B Cells thiab T Cells txawv txav hauv cov neeg mob uas xaiv IgA Defciency
Aug 09, 2023
Abstract
Keeb kwm
Selective IgA deficiency (SIgAD) yog qhov feem ntau tshwm sim hauv kev ua yuam kev ntawm kev tiv thaiv nrog yuav luag tsis paub txog etiology. Txoj kev tshawb no tsom los tshawb xyuas cov kev kuaj mob thiab kev soj ntsuam qhov tseem ceeb ntawm cov lymphocyte subsets thiab ua haujlwm hauv cov neeg mob SIgAD.
Cov txheej txheem
Tag nrho ntawm 30 muaj SIgAD cov neeg mob los ntawm Iranian kev sau npe thiab 30 hnub nyoog-poj niam txiv neej-kev tswj hwm kev noj qab haus huv tau suav nrog hauv txoj kev tshawb no. Peb tau soj ntsuam B thiab T cell peripheral subsets thiab T cell proliferation assay los ntawm ntws cytometry nyob rau hauv SIgAD cov neeg mob uas mob me thiab hnyav phenotypes.
Cov txiaj ntsig
Peb cov txiaj ntsig tau qhia tias muaj kev nce ntxiv hauv cov hlwb tsis zoo thiab hloov pauv B hlwb thiab muaj zog txo qis hauv thaj chaw zoo li thiab hloov lub cim xeeb B-hlwb hauv cov neeg mob SIgAD. Peb pom tias tsis zoo thiab lub hauv paus nco CD4+ T cell subsets, nrog rau Th1, Th2, thiab tswj T hlwb, tau txo qis. Ntawm qhov tod tes, muaj qhov txo qis hauv central thiab effector nco CD8+ T cell subsets, whereas proportions ntawm ob qho tib si (CD4+ thiab CD8+) terminally txawv effector memory T cells. (TEMRA) tau nce siab hauv peb cov neeg mob. Txawm hais tias qee qhov T cell subsets hauv SIgAD hnyav tau zoo sib xws, qhov txo qis hauv marginal-zone thiab hloov lub cim xeeb B hlwb thiab nce hauv CD21low B hlwb ntawm cov neeg mob SIgAD loj me ntsis. Tsis tas li ntawd, kev ua haujlwm loj ntawm CD4+ T hlwb tau ua rau muaj kev cuam tshuam loj heev hauv SIgAD cov neeg mob uas muaj phenotype hnyav.
Xaus
Cov neeg mob SIgAD muaj ntau yam cellular thiab humoral tsis txaus. Yog li ntawd, kev ntsuam xyuas T cell thiab B cell yuav pab tau kom nkag siab zoo txog cov kab mob heterogeneous thiab kev kwv yees kwv yees ntawm tus kab mob.
Ntsiab lus
Inborn yuam kev ntawm kev tiv thaiv, Primary immunodeficiency, Selective IgA deficiency, B cell subsets, T cell subsets, Flow cytometry, Proliferationsoj ntsuam
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
cistanche extract
Taw qhia
Selective IgA deficiency (SIgAD) yog thawj qhov kev tiv thaiv kab mob tiv thaiv kab mob ntau tshaj plaws (PID) lossis qhov ua tsis zoo ntawm kev tiv thaiv kab mob hauv lub cev (IEI), txheeb xyuas los ntawm cov ntshav concentration ntawm IgA qis dua 7 mg / dL thiab qhov ib txwm muaj ntawm IgG thiab IgM hauv cov neeg mob hnub nyoog plaub xyoos. . Feem ntau ntawm cov neeg mob SIgAD yog asymptomatic, txawm hais tias qee tus ntawm lawv pom cov tsos mob sib txawv, suav nrog kab mob plab hnyuv thiab ua pa, kab mob ua xua, thiab kab mob autoimmune. Cov kab mob kis mus rau qhov sib txawv ntawm kev tiv thaiv kab mob sib txawv (CVID) hauv ib pawg neeg xaiv ntawm SIgAD cov neeg mob uas muaj IgG subclasses deficiency lossis autoimmune disorders tau raug tshaj tawm [1]. Tsis muaj ib qho laj thawj tshwj xeeb rau cov kab mob pathogenesis ntawm SIgAD tseem tsis tau tshaj tawm. Txawm li cas los xij, qhov tsis xws luag hauv cov txheej txheem ntawm IgA chav kawm hloov pauv hloov pauv (CSR), IgA ntau lawm thiab zais cia, nrog rau kev muaj sia nyob ntev ntawm IgA, hloov lub cim xeeb B hlwb, thiab cov plasma hlwb ntawm SIgAD cov neeg mob tau raug txheeb xyuas hauv cov xwm txheej tsis tau daws [2 ]. Cov teeb meem hauv cov txheej txheem immunologic no cuam tshuam nrog kev txawv txav hauv cov lymphocytes ntawm SIgAD cov neeg mob. Yog li, kev ntsuam xyuas ntawm lymphocytes, tshwj xeeb tshaj yog B cell thiab T cell subsets, yuav muaj txiaj ntsig thiab pab tau. Ntau qhov kev tshawb fawb tau pom tias B cell thiab T cell txawv txav hauv qee pawg ntawm SIgAD cov neeg mob [3, 4]. Hais txog B cell subsets, qhov txo qis ntawm cov lej hloov pauv B hlwb, IgA plasma hlwb, thiab kev hloov pauv IL-10+ kev tswj hwm B hlwb ntawm SIgAD cov neeg mob tau tshaj tawm [5–8]. Ntawm qhov tod tes, qhov tsis xws luag hauv qee qhov T cell subsets ntawm SIgAD cov ntaub ntawv tau raug tshaj tawm uas tau txuas rau IgA-tsim B hlwb tsis txaus [5, 8, 9]. Flow cytometric immunophenotyping tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev kuaj mob, kev kuaj mob, kev faib tawm, thiab kev tswj xyuas cov neeg mob nrog SIgAD. Yog li ntawd, thawj zaug, peb tsom mus soj ntsuam cov subpopulations tseem ceeb ntawm B thiab T lymphocytes nrog rau kev ntsuam xyuas ntawm T cell muaj nuj nqi, kom paub meej txog kev sib raug zoo ntawm cov yam ntxwv ntawm kev tiv thaiv kab mob thiab kev kho mob tshwm sim nyob rau hauv cov neeg mob symptomatic nrog SIgAD.
