FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2960561647> ?p ?o ?g. }

• W2960561647 endingPage "3175" @default.
• W2960561647 startingPage "3162" @default.
• W2960561647 abstract "Bronchiolitis obliterans syndrome is the main limitation for long-term survival after lung transplantation. Some specific B cell populations are associated with long-term graft acceptance. We aimed to monitor the B cell profile during early development of bronchiolitis obliterans syndrome after lung transplantation. The B cell longitudinal profile was analyzed in peripheral blood mononuclear cells from patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow-up. CD24hiCD38hi transitional B cells were increased in stable patients only, and reached a peak 24 months after transplantation, whereas they remained unchanged in patients who developed a bronchiolitis obliterans syndrome. These CD24hiCD38hi transitional B cells specifically secrete IL-10 and express CD9. Thus, patients with a total CD9+ B cell frequency below 6.6% displayed significantly higher incidence of bronchiolitis obliterans syndrome (AUC = 0.836, PPV = 0.75, NPV = 1). These data are the first to associate IL-10-secreting CD24hiCD38hi transitional B cells expressing CD9 with better allograft outcome in lung transplant recipients. CD9-expressing B cells appear as a contributor to a favorable environment essential for the maintenance of long-term stable graft function and as a new predictive biomarker of bronchiolitis obliterans syndrome–free survival. Bronchiolitis obliterans syndrome is the main limitation for long-term survival after lung transplantation. Some specific B cell populations are associated with long-term graft acceptance. We aimed to monitor the B cell profile during early development of bronchiolitis obliterans syndrome after lung transplantation. The B cell longitudinal profile was analyzed in peripheral blood mononuclear cells from patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow-up. CD24hiCD38hi transitional B cells were increased in stable patients only, and reached a peak 24 months after transplantation, whereas they remained unchanged in patients who developed a bronchiolitis obliterans syndrome. These CD24hiCD38hi transitional B cells specifically secrete IL-10 and express CD9. Thus, patients with a total CD9+ B cell frequency below 6.6% displayed significantly higher incidence of bronchiolitis obliterans syndrome (AUC = 0.836, PPV = 0.75, NPV = 1). These data are the first to associate IL-10-secreting CD24hiCD38hi transitional B cells expressing CD9 with better allograft outcome in lung transplant recipients. CD9-expressing B cells appear as a contributor to a favorable environment essential for the maintenance of long-term stable graft function and as a new predictive biomarker of bronchiolitis obliterans syndrome–free survival. Lung transplantation (LT) is the treatment for patients suffering from end-stage pulmonary diseases. Chronic lung allograft dysfunction (CLAD) is responsible for the poor long-term outcome of LT, with an occurrence of 50% within 5 years.1Royer P-J Olivera-Botello G Koutsokera A et al.Chronic lung allograft dysfunction: a systematic review of mechanisms.Transplantation. 2016; 100: 1803-1814Crossref PubMed Scopus (68) Google Scholar The most prevalent morphological feature in CLAD is bronchiolitis obliterans syndrome (BOS), defined as an obstructive pulmonary function defect in the absence of other identifiable causes, mostly not amenable to treatment.2Meyer KC Raghu G Verleden GM et al.An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503Crossref PubMed Scopus (361) Google Scholar Currently, the clinical surrogates used to define BOS do not allow for detecting early stages of the pathology, thus making the recognition of damage prior to its development necessary in designing efficient therapies. In this context, studies have been performed to identify early indicators such as lung biopsy profiling,3Jonigk D Izykowski N Rische J et al.Molecular profiling in lung biopsies of human pulmonary allografts to predict chronic lung allograft dysfunction.Am J Pathol. 