2 receptor thiab IL-6 receptor thiab ua rau txo qis ntawm co-stimulatory molecule qhia los ntawm dendritic hlwb, yog li txwv T cell maturation thiab cuam tshuam rau txoj kev loj hlob ntawm lub hlwb. T1 teb [80]. Kev tswj hwm ntawm T cell receptor (TCR) kev qhia kuj tuaj yeem tshwm sim thaum tso tawm ntawm arginase thiab tsim cov pa oxygen reactive (ROS) los ntawm neutrophils [58, 78].
Hloov pauv, kev tsim tawm ntawm NETs tuaj yeem txo T hlwb qhov pib ua haujlwm [81], thaum qhov kev tshem tawm ntawm T1- cov lus teb tshwj xeeb tau tshaj tawm thaum cov neutrophils tau depleted thaum lub sijhawm txhaj tshuaj tiv thaiv BCG ntawm nas [82].
Hauv cov ntsiab lus, muaj ob txoj kev sib raug zoo ntawm cov neutrophils thiab cov tshuaj tiv thaiv kab mob uas tau txais nrog tus cwj pwm neutrophil uas muaj feem cuam tshuam rau T cell-mediated tiv thaiv qhov zoo lossis tsis zoo nyob ntawm qhov chaw tiv thaiv kab mob.
Daim duab 1 piav qhia txog ntau yam peev xwm ntawm neutrophils hauv NTM pulmonary kab mob.
NTM, neutrophils, thiab humoral tiv thaiv kab mob
Mycobacteria yog cov kab mob intracellular thiab yog li, cell-mediated tiv thaiv yog suav tias yog ib feem tseem ceeb ntawm tus tswv tsev tiv thaiv kab mob tiv thaiv cov kab mob no. Txawm li cas los xij, kev nkag siab txog kev sib cuam tshuam ntawm kev tiv thaiv kab mob hauv lub cev, kev tiv thaiv kab mob hauv nruab nrog cev, thiab kev tiv thaiv ntawm tes yog qhov muaj txiaj ntsig los txiav txim siab cov tswv yim (ob qho tib si kev kho mob thiab tshuaj tiv thaiv) uas tuaj yeem tiv thaiv kab mob NTM thiab kab mob.
Kev sib cuam tshuam ntawm T hlwb, B hlwb, thiab antigen-presenting cells (APCs) nrog cov neutrophils tso cai rau cov neutrophils hloov pauv kev tiv thaiv kab mob humoral adaptive [76]. Piv txwv li, activated neutrophils muaj lub luag haujlwm hauv B-cell txoj kev loj hlob los ntawm kev tsim cov B-cell activating factor (BAFF), uas yog ib qho tseem ceeb cytokine rau B-cell txoj kev loj hlob, thiab granulocyte colony-stimulating factor (G-CSF) [76. , 83] ib. Reciprocally, B hlwb tuaj yeem cuam tshuam kev ua haujlwm ntawm neutrophil los ntawm kev tsim cov tshuaj tiv thaiv kab mob uas opsonize mycobacteria thiab yog li txhim kho neutrophil phagocytosis (sib tham saum toj no).
Cov nyhuv tiv thaiv ntawm kev tiv thaiv kab mob humoral tiv thaiv mycobacterial antigens tau pom nyob rau hauv ntau tus qauv siv Mtb. Kunnath et al. tau piav qhia txog kev koom tes ntawm kev tiv thaiv kab mob humoral rau kev tswj hwm ntawm Mtb [84] thiab Hamasur li al. tau qhia txog kev tiv thaiv ntawm nas monoclonal IgG1 antibody rau lipoarabinomanan (SMITB14) tiv thaiv kab mob thaum nas kis kab mob hauv lub cev [85]. Zimmermann et al. pom tau tias IgA (tab sis tsis yog IgG) cov tshuaj tiv thaiv tshwj xeeb rau Mtb nto antigens sib txawv thaiv Mtb kev ua [86]. Nws tsis paub meej tias tib yam siv rau NTM - thiab qhov no yog thaj chaw uas yuav tsum tau tshawb xyuas ntxiv.