Khoom siv thiab cov txheej txheem
Cov neeg mob
Tag nrho ntawm 30 tus neeg mob SIgAD muaj cov tsos mob (los ntawm Iranian IEI npe [10, 11]) thiab 30 hnub nyoog-poj niam txiv neej-matched noj qab haus huv tswj (HCs) tau suav nrog hauv txoj kev tshawb no. Te HCs tau raug lees paub tom qab kev soj ntsuam thiab kev soj ntsuam kuaj kom tsis muaj kev tiv thaiv kab mob lossis kab mob hauv qab. Cov neeg mob tau raug xa mus rau Children's Medical Center (Pediatrics Center of Excellence koom nrog Tehran University of Medical Sciences, Tehran, Iran). Txhua tus neeg mob tau kuaj pom tias muaj SIgAD raws li European Society for Immunodeficiencies [12]. Txoj kev tshawb no tau pom zoo los ntawm Pawg Saib Xyuas Kev Ncaj Ncees ntawm Tehran University of Medical thiab sau ntawv tso cai tau txais los ntawm txhua tus neeg (IR.TUMS.VCR.REC.1396.2018). Cov pej xeem, kev kho mob tshwm sim, thiab cov ntaub ntawv tiv thaiv kab mob ntawm cov neeg mob tau sau tseg rau hauv daim ntawv nug.
Kev faib cov neeg mob
Txhawm rau sib piv cov ntaub ntawv pej xeem, chaw kho mob, thiab kev tiv thaiv kab mob, cov neeg mob tau muab faib ua ob pawg mob hnyav thiab mob me (raws li kev kho mob tshwm sim) nrog rau cov pab pawg tsis sib xws thiab tsis sib xws (raws li niam txiv consanguinity). Yam tsawg kawg nkaus suav nrog rau tus neeg mob yuav tsum suav tias yog cov tsos mob yog kaum ceeb toom ntawm Jeffrey Modell Foundation. Cov neeg mob tau muab faib ua ob pawg me me thiab hnyav, raws li cov neeg mob uas muaj kab mob hnyav (piv txwv li, cov hlab ntsha, hauv nruab nrab lub paj hlwb, thiab cov kab mob sib sib zog nqus zoo li osteomyelitis thiab mob caj dab), autoimmunity, lossis malignancy tau muab faib rau hauv pawg loj, thiab lwm yam teeb meem. raug suav hais tias yog ib pab pawg me. Txij li thaum mob ntsws thiab lwm yam kab mob ua pa yog tshwm sim nyob rau hauv cov neeg mob SIgAD thiab peb xav kuaj nws raws li qhov tsis sib xws ntawm pawg neeg mob hnyav thiab mob me, yog li peb tsis tau muab faib rau hauv pawg loj.
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Lymphocyte subsets assay
Peripheral ntshav mononuclear hlwb (PBMCs) raug cais los ntawm 8 ml cov ntshav kuaj sau hauv cov hlab ntsha sodium heparin siv Ficoll-Hypaque density gradient centrifugation ntawm 600 g rau 25 min ntawm 22 degree. Rau kev staining extracellular, PBMCs tau muab faib ua 5- vaj huam sib luag feem thiab stained rau 20 min ntawm 2-8 degree nyob rau hauv ib qho chaw tsaus nrog txhua cocktail uas muaj cov tshuaj tiv thaiv kab mob monoclonal ntawm qhov kev pom zoo. Te B1 vaj huam sib luag tau siv los txiav txim siab tsis zoo (CD19+CD27−IgM+IgD+), IgM-tsuas nco (CD19+CD27+ IgM++IgD−), hloov nco (CD19+CD27+IgM−IgD−) thiab marginal zone-zoo li B hlwb (CD19+CD27+IgM++IgD+). Te B2 vaj huam sib luag tau siv los txheeb xyuas CD21low B hlwb (CD19+CD21−/lowCD38−/lowIgM+++), plasmablast (CD19+CD21−/lowCD38++/{ {34}}IgM−) thiab transitional B hlwb (CD19+CD21+CD38++IgM+). Lub vaj huam sib luag T1 tau siv los faib cov tsis zoo (CD4+ lossis CD8+ thiab CD45RA+CCR7+), effector nco (CD4+ lossis CD8+ thiab CD45RA-CCR7−), central memory (CD4+ lossis CD8+and CD45RA-CCR7+) thiab TEMRA (terminally differentiated effector memory) T cells (CD4+ lossis CD8+ thiab CD45RA+CCR7−). Te T2 vaj huam sib luag tau siv los faib cov kev tswj hwm T hlwb (TregsCD4+CD25+FOXP3+CD127−/low). Rau intracellular staining, tom qab lub nto molecule staining, lawv tau tsau thiab permeabilized thoob plaws hauv FOXP3 / Permeabilization tsis (eBioscience, US) raws li cov chaw tsim tshuaj paus cov lus qhia rau cov nram qab no: Anti-Human FOXP3 (PE), Anti-Human IL{{67} } (PE), Anti-Human IL-4 (APC) thiab Anti-Human IFN- (FITC). Tag nrho cov tshuaj tiv thaiv kab mob thiab isotype tswj tau yuav los ntawm eBioscience, ib lub koom haum Asmeskas. Txhawm rau ntsuas T tus pab hlwb (xws li T1, T2, thiab T17), 1 × 106 (cell / mL) ntawm PBMCs tau coj mus rau hauv Roswell Park Memorial Institute (RPMI 1640) cell kab lis kev cai nruab nrab, ua raws li kev txhawb nqa nrog phorbol myristate acetate (PMA) , 50 ng/mL, Sigma-Aldrich, US) / ionomycin (1 ug/mL, Sigma-Aldrich), thiab nyob rau hauv lub xub ntiag ntawm brefeldin (5 ug / mL, eBioscience). Tom qab ntawd, cov hlwb raug incubated ntawm 37 degree hauv 5% CO2 thiab 95% humidity incubator rau 5 h. Cov hlwb uas txhawb nqa tau raug ntxuav nrog phosphate-buffered saline (PBS), thiab qhov chaw staining nrog anti-tib neeg CD4 (PerCp)-Cy5.5 tau ua. Intracellular cytokine staining antibodies (anti-IFN- FITC, anti-IL-17 PE, thiab anti-IL-4 APC rau kev ntsuam xyuas ntawm T subsets thiab anti-FoxP3 PE rau kev soj ntsuam ntawm Treg) tau ntxiv thiab incubated ntawm chav tsev kub rau 30 min. Cells raug ntxuav nrog permeabilization tsis, thiab rov ua dua nyob rau hauv txias staining tsis, thiab suav tau txiav txim siv BD FACSCalibur Flow Cytometer (BD Biosciences) (Cov ntaub ntawv ntxiv 1: Table S1). Lub tswv yim gating zoo ib yam li peb txoj kev kawm yav dhau los [13, 14].