2015; 185: 3178-3188Abstract Full Text Full Text PDF PubMed Google Scholar broncho-alveolar lavage (BAL) neutrophilia,4Neurohr C Huppmann P Samweber B et al.Prognostic value of bronchoalveolar lavage neutrophilia in stable lung transplant recipients.J Heart Lung Transplant. 2009; 28: 468-474Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar cytokines,5Hall DJ Baz M Daniels MJ et al.Immediate postoperative inflammatory response predicts long-term outcome in lung-transplant recipients.Interact Cardiovasc Thorac Surg. 2012; 15: 603-607Crossref PubMed Scopus (15) Google Scholar blood level of endothelin-1,6Salama M Jaksch P Andrukhova O Taghavi S Klepetko W Aharinejad S Endothelin-1 is a useful biomarker for early detection of bronchiolitis obliterans in lung transplant recipients.J Thorac Cardiovasc Surg. 2010; 140: 1422-1427Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar plasma level of soluble CD59,7Budding K van de Graaf EA Kardol-Hoefnagel T et al.Soluble CD59 is a novel biomarker for the prediction of obstructive chronic lung allograft dysfunction after lung transplantation.Sci Rep. 2016; 6: 26274Crossref PubMed Scopus (17) Google Scholar human leukocyte antigen G (HLA-G),8Brugière O Thabut G Krawice-Radanne I et al.Role of HLA-G as a predictive marker of low risk of chronic rejection in lung transplant recipients: a clinical prospective study.Am J Transplant. 2015; 15: 461-471Crossref PubMed Scopus (0) Google Scholar or matrix metalloproteinase-9 (MMP-9)9Pain M Royer P-J Loy J et al.T cells promote bronchial epithelial cell secretion of matrix metalloproteinase-9 via a C-C chemokine receptor type 2 pathway: implications for chronic lung allograft dysfunction.Am J Transplant. 2017; 17: 1502-1514Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar but none have yet demonstrated sufficient robustness to achieve clinical acceptance. Nowadays, many studies focus on the involvement and correlation between long-term allograft survival and B cells. Recently, we described the down-regulation of three genes associated with B cells able to predict BOS in whole blood.10Danger R Royer P-J Reboulleau D et al.Blood gene expression predicts bronchiolitis obliterans syndrome.Front Immunol. 2017; 8: 1841Crossref PubMed Scopus (19) Google Scholar Growing evidence suggests that B cells with regulatory properties (Breg) are associated with maintenance of long-term allograft function in skin, hematopoietic stem cell, and kidney transplantation.11Moreau A Blair PA Chai J-G et al.Transitional-2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival.Eur J Immunol. 2015; 45: 843-853Crossref PubMed Scopus (35) Google Scholar, 12Chesneau M Michel L Dugast E et al.Tolerant kidney transplant patients produce b cells with regulatory properties.J Am Soc Nephrol. 2015; 26: 2588-2598Crossref PubMed Scopus (115) Google Scholar, 13Shabir S Girdlestone J Briggs D et al.Transitional B lymphocytes are associated with protection from kidney allograft rejection: a prospective study.Am J Transplant. 2015; 15: 1384-1391Crossref PubMed Scopus (76) Google Scholar, 14Pallier A Hillion S Danger R et al.Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype.Kidney Int. 2010; 78: 503-513Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar They are thought to mediate their regulatory capacity predominantly via the secretion of IL-10.15Bouaziz J-D Yanaba K Tedder TF Regulatory B cells as inhibitors of immune responses and inflammation.Immunol Rev. 2008; 224: 201-214Crossref PubMed Scopus (361) Google Scholar,16Rosser EC Mauri C Regulatory B cells: origin, phenotype, and function.Immunity. 2015; 42: 607-612Abstract Full Text Full Text PDF PubMed Google Scholar IL-10-secreting CD19+CD38hiCD24hi transitional B cells were thus described to play an important role not only in maintaining long-term allograft function but also in promoting allograft tolerance.13Shabir S Girdlestone J Briggs D et al.Transitional B lymphocytes are associated with protection from kidney allograft rejection: a prospective study.Am J Transplant. 2015; 15: 1384-1391Crossref PubMed Scopus (76) Google Scholar,17Bigot J Pilon C Matignon M et al.Transcriptomic signature of the CD24hi CD38hi transitional b cells associated with an immunoregulatory phenotype in renal transplant recipients.Am J Transplant. 2016; 16: 3430-3442Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 18Sagoo P Perucha E Sawitzki B et al.Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans.J Clin Invest. 2010; 120: 1848-1861Crossref PubMed Scopus (436) Google Scholar, 19Newell KA Asare A Kirk AD et al.Identification of a B cell signature associated with renal transplant tolerance in humans.J Clin Invest. 2010; 120: 1836-1847Crossref PubMed Scopus (552) Google Scholar, 20Svachova V Sekerkova A Hruba P et al.Dynamic changes of B-cell compartments in kidney transplantation: lack of transitional B cells is associated with allograft rejection.Transpl Int. 2016; 29: 540-548Crossref PubMed Scopus (35) Google Scholar, 21Burton H Dorling A Transitional B cell subsets-a convincing predictive biomarker for allograft loss?.Kidney Int. 2017; 91: 18-20Abstract Full Text Full Text PDF PubMed Google Scholar We have previously demonstrated that murine IL-10+ Bregs were enriched in a CD9+ B cell subset and that and adoptive transfer of CD9+ B cells alone was sufficient to abrogate asthma in an IL-10-dependent manner.22Braza F Chesne J Durand M et al.A regulatory CD9(+) B-cell subset inhibits HDM-induced allergic airway inflammation.Allergy. 2015; 70: 1421-1431Crossref PubMed Scopus (56) Google Scholar We have also shown that CD9 expression in humans was dramatically increased at the surface of CD24hiCD38hi B cells, thus defining an important IL-10 Breg subset. This finding has been confirmed by others,23Sun J Wang J Pefanis E et al.Transcriptomics identify CD9 as a marker of murine IL-10-competent regulatory B cells.Cell Rep. 2015; 13: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar,24Matsushita T Le Huu D Kobayashi T et al.A novel splenic B1 regulatory cell subset suppresses allergic disease through phosphatidylinositol 3-kinase-Akt pathway activation.J Allergy Clin Immunol. 2016; 138 (e9): 1170-1182Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar and CD9 thus appears as a reliable marker for defining more precisely both mouse and human IL-10-secreting Bregs with suppressive properties. In this study, we aimed to analyze the modifications of the B lymphocyte subset profile in lung transplant recipients (LTR) and/or to identify a potential B lymphocyte signature predictive of BOS and/or functional stability in LT. We report here a higher level of CD19+CD38hiCD24hi transitional B cells expressing the CD9 marker and secreting IL-10 in patients with stable graft function and suggest that CD9 may serve as a potential blood biomarker of BOS. The local ethical committee (Comité de Protection des Personnes Ouest 1-Tours, 2009-A00036-51) approved this study. Patients who participated in this study gave written informed consent. Blood samples were selected from patients included in the multicenter longitudinal cohort COLT (Cohort in Lung Transplantation, NCT00980967) with 3 years of follow-up. Pulmonary function tests, clinical data, and blood samples were collected at the inclusion visit before transplantation, the day of transplantation, 1 month and every 6 months post-LT. Stable (STA) and BOS phenotypes were confirmed by an adjudication committee of clinicians and researchers based on the values of the pulmonary function test, computerized tomography, and after elimination of confounding factors in line with the charter ISHLT/ERS/ATS.2Meyer KC Raghu G Verleden GM et al.An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503Crossref PubMed Scopus (361) Google Scholar BOS was defined by a decrease of at least 20% of the maximum FEV1 value recorded after transplantation. Donor-specific antibody (DSA) levels were measured for all LTR selected by Luminex High Performance assay. A kinetic was performed up to 36 months post-LT. All data are summarized in Tables 1 and 2 for the cohort of investigation and validation, respectively.TABLE 1Demographic and clinical dataStableBOSHVP-valueNumber of patients202119Recipient age (median, years) [range]48 [23-71]59 [27-68]50 [21-66].396Recipient gender, n (%).252Male8 (40)10 (48)13 (68)Female12 (60)11 (52)6(32)Donor age (median, years) [range]49 [18-71]44 [16-65].640Donor gender, n (%).661Male10 (50)12 (57)Female10 (50)9 (43)Pathology leading to Tx, n (%)0.030Emphysema/COPD7 (35)9 (43)Cystic fibrosis10 (50)3 (14)Pulmonary arterial hypertension2 (10)6 (29)Idiopathic pulmonary fibrosis1 (5)2 (9)Other01 (5)Type of Tx, n (%)0.550Bilateral—heart-lung15 (75)14 (67)Single5 (25)6 (28)Lobar01 (5)Median ischemic time (min) [range]315 [215-467]330 [150-540].648Induction agent, n (%).350Basiliximab9 (45)5 (24)Thymoglobulin8 (40)12 (57)None3 (15)4 (19)Immunosuppressive therapy (follow-up treatment), n (%)Steroids (corticosteroids)18 (90)18 (86).440MMF (Cellcept)7 (35)11 (52)Tacrolimus12 (60)8 (38).148Cyclosporin7 (35)12 (58)Infections, n (%).588Bacteria15 (75)18 (89)Virus14 (70)16 (73)Fungi14 (70)10 (42)MismatchCMV, n (%)10 (50)9 (43).661Toxoplasmosis, n (%)7 (35)7 (37).841EBV, n (%)2 (10)9 (9).978HLA-A n ≥ 1/220 (100)17 (89).3152HLA-B n ≥ 1/220 (100)19 (100).4506HLA-DR n ≥ 1/220 (100)19 (100).1110HLA-DQ n ≥ 1/220 (100)18 (95).0472Median occurrence of BOS, month after Tx [range]-24 [12-42]-Acute cellular rejections, n (%).390Ever A1 grade8 (40)9 (43)Ever ≥A2 grade7 (35)4 (19)Abbreviations: BOS, bronchiolitis obliterans syndrome; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; EBV, Epstein-Barr Virus; HLA, human leukocyte antigen; HV, healthy volunteers; MMF, mycophenolate mofetil; Tx, transplantation. Open table in a new tab TABLE 2Demographic and clinical data of the validation cohortStableBOSP-valueNumber of patients1816Recipient age (median, years) [range]48 [25-61]36 [15-60].275Recipient gender, n (%).505Male8 (44)6 (37)Female10 (56)10 (63)Donor age (median, years) [range]41 [26-55]46 [10-66].931Donor gender, n (%)1.000Male11 (61)6 (37)Female7 (39)10 (63)Pathology leading to Tx, n (%).731Emphysema/COPD7 (39)7 (44)Cystic fibrosis5 (28)5 (31)Pulmonary arterial hypertension1 (6)1 (6)Idiopathic pulmonary fibrosis4 (22)1 (6)Other1 (6)2 (13)Type of Tx, n (%).882Bilateral—heart-lung12 (67)12 (75)Single4 (22)3 (19)Lobar2 (11)1 (6)Median ischemic time (min) [range]285 [120-420]270 [120-500].543Induction agent, n (%).168Basiliximab4 (22)1 (6)Thymoglobulin4 (22)8 (50)None10 (56)7 (44)Immunosuppressive therapy (follow-up treatment), n (%)Steroids (corticosteroids)17 (94)16 (100).885MMF (Cellcept)16 (89)14 (88)Tacrolimus16 (89)14 (88).654Cyclosporin5 (28)6 (38)Infections, n (%).953Bacteria15 (83)11 (69)Virus14 (78)9 (56)Fungi13 (72)10 (63)MismatchCMV, n (%)3 (17)2 (13)1.000Toxoplasmosis, n (%)2 (12)6 (38).117EBV, n (%)0 (0)3 (19).093HLA-A n ≥ 1/218 (100)16 (100).509HLA-B n ≥ 1/218 (100)16 (100).681HLA-DR n ≥ 1/217 (94)16 (100).290HLA-DQ n ≥ 1/216 (94)13 (81).522Median occurrence of BOS, month after Tx [range]-27 [11-42]-Acute cellular rejections, n (%)1.000Ever A1 grade10 (56)6 (40)Ever ≥A2 grade4 (22)3 (20)Abbreviations: BOS, bronchiolitis obliterans syndrome; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; EBV, Epstein-Barr Virus; HLA, human leukocyte antigen; MMF, mycophenolate mofetil; Tx, transplantation. Open table in a new tab Abbreviations: BOS, bronchiolitis obliterans syndrome; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; EBV, Epstein-Barr Virus; HLA, human leukocyte antigen; HV, healthy volunteers; MMF, mycophenolate mofetil; Tx, transplantation. Abbreviations: BOS, bronchiolitis obliterans syndrome; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; EBV, Epstein-Barr Virus; HLA, human leukocyte antigen; MMF, mycophenolate mofetil; Tx, transplantation. Twenty STA and 21 BOS patients were selected based on sample availability (at least seven time points per patient, up to 60 months for stable patients) and were matched regarding age and sex. Also, 19 healthy volunteers (HV) were used as controls but, as these individuals are not transplanted, they were not used in statistical analyses. Demographic features and clinical data are summarized in Table 3.TABLE 3Kinetic of DSA development in stable patients (Median Fluorescence Intensity [MFI])Months post-LTBefore LTTime of LT1612182430361STANODQ7 (6512)DQ7 (4045)DQ7 (1174)NONONONONO2STANONONONONONONONONO3STANODQA1(1000)NONONONONONONO4STANONONONODQ7 (1200)NONONONO5STANONONONONONONONONO6STA-----NONO--7STA------NO-NO8STANONONONONONONONONO9STANONONONONONONONONO10STA-NODR7, DR8, DQ2DQ2, DQ7NONONONONO11STANONONONONONONONONO12STANONOA2, DQ6NONONONONONO13STANONODQ2, DQ4DQ4NONONONONO14STANONONONONONONONONO15STANONONONONONONONONO16STANONONONONONONONONO17STANONONONONONONONONO18STANONONONONONONONONO19STADR17--B8, DR4, DR17, DQ7 