Glycopeptidolipids (GPLs) yog ib chav kawm ntawm glycolipids qhia nyob rau hauv txheej txheej ntawm ntau hom NTM, suav nrog MAC thiab M. abscessus. GPLs ntawm MAC yog cov antigenic heev thiab serovar-specific thiab muaj feem xyuam nrog MAC virulence [87, 88]. Kev kuaj mob serological ntsuas cov ntshav IgA cov tshuaj tiv thaiv kab mob tiv thaiv MAC GPLs tau tsim thiab siv kho mob los kuaj mob MAC. Kev nce qib ntawm cov tshuaj tiv thaiv kab mob tau sau tseg hauv cov neeg mob nrog NTM-PD tshwm sim los ntawm MAC thiab tsis yog hauv cov neeg mob Mtb [89].
Ib txoj kev tshawb fawb tsis ntev los no tau qhia txog kev siv hluav taws xob ntawm kev ntsuas serological hauv kev tshawb nrhiav cov kab lis kev cai zoo ntawm M. abscessus kab mob hauv CF cov neeg mob [90]. Qhov kev ntsuam xyuas tau ua raws li kev tshawb pom ntawm IgA tiv thaiv M. abscessus protein, recombinant PLC (HPLC), thiab TLR2eF extract. Qhov no IgA ELISA muaj peev xwm sib txawv M. abscessus los ntawm M. avium thiab M. chimaera kab mob (tab sis tsis yog los ntawm M. intracellulare kab mob) raws li kev lees paub ntawm MABC proteins los yog rho tawm, sib piv rau cov laus xeem uas yog raws li kev kuaj pom. ntawm cov tshuaj tiv thaiv pom GPL core antigen ntawm M. avium [90]. Kev kis tus kab mob NTM hauv cov neeg mob CF yog tam sim no raug sim hauv txoj kev tshawb fawb yav tom ntej (kev soj ntsuam tus lej ID RCB:2017-A00025-48) siv ob qho ELISAs.
Zuag qhia tag nrho, kev tshawb fawb tau txheeb xyuas lub luag haujlwm muaj peev xwm rau cov tshuaj tiv thaiv kab mob mycobacterial thaum kis kab mob thiab sib cav rau kev ua haujlwm ntxiv los pab qhia lawv cov txheej txheem ntawm kev ua haujlwm [91–94]. Tshwj xeeb, cov tshuaj tiv thaiv kab mob sib kis ntawm mycobacteria nrog kev txhim kho phagocytosis los ntawm neutrophils yuav tsum tau tshawb xyuas.
Cov kab mob NTM suav nrog bronchiectasis thiab cavitation, ob qho tib si tau nkag siab tias yuav tsum tau tsav los ntawm cov neutrophils, nrog rau lub luag haujlwm tshwj xeeb rau neutrophil elastase [95, 96].
MAC thiab MABC yog hom kab mob ntau tshaj plaws uas ua rau NTM-PD, suav txog 95 feem pua ntawm cov neeg mob [97, 98]. MABC kab mob, feem ntau pom nyob rau hauv cov neeg mob uas muaj keeb kwm ntawm cov kab mob pulmonary xws li cystic fibrosis thiab bronchiectasis, muaj cov neeg tuag coob tshaj plaws ntawm cov kab mob mycobacteria loj hlob sai [3, 99–101]. MAC tsis tshua muaj kev cuam tshuam nrog cov kab mob hnyav, tab sis nyob ib ncig ntawm 35-42 feem pua ntawm cov kab mob hnoos qeev zoo rau MAC sawv cev rau NTM-PD [102, 103].
Vim li cas NTM thiaj li hloov pauv pathogenic hauv tib neeg tsis paub meej. Qhov no yog rooj plaub txawm nrog M. avium, uas nws tus tswv teb cov lus teb yog qhov zoo tshaj plaws to taub [104].
Thaum nkag mus rau hauv lub cev, NTM feem ntau nyob hauv cov hlab ntsws qis thiab, yog tias muaj mob hauv chaw kho mob, qhov no tshwm sim raws li kev mob hauv zos (mob ntsws, mob ntsws, cavitation) [105].