T-cell proliferation assay
Txhawm rau soj ntsuam T cell proliferation, PBMCs tau coj los ntawm fluorescent 5, 6-carboxyfluorescein succinimidyl ester (CFSE, Biolegend, US). Cov tshuaj CFSE cov khoom lag luam tau npaj los ntawm kev sib cais CFSE hauv dimethyl sulfoxide (DMSO) ntawm qhov concentration ntawm 5 mM / L, raws li cov chaw tsim khoom cov lus qhia. Cov khoom no tau khov rau hauv me me aliquots los tiv thaiv ntau khov thiab thaw mus. CFSE tau muab ntxiv rau hauv lub raj falcon transverse uas muaj 500μL ntawm PBMC ncua (5 × 106 cell / mL) hauv RPMI 1640 cell kab lis kev cai nruab nrab uas muaj 10% FBS (fetal bovine serum, Biosera, Fabkis) nrog qhov kawg ntawm 5 μM thiab 2 mM L-glutamine, 100 U / mL penicillin thiab 100 ug / mL streptomycin (Lymphosep; Biosera, Fabkis). Lub raj tig nrawm thiab vortexed kom ntseeg tau tias homogenous dispersal. Tom qab daim ntawv lo, lub cell raug ncua rau 5 feeb ntawm 37 degree. Tom qab ntawd, 9 mL ntawm RPMI1640 uas muaj 10% FBS tau ntxiv rau hauv kev ncua ntawm tes thiab nws tau centrifuged ntawm 500 g rau 5 min. Cells raug ntxuav peb zaug thiab 1 mL ntawm RPMI1640 nrog 10% FBS tau ntxiv. Hais txog qhov tshwj xeeb T cell stimulation thiab proliferation, anti-CD3 antibody (1 µg / ml) tau ntxiv rau 500 μL ntawm sterile PBS, thiab lub phaj yog incubated ntawm 37˚C rau 2 h. Cov phaj coated tau ntxuav ob zaug nrog tsis muaj menyuam PBS thiab cov ntawv sau npe tau ncaj qha ntxiv, thiab thaum kawg, cov tshuaj tiv thaiv CD28 (2 µg / ml) tau ntxiv los ua cov tshuaj tiv thaiv rau T hlwb. Lub phaj yog incubated ntawm 37 ºC nyob rau hauv 5% CO2 thiab 95% humidity incubator rau 96 h [15-17]. Ib lub qhov dej uas tsis muaj zog tau raug suav hais tias yog kev tswj hwm rau cov hlwb uas tsis muaj kev loj hlob. Tom qab 96 teev, lub hlwb tau sau thiab ntxuav. Tom qab staining nrog Anti Human CD4 (PerCPCy5.5), cov hlwb tau tshawb xyuas los ntawm BD FACSCalibur™ Flow cytometer thiab CellQuest Pro software (BD, Biosciences, San Jose, CA, US). Kev soj ntsuam kev loj hlob tau ua los ntawm kev sib piv peb cov qauv, suav nrog feem pua ntawm cov cell faib (% faib), qhov nruab nrab ntawm cov cell faib uas ib lub xov tooj tau dhau mus (Division Index), thiab qhov nruab nrab ntawm cov cell faib uas tshwm sim nyob rau hauv tag nrho cov thawj cell cov pejxeem. (Proliferation Index) los ntawm FlowJo 7.6 software.
Kev txheeb cais
SPSS software (Windows version 16.0; SPSS Inc., Chicago, IL, US) tau siv rau kev txheeb xyuas kev txheeb cais. Peb siv Kolmogorov-Smirnov test los kwv yees seb cov ntaub ntawv puas tau muab faib. Cov kev tshawb pom tau nthuav tawm raws li qhov nruab nrab (interquartile range [IQR], nthuav tawm raws li qhov ntau nrog 25th-75th feem pua) qhov tseem ceeb. Ib qho kev xeem chi-squared los yog Fisher qhov tseeb yog siv rau kev sib piv. Rau kev sib piv ntawm ntau tshaj ob pawg, yog tias cov ntaub ntawv faib tawm yog qhov qub, ANOVA tau siv, thiab yog tias cov ntaub ntawv faib tawm tsis zoo li qub, Kruskal Wallis qhov kev sim tau siv. Te sib txawv tau suav hais tias yog qhov tseem ceeb rau P-tus nqi uas yog<0.05.