DR52NONONONONO20STA-------DR4 (609)-21STA-NONO-----NO22STANONODQ6 (532) DQ8 (1381)NONO----23STA-NONONONO-NO-24STA---------25STA-------DR4(726)NO26 STANONONONONO----27STA---------28STA---------29STANONONONONONONONONO30STANONONONONONONONONO31STANONONO--NONO--32STANONONONONONONONO33STA----NONONONONO34STANONONONONONONONONO35STANONONONONONONONONO36STANONONONONONONONONO37STANONONONONONONONONO38STANONONONONONONONONOAbbreviations: DSA, donor-specific antibody; LT, lung transplant; STA, stable. Open table in a new tab Abbreviations: DSA, donor-specific antibody; LT, lung transplant; STA, stable. For the cohort of validation, another 19 STA and 15 BOS patient samples were analyzed at 24 months post-LT and were matched regarding age, sex, and initial disease. Demographic features and clinical data are summarized in Table 4.TABLE 4Kinetic of DSA development in BOS patients ( Median Fluorescence Intensity [MFI])Months post-LTBefore LTTime of LT1612182430361BOSNONONONONONONONONO2BOSNONONONONONONONONO3BOSNODR7 DR11 DQ2 DQ7 (301)--DR7 DR11 DQ2 DQ4 DQ7 DQ8 DQ9 (4852)DR7 DR11 DQ2 DQ4 DQ7 DQ8 DQ9 (15673)DR7 DR11 DQ2 DQ4 DQ7 DQ8 DQ9 (17341)DR7 DR11 DQ2 DQ4 DQ7 DQ8 DQ9DR7 DR11 DQ2 DQ4 DQ7 DQ8 DQ94BOSNONONONONONONONONO5BOSNONONONONONODQ2 (3384)DQ2 (3434)DQ2 (1046)6BOSNONOYESYESYESYESYESYESNO7BOSNONONONONO-YESYESYES8BOSNONOYESYESNOYESYESYESYES9BOSDQDQ (1308)DQ (1851)NONONONONONO10BOSNONONONONONONONONO11BOSNONONONONONONONONO12BOSDR17 (1000)DQB1 (700)NONO-DP14 (512) DQ4 (811)DQ4 (1635) DQB1(704)NO-13BOS---NONO---DQ2 (15510)14BOS---NODQ2(3600) DR53 (2529)NODPB1 (659)15BOS------NO-NO16BOSNONONONONONONONONO17BOSNONONONONONONONONO18BOS---------19BOSDR11DR11DR11YESNONONONONO20BOSNONONONONONODQ7DQ7NO21BOSNONODQ7DQ7NONONONONO22BOSNONONODQ8, DR7NONONONONO23BOSB7B7B7B7B7B7B7B7B724BOSNONONONONONONONONO25BOSNONOB38, DR7, DQ2DQ2NONODQ2NODQ226BOSNONONONONONONONONO27BOSNONONONONONONONONO28BOS--------NO29BOSYESNODQ9 (2571) DQ7 (2850)DR4 (521)NONO---30BOS-B44 (813)DQ6 (624)NONONO--31BOSNONONONONONONONONO32BOS--------DR1 (649)33BOS-NONONONO-NONODR1 (698), DP04 (699), DP13 (887)34BOS---------35BOSNODR18 DR4 DR53 (468) DQ2 (387)-NONONONONODQ2 (1245)36BOSNONO-NO-NO-A1 (529)-37BOSNONONONONONONONONOAbbreviation: BOS, bronchiolitis obliterans syndrome. Open table in a new tab Abbreviation: BOS, bronchiolitis obliterans syndrome. Peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Paque (GE Healthcare, Marolles-en-Hurepoix, France) gradient centrifugation, frozen, and stored at the Centre de Ressources Biologiques (CRB) of Nantes. PBMC were rapidly thawed by placing cryovials at 37°C, washed, and stained according to standard protocols using the following mAbs: CD19-BUV395, CD27-BUV737, CD38-BV605, CD138-APC, CD24-PerCP-Cy5.5, CD9-BV510, CD22-PeCy7, IgD-PE, and IgM-FITC (BD Biosciences, Le Pont de Claix, France). Markers were used to distinguish CD19+ B lymphocytes, CD19+CD27+ memory cells, CD19+CD27– naive cells, CD19+CD24hiCD38hi transitional cells, and CD19+CD24–CD38+ plasma cells. Dead cells were excluded using the Zombie NIR Fixable Viability kit (BioLegend, London, UK). Samples were run on a BD LSRFORTESSA X-20 (BD Biosciences, Le Pont de Claix, France), and data were analyzed using FlowJo v10 software (FlowJo LLC, Ashland, OR). Cells were stimulated for 5 hours with phorbol 12-myristate 13-acetate (PMA) (50 ng/mL), ionomycin (0.5 mg/mL), and brefeldin-A (10 mg/mL) (Sigma-Aldrich, St. Louis, MO). For detection of intracellular IL-10, cells were fixed and permeabilized using the Permeabilization/Fixation Kit (BD Biosciences) and staining was performed using anti-IL-10-PE (BD Biosciences). Gaussian distribution was assessed with the D’Agostino-Pearson test. For longitudinal analysis, STA and BOS groups were compared using linear mixed-effect models (lmer R package) to account for repeated and missing measures using R version 3.4.3. P-values were obtained from F tests with Satterthwaite’s method (lmerTest R package) with Benjamini-Hochberg multiple comparison correction. Total, plasmocyte, transitional and memory B cells data were log transformed (ln) and naive B cells data were transformed with logit to account for right and left skewed distributions, respectively. When group effect was significantly associated with analyzed parameter (P < .05), Student’s t-tests were used to compare BOS and STA groups at each time points with Benjamini-Hochberg correction for multiple comparisons (adjusted P-values). Logistic regression (glm package) was used to assess association between DSA presence and transitional B cells. Positive and negative predictive values and the Youden index, as the value maximizing specificity and sensitivity discriminating BOS and STA according to a receiver operating characteristic (ROC) curve, were computed using the pROC R package. Pearson correlations, ROC curves, survival analyses with Kaplan-Meier (log-rank test), Student’s t-tests or chi-squared for qualitative variables were performed using the GraphPad Prism v.5 (GraphPad Software, La Jolla, CA). A P < .05 was considered to be significant. Variations are expressed as standard deviation. CLAD is a heterogeneous disorder that may develop through different clinical phenotypes.1Royer P-J Olivera-Botello G Koutsokera A et al.Chronic lung allograft dysfunction: a systematic review of mechanisms.Transplantation. 2016; 100: 1803-1814Crossref PubMed Scopus (68) Google Scholar,2Meyer KC Raghu G Verleden GM et al.An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503Crossref PubMed Scopus (361) Google Scholar We focused on BOS, the most common phenotype (Table 1). We compared them with STA and HV. Age and sex are not different between LTR (BOS and STA) and HV. None of the usual risk factors of CLAD significantly differ between STA and BOS. Most of the patients received bilateral LT (75% and 67% of STA and BOS, respectively; P = .550). Recipient immunosuppressive treatments, ischemic time, number of acute cellular rejection events, infections, cytomegalovirus, Epstein-Barr virus and human leukocyte antigen (HLA) mismatches were not significantly different between BOS and STA. Concerning the initial disease leading to LT, cystic fibrosis is more prevalent in STA (50% vs 14%, respectively; P = .03), which is representative of the COLT cohort. Finally, STA patients present less DSA than BOS patients (P = .0001). Because B cell homeostasis is reshaped in the context of skin, hematopoietic stem cells, and kidney dysfunction,11Moreau A Blair PA Chai J-G et al.Transitional-2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival.Eur J Immunol. 2015; 45: 843-853Crossref PubMed Scopus (35) Google Scholar,12Chesneau M Michel L Dugast E et al.Tolerant kidney transplant patients produce b cells with regulatory properties.J Am Soc Nephrol. 2015; 26: 2588-2598Crossref PubMed Scopus (115) Google Scholar,25de Masson A Bouaziz J-D Le Buanec H et al.CD24(hi)CD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease.Blood. 2015; 125: 1830-1839Crossref PubMed Google Scholar,26Chesneau M Pallier A Braza F et al.Unique B cell differentiation profile in tolerant kidney transplant patients.Am J Transplant. 2014; 14: 144-155Crossref PubMed Scopus (114) Google Scholar we assessed whether profile of peripheral blood B lymphocyte subsets may evolve differently over time between BOS and STA (before LT to 60 months post-LT) and HV. We determined the percentage of naive, memory, transitional and plasma cells based on the expression of CD19, CD27, CD38, CD22, and CD24 (Figure 1A). Neither CD19+ total B cells nor naive, memory, and plasma cell subtype frequencies were significantly different between BOS and STA at any time points (Figure 1B). In contrast, whereas remaining low over time in BOS (1.1% ± 0.1, mean ± standard deviation), the percentage of CD19+CD24hiCD38hi transitional B cells dramatically increased in STA reaching a maximum at 24 months and exceeding the physiological level of CD24hiCD38hi transitional B cells in HV and that stay high in time (6.3% ± 0.1 vs 3.3% ± 0.4; P = .0011). This effect was neither associated with age, lung function, induction, or immunosuppressive treatments nor with BOS grade (Figure 1C). We then analyzed the frequency of CD19+CD24hiCD38hi transitional B cell subsets according to their differentiation states in STA, BOS, and HV 24 months post-LT. Surface markers were used to distinguish CD27–IgD+IgM+ T1/2, CD27–IgD+IgM– T3, and CD27+ nonconventional memory CD24hiCD38hi transitional B cells (Figure 2A). The percentage of all transitional B cell subsets are significantly