NTM-PD feem ntau pom nyob rau hauv kev koom tes nrog bronchiectasis, uas tej zaum yuav ua ntej los yog qhov tshwm sim ntawm tus kab mob. Hauv cov ntsiab lus dav dav, bronchiectasis tuaj yeem tshwm sim los ntawm qhov mob hauv qab xws li CF lossis lwm yam kev mob ntawm ciliary muaj nuj nqi, cuam tshuam nrog kev tiv thaiv kab mob tsis muaj zog (tshwj xeeb tshaj yog cov tshuaj tiv thaiv kab mob tsis txaus), lossis tshwm sim tom qab kis mob [106, 107]. Nws feem ntau tshwm sim nrog qhov hnoos tsis tu ncua thiab yog tus cwj pwm los ntawm kev ua tsis zoo ntawm cov hnoos qeev tshem tawm ntawm txoj hlab pa. Kev sib sau ntawm cov hnoos qeev hauv cov hlab ntsws puas ntawm lub ntsws ua rau muaj qhov chaw zoo rau cov kab mob (xws li NTM) kom loj hlob, ua rau muaj kev mob ntxiv nrog rau kev puas tsuaj thiab nthuav dav ntawm txoj hlab pa, feem ntau hauv nruab nrab lobe lossis ntu lingula. Qhov kev puas tsuaj no feem ntau yog nrog los ntawm kev kho mob tshwm sim thiab tsim kom muaj 'lub voj voog vicious' vim muaj kev cuam tshuam ntawm kev pheej hmoo los yog rov tshwm sim thiab mob ntau dhau [108].
Neutrophils yog lub luag haujlwm rau kev puas tsuaj rau txoj hlab ntsws los ntawm kev tso tawm cov ntsiab lus granule (tib neeg NE tshwj xeeb) thaum lub sij hawm degranulation [109] thiab cuam tshuam rau txoj kev loj hlob ntawm bronchiectasis. Granule-derived molecules muaj cov khoom siv tshuaj tua kab mob uas pab tiv thaiv kab mob (saib saum toj), tab sis lawv tuaj yeem ua rau cov ntaub so ntswg puas (ua rau bronchial dilation) [58].
Neutrophil-dominant o yog ib qho tseem ceeb ntawm bronchiectasis pathogenesis. Cov theem siab ntawm NE nyob rau hauv cov hlab ntsws yog txuam nrog exacerbations thiab ua rau lub ntsws tsis zoo nyob rau hauv ob qho tib si CF thiab non-CF bronchiectasis [110].
Qee qhov kev tshawb fawb tau tshaj tawm tias muaj ntau dua neutrophil suav hauv cov hnoos qeev ntawm cov neeg mob bronchiectasis piv rau kev noj qab haus huv uas cuam tshuam nrog kev kis kab mob [111- 113]. Cov neeg mob uas muaj bronchiectasis, uas muaj kev pheej hmoo siab ntawm NTM-PD [114, 115], pom 'reprogramming' ntawm peripheral ntshav neutrophils thaum lub sij hawm ruaj khov thiab ntev neutrophil ciaj sia nrog tsis muaj peev xwm tua thiab phagocytose cov kab mob, yog li perpetuating lub vicious. lub voj voog [116, 117]. Txawm li cas los xij, qhov no zoo li txhim kho tom qab kev kho tshuaj tua kab mob [116]. Tsis tas li ntawd, kev puas tsuaj ntawm neutrophils 'phagocytic muaj peev xwm thiab ROS ntau lawm hauv CF airways tau tshaj tawm [118].
Ib qho kev puas tsuaj ntawm neutrophils lub peev xwm rau phagocytose thiab tua cov kab mob, suav nrog NTM, tuaj yeem ua rau muaj kev pheej hmoo ntawm lub voj voog vicious hauv bronchiectasis [116].
Neutrophils tuaj yeem extrude cov ntsiab lus ntawm lawv cov nuclei extruded mus rau qhov chaw extracellular li neutrophil extracellular ntxiab (NETs). NETs yog tsim los ntawm chromatin, histones, thiab ntau yam neutrophil granule proteins, suav nrog NE, cathelicidin, cathepsin G, thiab myeloperoxidase (MPO) [119]. NETs yog siv los tawm tsam cov kab mob hauv cov txheej txheem hu ua NETosis, hom kev tuag ntawm tes [120]. Cytokines xws li IL8, TNF, thiab IFN- tuaj yeem ua rau NETosis ntxiv rau cov kab mob, feem ntau yog lipopolysaccharide (LPS) thiab lipophosphoglycan (LPG) [121].