cistanche cov txiaj ntsig rau txiv neej-ua kom muaj zog tiv thaiv kab mob
Cov txiaj ntsig
Demographic, immunologic thiab soj ntsuam kev tshawb pom
Ntawm tag nrho cov neeg mob Iranian SIgAD sau npe, 30 cov neeg mob muaj (23 tus txiv neej thiab xya tus poj niam) tau nrhiav hauv txoj kev tshawb no. Qhov nruab nrab (IQR) hnub nyoog ntawm cov neeg mob yog 11 (7.3-16) xyoo thaum lub sijhawm kawm. Cov niam txiv consanguinity muaj nyob rau hauv 16 (53.3% ntawm) cov neeg mob. Kev mob ntsws (42.3%) yog qhov tshwm sim tshwm sim ntau tshaj plaws hauv cov neeg mob uas tau kawm thiab mob qog noj ntshav tsis tau kuaj pom hauv pawg no. Cov yam ntxwv ntawm cov neeg mob, kev kho mob, thiab kev tiv thaiv kab mob tau sau tseg nyob rau hauv Table 1. Tom qab categorizing cov neeg mob raws li cov phenotypes hnyav thiab mob me, cov pej xeem, cov ntaub ntawv kho mob, thiab cov tshuaj tiv thaiv kab mob tau muab piv rau (Table 1, Fig. 1). Te cov neeg mob uas muaj phenotypes hnyav tshwm sim ua pa nyuaj dua li pab pawg me. Lwm qhov kev ntsuas tsis tau pom qhov sib txawv tseem ceeb. Tib qhov kev sib piv tau ua nyob rau hauv cov neeg mob uas muaj thiab tsis muaj kev sib raug zoo, thiab tsis muaj qhov sib txawv tseem ceeb. Hauv qhov sib piv, cov neeg mob uas muaj cov phenotypes me me tau nthuav tawm me ntsis ntawm kev ua xua thiab plab hnyuv tshwm sim nrog kev nce qib hauv cov ntshav IgE, qhia txog kev hloov pauv mus rau IgE ntau lawm.
Table 1 Kev sib piv ntawm cov pej xeem, chaw kho mob, thiab cov ntaub ntawv tiv thaiv kab mob ntawm SIgAD cov neeg mob uas muaj phenotypes hnyav thiab me me
Fig. 1 Kev sib piv ntawm kev kho mob tshwm sim ntawm SIgAD hnyav thiab mob me
B-cell subsets
Cov neeg mob SIgAD tau pom muaj qhov ntau zaus ntawm CD{{0}} B-cells [11.2% (9.4–13.07%) vs. 7.2% (6–8.6%), p < 0.001], nrog nce naïve B-cells [71% (63.7–80%) vs. 66.5% (56.2–71.1%), p=0.036] thiab transitional B-cells [ 8% (3.6–13.5%) vs. 4.8% (2.6–9.5%), p=0.032] piv nrog HCs. Hauv qhov sib piv, qhov feem pua ntawm thaj chaw marginal zoo li [2.3% (2–3.5%) vs. 3.4% (2.3–4.8%), p=0.022) thiab hloov lub cim xeeb B-cells [3.5% (1.9). -5.5%) vs. 6% (3.5–8.4%), p=0.006] tau qis dua HCs. Txawm li cas los xij, txo qis IgM-tsuas nco thiab plasmablasts thiab nce CD21low B-hlwb hauv cov neeg mob dua li cov hauv HCs tsis tseem ceeb (Daim duab 2). Interestingly, qee qhov kev sib piv yog qhov tseem ceeb ntawm cov neeg mob cov pab pawg kho mob. Qhov feem pua ntawm CD19+ B hlwb hauv cov phenotypes me thiab hnyav tau ntau dua li HCs [11.6% (8.7–13) vs. 7.2% (6–8.6), p < 0.0001, 10.8% (9.6–13.2). ) vs. 7.2% (6–8.6), p < 0.0001], ntsig txog. Cov neeg mob SIgAD hnyav tau pom tias muaj qhov nce ntxiv hauv feem pua ntawm CD21low B-cells [1.5% (1–2.2) vs. 2.7% (1.6–5.6), p=0.025], thiab qhov feem pua ntawm cov neeg poob qis heev. ntawm ob qho tib si marginal-zone thiab switched nco B cell subsets [3.4% (2.3–4.8) vs. 2.2% [2, 3], p=0.040, 6% (3.5–8.4) vs. 2.7% ( 1.7–4.7), p=0.003], raws. Qhov feem pua ntawm kev hloov pauv B hlwb hauv cov neeg mob SIgAD me me yog siab dua HCs [10.7% (3.9–13.8) vs. 4.8% (2.6–9.5), p=0.047] (Fig. 3). Qhov feem pua ntawm IgM-tsuas nco tau ntau dua hauv cov neeg mob uas muaj kev sib koom ua ke dua li cov tsis muaj kev sib koom ua ke. Peb kuj tau categorized qhov zaus ntawm B cell subsets ntawm SIgAD cov neeg mob ua peb pawg: ib txwm, txo qis, thiab nce raws li qhov qub ntawm HCs (Table 2). Raws li qhov kev tshuaj ntsuam no, qhov txo qis hauv B cell subsets feem ntau cuam tshuam nrog kev hloov pauv ntawm B-cells (23%), thaum qhov kev nce siab tshaj plaws yog cuam tshuam nrog naïve B hlwb (27%) hauv cov neeg mob SIgAD. Tsuas yog nce CD21low B-hlwb hauv cov neeg mob SIgAD hnyav piv nrog cov neeg mob SIgAD me.