higher in STA compared to BOS: T1/T2 (2.5% ± 0.5% vs 0.5% ± 0.1% in STA and BOS; P = .0001), T3 (2.6% ± 0.6% vs 0.8% ± 0.5%; P = .0076), and CD27+ nonconventional B cells (0.5% ± 0.07% vs 0.15% ± 0.06%; P = .0005) (Figure 2B). Altogether, 24 months post-LT, LTR who keep a stable graft function over 60 months harbor a CD19+CD24hiCD38hi transitional B cells elevation whereas this level remains very low in patients who will develop a BOS. Previous studies revealed that CD24hiCD38hi transitional cells are enriched in IL-10-secreting B cells with regulatory properties.16Rosser EC Mauri C Regulatory B cells: origin, phenotype, and function.Immunity. 2015; 42: 607-612Abstract Full Text Full Text PDF PubMed Google Scholar,27Simon Q Pers J-O Cornec D Le Pottier L Mageed RA Hillion S In-depth characterization of CD24(high)CD38(high) transitional human B cells reveals different regulatory profiles.J Allergy Clin Immunol. 2016; 137 (e10): 1577-1584Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar We analyzed the CD24hiCD38hi transitional cells IL-10 production after activation with PMA and ionomycin in vitro in BOS and STA patients 24 months post-LT. IL-10-producing B cells are mainly enriched in the CD24hiCD38hi transitional subset (Figure 3A) and as expected, IL-10-secreting B cells are significantly higher in STA patients compared to BOS (15.9% ± 3.5 vs 6.4% ± 1 respectively, P < .05) and similar to the rate of IL-10 secreting B cells in HV (P > .05) (Figure 3B). Despite this, CD24hiCD38hi transitional cells from STA and BOS secrete the same amount of IL-10 (mean fluorescence intensity is similar in both groups, Figure 3B). IL-10-secreting B cells rate is not associated with treatments. We also measured IL-10 level in the sera of 41 STA patients and 30 BOS patients using Bio-plex assay. The level of IL-10 between STA and BOS was not significantly different (P = .780) (mean = 0.7 pg/mL, data not shown). Next, we analyzed the expression of the CD9 surface marker within CD24hiCD38hi transitional. Transitional subsets are enriched in CD9+ B cells (Figure 3A) and as expected, CD9+ B cells are enriched in IL-10-secreting cells (Figure 3C). Moreover, at 24 months post-LT, the percentage of transitional cells correlates with the percentage of CD9+ B cells (r = .76, P < .001) suggesting that transitional cells and CD9+ B cells belongs to the same B cell subtype (Figure 3D). Finally, such as CD24hiCD38hi transitional B cells, the longitudinal time-course of the CD9+ B cell expression peaks 24 months post-LT in STA compared to BOS (12.2% ± 1.3 vs 5.9 ± 1.1 respectively, P = .0053) (Figure 3E) and remains constant among STA LTR. Altogether, we report that CD19+CD24hiCD38hi transitional B cells peaking at 24 months after LT in patients with stable graft function also express the CD9 marker and secrete IL-10. Because the rate of CD19+CD24hiCD38hi transitional cells is correlated with the rate of CD9+ B cells and because a biomarker with a single extracellular and dichotomistic molecule would be more appropriate for clinical use (easier gating strategy), we further explored whether the level of CD9+ B cells could be sufficient to discriminate properly between patients who will maintain stable graft function and those who will develop BOS in the 3 years after LT. Accordingly, using ROC curve analysis, CD9+ B cell frequencies allow excellent discrimination between STA and patients who will develop BOS at 24 months post-LT (AUC = 1) (Figure 4A). The FEV1 at 24 months pos" @default.
• W2960561647 created "2019-07-23" @default.
• W2960561647 creator A5002031193 @default.
• W2960561647 creator A5006871103 @default.
• W2960561647 creator A5006988074 @default.
• W2960561647 creator A5012056880 @default.
• W2960561647 creator A5018314005 @default.
• W2960561647 creator A5018936587 @default.
• W2960561647 creator A5024254480 @default.
• W2960561647 creator A5031799252 @default.
• W2960561647 creator A5032275769 @default.
• W2960561647 creator A5036579641 @default.
• W2960561647 creator A5038866215 @default.
• W2960561647 creator A5054026459 @default.
• W2960561647 creator A5058798173 @default.
• W2960561647 creator A5065386977 @default.
• W2960561647 creator A5068102630 @default.
• W2960561647 creator A5070849935 @default.