NETs tau pib pom tias yog kev tiv thaiv kab mob sib kis los ntawm kev ntes thiab tua cov kab mob [120]. Txawm li cas los xij, Nakamura et al. pom tias MACinduced NET tsim tsis koom nrog kev tua tab sis hauv kev tsim cov MMPs thiab IL-8 uas txhawb nqa kev loj hlob ntawm kev mob ntsws [122]. Tsis tas li ntawd, NET cov khoom xws li PR3, MPO, thiab NE, qhib thiab tso tawm thaum lub sijhawm NETosis, yog cytotoxic thiab tau pom tias ua rau muaj kev puas tsuaj ncaj qha rau endothelium.
Tsis tas li ntawd, kev tshawb fawb kuj tau qhia tias Hom I IFNinduced pulmonary NETosis tuaj yeem cuam tshuam ncaj qha rau TB pathogenesis hauv TB cov nas raug mob. Lub xub ntiag ntawm NETs nyob rau hauv necrotic mob ntsws mob nyob rau hauv cov neeg mob uas muaj tuberculosis kuj txhawb lub luag hauj lwm ua rau NETosis nyob rau hauv TB pathogenesis [123, 124].
Lwm txoj kev tshawb fawb tau qhia txog lub luag haujlwm ntawm NETs hauv cov kab mob hnyav thiab kev kho mob hauv bronchiectasis [125], nrog rau kev nplua nuj ntawm NET-txuas nrog cov proteins hauv cov neeg mob cov hnoos qeev txawv ntawm cov mob me thiab mob hnyav.
Targeting neutrophils rau kev kho mob
Txawm hais tias lawv tuaj yeem pab tswj NTM thaum ntxov, cov neutrophils zoo li muaj lub luag haujlwm hauv cov kab mob bronchiectasis cuam tshuam nrog tsim NTM-PD. Qee cov kev kho mob yog li ntawd tau sim ncaj qha mus rau lub hom phiaj neutrophils kom txwv tsis pub cov ntaub so ntswg puas tsuaj ntxiv. Cov no tau tsom mus rau neutrophil influx, neutrophil weaponry, thiab neutrophil muaj nuj nqi (Table 3). Txawm hais tias tsis muaj cov tswv yim neutrophil-targeting tam sim no muaj ntawv tso cai [126, 127], ntau qhov mob hnyav tau raug tswj hwm - tsawg kawg hauv ib feem - los ntawm kev hloov kho cov haujlwm neutrophil thiab cov lej hauv zos thiab hauv lub cev. Cov no muaj xws li mob hawb pob, ulcerative colitis, thiab rheumatoid mob caj dab [128].
Hauv qhov chaw kho mob, cov kev kho mob uas txo cov naj npawb neutrophil tsis zoo dua li lawv tau cuam tshuam nrog kev cuam tshuam tus neeg mob lub cev tiv thaiv kab mob thiab ua rau muaj kev pheej hmoo ntawm kev kis mob rov qab [129]. Txawm li cas los xij, kev txo qis ntawm neutrophil tsiv teb tsaws hauv cov neeg mob COPD zoo li txo lawv txoj kev pheej hmoo rau exacerbations [126, 130].
Nyob rau hauv bronchiectasis, neutrophil o thiab dysfunctional tua ntawm pathogens yog suav hais tias tseem ceeb yam tseem ceeb (saib saum toj no). Txawm hais tias nws tau raug pov thawj tias hnoos qeev NE yog ib qho tseem ceeb rau bronchiectasis thaum lub sij hawm ruaj khov thiab exacerbations, kev kho mob ntawm bronchiectasis los ntawm inhibition ntawm NE tseem nyob rau theem pib [131] -tab sis, qhov no tau raug npaj rau cov neeg mob COPD. thiab CF siv cov xaiv NE inhibitor AZD9668 [131–133].