Fig. 2 Kev txheeb xyuas ntau ntawm B cell thiab T cell subset feem pua ntawm cov neeg mob SIgAD thiab kev tswj hwm kev noj qab haus huv. Qhov nruab nrab yog sawv cev los ntawm kab rov tav. Cov ntaub ntawv tau txheeb xyuas siv Mann-Whitney U test. *p<0.05, statistical significance between patients and HCs. HC Healthy control
T-cell subsets
Te subset sib cais ntawm CD4+ T cells qhia qhov txo qis hauv tag nrho CD4+ T cells [36.5% (30.8–41.2%) vs. 40.1% (37.3–47.2%), p{{14 }}.038)], central memory cells [11% (7.3–13.1%) vs. 24.5% (16–29%), p<0.0001), T1 [7.7% (5.2–9.9%) vs. 12% (7.8–16%), p=0.002], T2 [0.3% (0.2–0.4%) vs. 0.6% (0.4–1.3%), p<0.0001] and Tregs [0.3% (0.03–0.7%) vs. 1.4% (1.1– 1.6%), p<0.0001] in patients compared with HCs. Oppositely, the percentage of TEMRA [9.5% (5.7–16.4%) vs. 2% (1.3–6.2%), p<0.0001] was meaningfully higher than HCs. Moreover, decreased effector memory and T17, and increased naïve helper T cells in patients in comparison with HCs were not significant (Fig. 2). Regarding the percentage of CD8+ T cell subsets, central memory [0.6% (0.3–0.8%) vs. 3% (2–6%), p<0.0001] and effector memory [12.3% (7.6–22.1%) vs. 23.9% (19.5– 27.2%), p<0.0001] were markedly diminished in patients compared with HCs. On the other hand, the percentage of cytotoxic TEMRA [44.1% (28.4–55.7%) vs. 24.4% (20– 31%), p<0.0001] was significantly higher than HCs. However, increased total CD8+ T cells and decreased naïve CD8+ T cells were not significant in patients compared to those in HCs (Fig. 2). Regarding the comparison of the percentage of CD8+ T cells subsets between severe SIgAD patients with HCs, naïve T cells, effector, and central memory cells demonstrated a significant reduction. Also, there was a significant decrease in the percentage of total CD4+ T-cells, central memory, T1, T2, and regulatory T cells, whereas TEMRA in both CD4+ and CD8+ T cells demonstrated an increase. On the other hand, the percentage of effector and central memory cells within CD8+ T cells, as well as central memory, TEMRA, T1, and regulatory T cells within CD4+ T cell subsets demonstrated a significant decrease in mild forms of SIgAD compared to HCs. In contrast, we found an increase in TEMRA CD8+ T cells and T2 CD4+ T cells in mild patients compared to controls (Fig. 3). Comparisons of the percentages of all T cell subsets between SIgAD patients with and without consanguinity have not indicated any significant difference. We also categorized the frequency of T cell subsets of SIgAD patients into three categories: normal, decreased, and increased based on a normal range of HCs (Table 2). Based on this analysis, the most decrease in T cell subsets is related to Tregs (67%), while the most increase is related to CD8+ TEMRA (37%) in SIgAD patients. Flow cytometry results of B cell and T cell subsets in 30 SIgAD patients have shown separately in Additional file 1: Tables S2 and S3. To evaluate the impact of the T cell subset on the switching process of B cells and the production of different Ig subtypes we performed a correlation analysis. Surprisingly only IgG but not IgM and IgE were significantly associated with specific T cell subsets (negative association with naïve CD4 and naïve CD8 T cells and positive association with CD4+ TEM and T17 cells, Additional file 1: Table S4) indicating the independent association of IgM to IgE from co-stimulation of T cell subsets in our patient cohorts. Moreover, correlation analysis of absolute counts and percentage of subsets should significant direct correlation in all measured parameters (Additional file 1: Table S5).
Fig. 3 Kev txheeb xyuas ntau ntawm B cell thiab T cell subset feem pua ntawm cov neeg mob SIgAD mob hnyav thiab mob me. Qhov nruab nrab yog sawv cev los ntawm kab rov tav. Cov ntaub ntawv tau txheeb xyuas siv Mann-Whitney U test. *p<0.05, statistical signifcance between severe and mild patien
Table 2 Kev faib tawm ntawm qhov qub, nce thiab txo qis ntawm T cell thiab B cell subsets hauv txhua tus neeg mob SIgAD. N =30
T cell proliferation
Cov ntaub ntawv tsim los ntawm CFSE-labeled kab lis kev cai tau txheeb xyuas kom muaj nuj nqis CD4+ T cell proliferation. Tsis muaj qhov sib txawv tseem ceeb hauv kev faib index (DI), qhov ntsuas kev loj hlob (PI), thiab feem pua raug faib (PD) ntawm SIgAD cov neeg mob thiab HCs (Fig. 4). Interestingly, thaum peb piv cov indexes ntawm SIgAD cov neeg mob uas mob hnyav thiab me phenotypes, peb pom tias qhov nruab nrab DI thiab PD nyob rau hauv cov neeg mob SIgAD hnyav nyob rau hauv kev sib piv nrog rau cov mob me yog abrogated [0.1 (0). . 26.4) vs. 42.5 (26.8–52.6), p=0.009, ntsig]. Txawm li cas los xij, tsis muaj qhov sib txawv ntawm PI ntawm pawg mob hnyav thiab mob me (Fig. 4). Ntawm qhov tod tes, kev sib piv ntawm DI, PI, thiab PD ntawm SIgAD cov neeg mob uas muaj thiab tsis muaj kev sib raug zoo tsis tseem ceeb.