• W2960561647 creator A5074387792 @default.
• W2960561647 creator A5088824087 @default.
• W2960561647 date "2019-11-01" @default.
• W2960561647 modified "2023-10-14" @default.
• W2960561647 title "Blood CD9+ B cell, a biomarker of bronchiolitis obliterans syndrome after lung transplantation" @default.
• W2960561647 cites W1485917060 @default.
• W2960561647 cites W1597667093 @default.
• W2960561647 cites W1782928917 @default.
• W2960561647 cites W1823693822 @default.
• W2960561647 cites W1898108769 @default.
• W2960561647 cites W1949741502 @default.
• W2960561647 cites W1951106665 @default.
• W2960561647 cites W1965174970 @default.
• W2960561647 cites W1981703286 @default.
• W2960561647 cites W1994786795 @default.
• W2960561647 cites W2006236831 @default.
• W2960561647 cites W2088922862 @default.
• W2960561647 cites W2089774344 @default.
• W2960561647 cites W2104087345 @default.
• W2960561647 cites W2115027948 @default.
• W2960561647 cites W2120772378 @default.
• W2960561647 cites W2134678150 @default.
• W2960561647 cites W2137442990 @default.
• W2960561647 cites W2141478377 @default.
• W2960561647 cites W2147557958 @default.
• W2960561647 cites W2239154376 @default.
• W2960561647 cites W2290727383 @default.
• W2960561647 cites W2301588580 @default.
• W2960561647 cites W2402027380 @default.
• W2960561647 cites W2416539102 @default.
• W2960561647 cites W2418706972 @default.
• W2960561647 cites W2562262846 @default.
• W2960561647 cites W2562982543 @default.
• W2960561647 cites W2735049310 @default.
• W2960561647 cites W2788170537 @default.
• W2960561647 doi "https://doi.org/10.1111/ajt.15532" @default.
• W2960561647 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31305014" @default.
• W2960561647 hasPublicationYear "2019" @default.
• W2960561647 type Work @default.
• W2960561647 sameAs 2960561647 @default.
• W2960561647 citedByCount "11" @default.
• W2960561647 countsByYear W29605616472020 @default.
• W2960561647 countsByYear W29605616472021 @default.
• W2960561647 countsByYear W29605616472022 @default.
• W2960561647 countsByYear W29605616472023 @default.
• W2960561647 crossrefType "journal-article" @default.
• W2960561647 hasAuthorship W2960561647A5002031193 @default.
• W2960561647 hasAuthorship W2960561647A5006871103 @default.
• W2960561647 hasAuthorship W2960561647A5006988074 @default.
• W2960561647 hasAuthorship W2960561647A5012056880 @default.
• W2960561647 hasAuthorship W2960561647A5018314005 @default.
• W2960561647 hasAuthorship W2960561647A5018936587 @default.
• W2960561647 hasAuthorship W2960561647A5024254480 @default.
• W2960561647 hasAuthorship W2960561647A5031799252 @default.
• W2960561647 hasAuthorship W2960561647A5032275769 @default.
• W2960561647 hasAuthorship W2960561647A5036579641 @default.
• W2960561647 hasAuthorship W2960561647A5038866215 @default.
• W2960561647 hasAuthorship W2960561647A5054026459 @default.
• W2960561647 hasAuthorship W2960561647A5058798173 @default.
• W2960561647 hasAuthorship W2960561647A5065386977 @default.
• W2960561647 hasAuthorship W2960561647A5068102630 @default.
• W2960561647 hasAuthorship W2960561647A5070849935 @default.
• W2960561647 hasAuthorship W2960561647A5074387792 @default.
• W2960561647 hasAuthorship W2960561647A5088824087 @default.
• W2960561647 hasBestOaLocation W29605616471 @default.
• W2960561647 hasConcept C126322002 @default.
• W2960561647 hasConcept C142724271 @default.
• W2960561647 hasConcept C185592680 @default.
• W2960561647 hasConcept C203014093 @default.
• W2960561647 hasConcept C2522874641 @default.
• W2960561647 hasConcept C2776739411 @default.
• W2960561647 hasConcept C2777714996 @default.
• W2960561647 hasConcept C2778821649 @default.
• W2960561647 hasConcept C2781197716 @default.
• W2960561647 hasConcept C2781448352 @default.
• W2960561647 hasConcept C2911091166 @default.
• W2960561647 hasConcept C55493867 @default.
• W2960561647 hasConcept C71924100 @default.
• W2960561647 hasConceptScore W2960561647C126322002 @default.
• W2960561647 hasConceptScore W2960561647C142724271 @default.

• next