Kev sim tshuaj kho mob tsis ntev los no ntawm brensocatib, ib qho inhibitor ntawm dipeptidyl peptidase 1 (DPP-1), tau qhia txog kev sib raug zoo ntawm kev ua thiab ntau ntawm neutrophil serine proteases thiab kev soj ntsuam rau cov neeg mob uas tsis yog-cystic bronchiectasis. Lub koom haum muaj zog tau pom nyob nruab nrab ntawm qhov tsis tuaj yeem kuaj pom cov hnoos qeev neutrophil elastase thiab txo qis ntawm lub ntsws exacerbations [134]
Qee qhov kev kho mob muaj nyob uas yuav cuam tshuam ncaj qha rau neutrophils txoj haujlwm; Prezzo et al. pom tias cov tshuaj txhaj tshuaj immunoglobulin (IVIg) hloov kho rau cov tshuaj tiv thaiv kab mob tsis zoo cuam tshuam rau neutrophil activation los ntawm kev txo cov ntshav IL-8 concentration, kev qhia ntawm nws cov receptor CXCR1 thiab tso tawm neutrophil elastase. Txoj kev tshawb no qhia tias qhov txo qis hauv IL-8/CXCR1 tom qab-IVIg infusion tuaj yeem ua lub luag haujlwm tiv thaiv kab mob neutrophil-mediated [135]. Tsis ntev los no, Hitoshi et al. tau txheeb xyuas tias cov tshuaj tiv thaiv lipoarabinomanan (anti-LAM) monoclonal IgMs, TMDU3 thiab LA066, cuam tshuam rau phagocytosis ntawm Mycobacterium avium los ntawm tib neeg neutrophils, thiab cov kab mob mycobacterial tau txo qis thaum muaj cov neutrophils thiab anti-LAM IgM nyob rau hauv qhov tsis muaj (albeit). ntawm lwm cov opsonins). Cov mannan core-directed monoclonal antibodies (mAbs) yog li no tau npaj los ua cov kev kho mob rau lub hom phiaj aberrant lossis ntau dhau ntawm cov tshuaj tiv thaiv kab mob neutrophil-associated [136].
Muab cov lus teb tsis zoo thiab muaj kev cuam tshuam loj heev uas pom nrog cov tshuaj tua kab mob tiv thaiv kab mob NTM, muaj qhov xav tau ceev rau cov kev kho mob tshiab.
Cov lus xaus
Hauv cov ntsiab lus, muaj pov thawj qhia tias neutrophils tuaj yeem pab txhawb kev tshem tawm ntxov ntawm kev kis kab mob ntawm phagocytosis thiab tua tab sis kuj tseem tuaj yeem nthuav tawm cov kab mob mus rau qhov chaw nyob deb. Neutrophils tuaj yeem cuam tshuam (zoo lossis tsis zoo) kev txhim kho ntawm kev tiv thaiv kab mob. Hauv cov kab mob tsim, cov khoom siv neutrophil pab txhawb rau kev puas tsuaj rau cov hlab ntsha thiab yog li cov hom phiaj tsim nyog rau kev kho tus tswv tsev. Tam sim no, ntau cov pov thawj tau nthuav tawm los ntawm kev tshawb fawb ntawm Mtb uas tej zaum yuav tsis yog tus qauv tsim nyog rau NTM, thiab hom NTM txawv ntawm ib leeg. Kev tshawb fawb ntxiv yuav tsum tau ua kom tag nrho cov yam ntxwv ntawm ntau hom neutrophils hauv NTM pulmonary kab mob.
Kev lees paub
Peb xav lees paub peb cov neeg mob uas tsis yog tuberculous mycobacterial kab mob uas tau qhia peb ntau xyoo dhau los.
Sau cov nyiaj pab
MA tau ua cov ntaub ntawv tshawb fawb thiab sau cov ntawv sau. ML thiab DML tau pab sau cov ntawv sau. Txhua tus kws sau ntawv tau nyeem thiab pom zoo cov ntawv sau kawg.
Nyiaj txiag
MA tau txais nyiaj los ntawm King Saud University cov nyiaj pabcuam pub dawb los ntawm tsoomfwv Saudi.
Muaj cov ntaub ntawv thiab cov ntaub ntawv
Tsis siv tau.
Cov lus tshaj tawm
Kev pom zoo ntawm kev ncaj ncees thiab kev tso cai los koom
Tsis siv tau.
Tso cai rau kev tshaj tawm
Tsis siv tau.
Kev nyiam sib tw
Cov kws sau ntawv tshaj tawm tias lawv tsis muaj kev sib tw nyiam.
Cov ntaub ntawv
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