Daim duab 4 Kev sib piv ntawm T lymphocyte proliferation indexes hauv cov neeg mob SIgAD mob hnyav thiab mob me. Qhov nruab nrab yog sawv cev los ntawm kab rov tav. *p<0.05, statistical significance between severe and mild patients
Kev sib tham
SIgAD yog IEI ntau tshaj plaws nrog ntau yam kev kho mob tshwm sim. Cov neeg mob no muaj qhov sib txawv ntawm kev kho mob tshwm sim. Yog li ntawd, kev tshawb nrhiav immunologic hauv cov neeg mob uas muaj qhov sib txawv ntawm kev kho mob tshwm sim yog pab tau. Qhov kev tshwm sim tshwm sim ntau tshaj plaws hauv IEIs, tshwj xeeb tshaj yog hauv SIgAD, yog cov kab mob ua pa rov tshwm sim [18-20]. Peb pom muaj mob ntsws ua rau muaj teeb meem ntau tshaj plaws hauv peb cov neeg mob cov tsos mob. Cov kab mob ua pa rov tshwm sim feem ntau tshwm sim nyob rau hauv daim ntawv ntawm cov kab mob ua pa sab saud thiab tej zaum yuav nyob twj ywm tsis kuaj tau ntau xyoo; Txawm li cas los xij, qee tus neeg mob SIgAD tshwm sim ntau dua phenotypes xws li bronchiectasis lossis obliterate bronchiolitis uas yuam kev tshawb nrhiav kev tiv thaiv kab mob hauv cov neeg mob no [21]. Muab hais tias cov kab mob ua pa rov tshwm sim tau raug tshaj tawm tias yog qhov tseem ceeb tshaj plaws ntawm kev mob thiab kev tuag ntawm cov menyuam yaus uas muaj IEIs, tshwj xeeb tshaj yog thawj cov tshuaj tiv thaiv kab mob tsis zoo [22, 23], kev kuaj mob ntxov thiab kev tswj xyuas cov kab mob ua pa cuam tshuam nrog SIgAD yog qhov tseem ceeb heev [24, 25] . Nws tau raug qhia tias qhov txawv txav hauv B cell subsets tau pom hauv qee tus neeg mob SIgAD [3, 4]. Peb cov txiaj ntsig tau qhia tias muaj kev nce ntxiv hauv cov hlwb tsis zoo thiab hloov pauv B hlwb thiab muaj zog txo qis hauv thaj chaw zoo li thiab hloov lub cim xeeb B-hlwb. Cov qauv B-cell txawv txav no qhia txog qhov tsis xws luag hauv cov theem kawg ntawm B-hlwb sib txawv, zoo ib yam li cov neeg mob CVID [26]. Muab hais tias CVID thiab SIgAD sib koom yuav luag cov keeb kwm caj ces zoo sib xws thiab tuaj yeem sib sau ua ntau qhov xwm txheej hauv ib tsev neeg, qhov zoo sib xws yog kwv yees. Feem ntau, ntau tshaj li ib nrab ntawm cov neeg mob IEI tau sau npe hauv Iranian kev sau npe muaj kev sib koom ua niam txiv, tab sis tus nqi no tseem tsawg dua hauv cov neeg mob SIgAD. Hauv SIgAD Iranian cov neeg mob piv rau cov neeg mob sab hnub poob, kev sib koom ua ke muaj ntau dua. Txawm hais tias monogenetic ua rau muaj tshwm sim, nws tseem tsis tau raug txheeb xyuas txawm hais tias muaj kev sib txuas ua ke tom ntej hauv ntau tus neeg mob [27]. Peb tau kuaj pom qhov txo qis hauv thaj chaw zoo li thiab hloov lub cim xeeb B-hlwb, tshwj xeeb tshaj yog nyob rau hauv cov neeg mob SIgAD hnyav, raws li tau tshaj tawm yav dhau los [28]. Tsis ntev los no peb tau tshaj tawm txog qhov txo qis hauv thaj tsam zoo li thiab hloov lub cim xeeb B-hlwb hauv cov neeg mob CVID [14].
cistanche ntxiv cov txiaj ntsig-nce kev tiv thaiv
Ntawm qhov tod tes, txawm hais tias peb tau pom qhov txo qis hauv kev hloov pauv hauv lub cim xeeb hauv Ataxia Telangiectasia (AT) cov neeg mob tab sis pom muaj kev nce ntxiv hauv thaj chaw marginal zoo li B hlwb tau pom [29]. Cov neeg mob SIgAD, tshwj xeeb tshaj yog ib pawg ntawm cov neeg mob uas muaj qhov tshwm sim loj heev (rov tshwm sim thiab mob hnyav, thiab autoimmunity), muaj qhov hloov pauv nco B-cells qis dua [28, 30, 31]. Nws tau raug pom tias qhov txo qis hauv kev hloov pauv ntawm lub cim xeeb B-cell subpopulation yog vim muaj qhov tsis xws luag hauv cov txheej txheem antibody class-switching recombination (CSR), tshwm sim los ntawm enzymatic deficiency, los yog qhov txawv txav hauv cytokine tes hauj lwm thiab lawv cov receptors [28]. Qee cov neeg mob SIgAD uas muaj phenotype loj zuj zus mus rau CVID, uas qhia txog cov pab pawg ntawm SIgAD no tuaj yeem koom nrog CVID cov kab mob tiv thaiv kab mob, tshwj xeeb hauv kev txhim kho CSR kauj ruam. Yog li, hloov lub cim xeeb B-hlwb yog suav tias yog kev kuaj mob biomarker hauv cov neeg mob [28]. Txawm li cas los xij, qhov zaus ntawm kev hloov pauv nco B-hlwb yog ib txwm muaj ntawm cov menyuam yaus hauv peb cov neeg kawm, thiab qhov txo qis tau pom ntau dua hauv cov neeg laus; qhia tias kev laus tej zaum yuav ua rau muaj kev loj hlob ntawm SIgAD mus rau CVID, tshwj xeeb tshaj yog nyob rau hauv cov neeg mob uas muaj mob hnyav (cov ntaub ntawv tsis qhia). Ntawm qhov tod tes, marginal cheeb tsam B hlwb yog cov neeg tshwj xeeb ntawm B hlwb uas tsim IgM rau kev tiv thaiv kab mob, tshwj xeeb tshaj yog cov kab mob encapsulated [32]. Txawm hais tias yav dhau los cov kev tshawb fawb tau pom tias tus naj npawb ntawm thaj chaw zoo li B hlwb hauv SIgAD cov neeg mob tsis txawv piv rau cov kev tswj hwm ib txwm muaj [33], txawm li cas los xij, peb tau txais qhov txo qis hauv marginal zone-zoo li B hlwb hauv peb qhov xwm txheej, zoo ib yam li cov kev tswj hwm ib txwm muaj. tsab ntawv ceeb toom dhau los hauv cov neeg mob CVID [34]. Kev txo qis qis ntawm B cell subsets hauv lwm cov neeg mob uas muaj cov tshuaj tiv thaiv kab mob ntau lawm tuaj yeem cuam tshuam nrog kev pheej hmoo ntawm kev kis kab mob xws li mob ntsws thiab txo qis hauv cov ntshav IgM, zoo ib yam li cov neeg mob CVID [35]. Peb pom muaj CD21low B hlwb ntau dua piv rau kev tswj hwm, feem ntau hauv cov neeg mob SIgAD hnyav. Cov kev tshawb fawb yav dhau los tau tshaj tawm txog kev nce hauv CD21low B hlwb hauv ob qho tib si SIgAD [3] thiab CVID cov neeg mob [36], thiab lwm yam kab mob autoimmune [37]. Tsis ntev los no kuj tau tshaj tawm txog qhov nce ntawm CD21low hauv cov neeg mob AT [29]. Kev nce ntawm cov CD21low hlwb yog ncaj qha cuam tshuam tsis yog tsuas yog rau autoimmunity tab sis kuj kis tau tus mob [36]. Ntawm qhov tod tes, kev kis tus kab mob mus ntev tuaj yeem ua rau kev hloov pauv ntawm antigen-reactive B hlwb kom tsis txhob teb CD21low B hlwb [38]. Kom paub meej qhov ua rau nthuav dav CD21low B hlwb; Nws yog ib qho tsim nyog yuav tsum tau tshawb xyuas ntxiv rau qhov B cell subpopulation. Muab cov neeg coob coob ntawm CD21low B hlwb hauv cov neeg mob CVID thiab kev loj hlob ntawm qee cov neeg mob nrog SIgAD rau CVID, pawg neeg mob SIgAD uas muaj CD21low B hlwb ntau dua yuav tsim CVID. Yog li ntawd, lawv xav tau kev soj ntsuam tas li ntxiv txhawm rau txheeb xyuas cov kab mob. Transitional B hlwb yog nyob rau theem nrab hauv kev loj hlob ntawm cov pob txha hlwb tsis paub tab thiab paub tab B hlwb hauv tus po [39]. Hauv txoj kev tshawb fawb tam sim no, peb tau pom muaj kev hloov pauv B hlwb hauv peb cov neeg mob SIgAD, tshwj xeeb tshaj yog nyob rau hauv cov neeg mob SIgAD hnyav, txawm hais tias tus naj npawb ntawm B hlwb hloov pauv hauv cov menyuam yaus nrog SIgAD yog ib txwm muaj (cov ntaub ntawv tsis qhia). Peb tsis ntev los no tau pom qhov txo qis hauv kev hloov pauv B hlwb AT [29]. Hauv kev sib piv rau cov kev tshawb fawb yav dhau los uas pom tau tias txo qis kev hloov pauv B hlwb [8, 28, 40], cov neeg laus cov neeg mob tau qhia me ntsis nce B hlwb. Ntxiv mus, Lemarquis et al. pom qhov txo qis hauv kev ua haujlwm ntawm kev hloov pauv B hlwb raws li IL-10 ntau lawm thiab CpG stimulation [40]. Muab qhov tsis xws luag hauv cov theem kawg ntawm B-hlwb hauv SIgAD, nws zoo li tias qhov nce ntawm B hlwb hloov pauv thiab tsis zoo B hlwb ntawm peb cov neeg mob yog vim muaj cov txheej txheem them nyiaj uas txhawb nqa B cell thaum ntxov. Hais txog cov txiaj ntsig sib txawv ntawm peb txoj kev tshawb fawb thiab lwm tus, nws zoo li qhov sib txawv no yog vim muaj kev xaiv sib txawv, vim peb txhua tus neeg mob tau mob, thaum lwm tus tau kawm heterogeneously asymptomatic thiab symptomatic SIgAD cov neeg mob. Hais txog T cell subsets, peb tau pom tsawg dua tag nrho CD4+ T hlwb, T1, T2, thiab Treg hlwb, thiab nce TEMRA hauv CD4+ thiab CD8+ hlwb. Raws li peb cov txiaj ntsig, cov kev tshawb fawb yav dhau los tau pom tias muaj kev nce thiab txo qis hauv CD8+ thiab CD4+ T lymphocytes pejxeem, feem [4]. Tsis tas li, peb pom tias lub hauv paus nco hauv CD4+ thiab CD8+ T hlwb thiab effector nco hauv CD8+ T lymphocytes tau txo qis hauv cov neeg mob SIgAD piv rau HCs. Peb pom muaj qhov nce ntxiv hauv TEMRA cell subset hauv CD4+ thiab CD8+ lymphocytes pejxeem, tshwj xeeb tshaj yog nyob rau hauv cov neeg mob SIgAD hnyav. TEMRA yog thib peb T cell nco subset nyob rau hauv peripheral inflammatory cov ntaub so ntswg uas qhia CD45RA tab sis tsis muaj kev qhia ntawm CCR7 los yog CD27. Hauv tib neeg, TEMRA cell accumululation yog cuam tshuam los ntawm cov kab mob ntev, xws li CMV [41, 42]. Ib qho kev nce ntxiv ntawm cov T-cell subsets uas tau txiav tawm no tuaj yeem yog vim muaj cov kab mob cellular teb rau cov kab mob hauv cov neeg mob no; Txawm li cas los xij, kev tshawb fawb ntxiv yuav tsum tau ua txog qhov tshwm sim no. Raws li peb cov txiaj ntsig, Nechvatalova li al. tau nthuav tawm CD4+ thiab CD8+ TEMRA hlwb hauv SIgAD cov neeg mob uas cuam tshuam nrog CMV kab mob [43]. Peb tsis tau tshuaj xyuas CMV tus kab mob hauv SIgAD cov neeg mob, tab sis qhov nce ntawm tus naj npawb ntawm TEMRA hlwb subset hauv peb cov neeg mob tuaj yeem cuam tshuam txog kev kis mob ntev. Tsis ntev los no peb tau soj ntsuam cov tshuaj tiv thaiv kab mob tshwj xeeb rau PPSV-23 hauv cov neeg mob SIgAD thiab AT thiab qhia tias 18.6% ntawm cov neeg mob SIgAD thiab 81.3% ntawm cov neeg mob AT muaj cov lus teb tsis txaus. Tus naj npawb ntawm plasmablasts, marginal zone B hlwb, transitional B hlwb, naïve CD8+ T cells, thiab feem pua ntawm CD8+ T cells, IgM nco B hlwb, thiab hloov lub cim xeeb B hlwb hauv SIgAD cov neeg mob tau qis dua nyob rau hauv ib pawg tsis teb ntau dua li pab pawg neeg teb. Txawm hais tias cov tshuaj tiv thaiv tshwj xeeb tsis txaus muaj ntau zaus hauv cov neeg mob AT dua li cov neeg mob SIgAD [44]. Regulatory T hlwb ua lub luag haujlwm tseem ceeb hauv kev tsim cov tshuaj tiv thaiv IgA los ntawm kev hloov pauv kev loj hlob-beta (TGF- ) secretion [45–47]. Peb pom muaj qhov txo qis Tregs hauv peb cov neeg mob raws li cov kev tshawb fawb yav dhau los luam tawm [48], txawm hais tias ib txoj kev tshawb fawb tau qhia tias Tregs nce ntxiv hauv SIgAD cov neeg mob [43]. Nws kuj tau tshaj tawm txog kev sib raug zoo ntawm Treg cov hlwb txo qis thiab qhov hnyav ntawm SIgAD kab mob, tshwj xeeb tshaj yog nyob rau hauv cov neeg uas muaj autoimmunity, thiab IgA CSR deficiency nyob rau hauv cov neeg mob uas muaj mob loj heev tshwm sim [30, 48]. Qhov tsawg zaus ntawm Treg hlwb thiab lwm T cell subsets, nrog rau T1 thiab T2 nyob rau hauv peb cov neeg mob, tej zaum yuav yog vim tsawg thymic emigrants tshwm sim los ntawm thymopoiesis tsis zoo thiab los yog nce apoptosis ntawm cov hlwb [49]. T-cell functional assay los ntawm mitogenic lossis antigenic stimulation yog ib qho tseem ceeb hauv kev kuaj mob ntawm ntau yam kev tiv thaiv kab mob thiab kev tiv thaiv kab mob [50]. Kev lig kev cai, muaj ib txoj cai rau kev soj ntsuam cov kev ua ntawm T hlwb raws li uptake ntawm [3H] thymidine tom qab PHA stimulation siv radioactive Cheebtsam uas xav tau kev kuaj mob tshwj xeeb thiab kuj nws tsis yog T cell-specific raws li nws muaj peev xwm txhawb ob peb lwm yam kab mob. zoo. Ntawm qhov tod tes, qhov tsis muaj zog tseem ceeb tshaj plaws yog tias tsis muaj cov ntaub ntawv hais txog cov xov tooj ntawm tes tshwj xeeb tuaj yeem tau txais. CFSE proliferation assay yog ib qho kev xaiv zoo rau kev ntsuam xyuas T cell teb rau ib qho antigen los yog mitogen hauv cov neeg mob IEI, tshwj xeeb tshaj yog SIgAD rau kev tsom mus ntxiv qhov muaj peev xwm T cell defects soj ntsuam hauv cov neeg mob no [51]. Txog tam sim no, muaj ob peb tsab ntawv ceeb toom ntawm T-cell teb qhov tsis xws hauv cov neeg mob SIgAD. Raws li qhov xav tau, peb txoj kev tshawb fawb tsis qhia qhov sib txawv tseem ceeb hauv T cell teb ntawm cov neeg mob thiab kev tswj hwm. Txawm li cas los xij, thaum peb faib cov neeg mob ua ob pawg raws li qhov mob hnyav thiab mob me, cov neeg mob hnyav qhia tias T cell proliferation txo qis dua piv rau cov neeg mob me. Qhov txiaj ntsig no tuaj yeem yog qhov tseem ceeb rau kev txheeb xyuas cov neeg mob SIgAD kom paub txog qhov tshwm sim ntawm tus neeg mob. Peb tsis ntev los no tau tshaj tawm tias T cell proliferation tau poob qis heev piv rau kev tswj kev noj qab haus huv hauv cov neeg mob CVID thiab cov neeg mob AT [29, 52]. Ntxiv mus, qhov no qhia tau hais tias SIgAD cov neeg mob uas muaj qhov tsis zoo T-cell proliferation yuav tsum tau ua raws li ntxiv rau kev tswj xyuas kev kho mob. Peb pom zoo kom muaj kev tshawb fawb ntxiv rau kev ntsuam xyuas qhov kev ua ntawm T cell ua haujlwm rau SIgAD cov neeg mob raws li cov phenotypes hnyav thiab me me hauv lwm cov kev tshawb fawb. Cov kev txwv ntawm qhov kev sim suav nrog cov neeg mob me me, qhov tsis muaj ntau ntawm lawv thiab e, thiab txawm tias kev txhim kho ntawm qee tus neeg mob.
Cov lus xaus
Peb cov txiaj ntsig tau qhia tias muaj kev ua phem loj hauv B cell qauv zoo ib yam li cov neeg mob CVID. Muab hais tias CVID thiab cov ntaub ntawv hnyav ntawm SIgAD sib koom yuav luag zoo ib yam li kev kho mob thiab kev tiv thaiv kab mob thiab feem ntau yuav muaj keeb kwm caj ces, qhov kev xav no yog kwv yees. Raws li kev soj ntsuam phenotype, peb tau pom qee qhov txawv txav hauv SIgAD cov neeg mob uas muaj cov phenotypes hnyav xws li cov neeg coob coob ntawm CD21low B cells thiab T cell proliferation defect. Yog li, cov neeg mob hnyav tshwm sim ntau dua ntawm cov kab mob ua pa piv rau SIgAD me me, nrog ntau tus neeg mob ntawm sinusitis, otitis, pneumonia, thiab b, bronchiectasis, qhia ntxiv txog kev soj ntsuam ntxiv thiab kev tswj xyuas meej dua hauv cov neeg mob no. Cov txiv ntawm txoj kev tshawb fawb tam sim no qhia tias kev tshawb fawb ntawm B thiab T cell subsets tuaj yeem pab tau kom nkag siab zoo dua ntawm cov kab mob thiab cov kab mob ntawm cov kab mob.
Cov ntaub ntawv
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