PTPN22 SNPs and outcome after lung transplantation
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ABSTRACT:
PROVIDER: EGAS00001003380 | EGA |
REPOSITORIES: EGA
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Project description:Bronchiolitis obliterans syndrome (BOS) is the main reason for poor outcomes after lung transplantation (LTx). We and others have recently identified B cells as major contributors to BOS after LTx. The extent of B cell heterogeneity and the relative contributions of B cell subpopulations to BOS, however, remain entirely unclear. Here, we provide a comprehensive analysis of cell population changes and their gene expression patterns during chronic rejection after orthotopic LTx in mice. Out of a total of 11 major cell types, Mzb1-expressing plasma cells (PCs) were the most prominently increased population in BOS lungs. These findings were validated in two different cohorts of human BOS after LTx. A Bhlhe41, Cxcr3, Itgb1-triple positive-B cell subset, also expressing classical markers of the innate-like B-1 B cell population, served as the progenitor pool for Mzb1+ PCs. This subset accounted for the increase in IgG2c production within BOS lung grafts. A genetic lack of immunoglobulins decreased BOS severity after LTx. In summary, we provide a detailed analysis of cell population changes during BOS. IgG-positive PCs and their progenitors – an innate B cell subpopulation – are the major source of local antibody production and a significant contributor to BOS after LTx.
2022-07-25 | GSE166386 | GEO
Project description:Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor.
Methods: Since a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) is associated with long-term outcome after solid organ transplantation, we investigated this SNP in relation to LTx. In addition, we looked at local production of C3 by analyzing bronchoalveolar lavage fluid (BALF) of LTx patients using isoelectric focusing (IEF).
Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients (p=0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival (p=0.044).
Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation.
| EGAS00001003843 | EGA
Project description:Background: Mesenchymal stromal cells (MSC) have been proposed as a future cell based therapy for lung diseases like bronchiolitis obliterans syndrome (BOS). Theoretically, it might be beneficial to use lung resident MSC already adapted to the pulmonary environment. We therefore aimed to compare lung MSC with the well-characterized bone marrow MSC. Furthermore, MSC isolated from lung-transplanted patients with BOS were compared to MSC isolated from good outcome recipients. Methods: MSC were isolated from bone marrow (BM) and adult/fetal lung tissues and compared by a comprehensive panel of assays. Results:The gene expression profiles of adult lung derived and fetal lung derived MSC were very similar compared to BM derived MSC, with only 235 and 338 genes, respectively, being significantly differently expressed. Out of the 235 genes that were significantly different between adult lung derived and BM derived MSC, 90 genes were higher expressed in the lung derived MSC. In case of fetal lung derived MSC, 166 genes were higher expressed compared to the BM derived MSC. Interestingly, only, 89 genes were found to be expressed differently when comparing BM derived MSC to both, fetal and adult lung derived MSC, indicating that these genes are lung specific. Next, we went on to evaluate if MSC isolated from biopsies of lung-transplanted patients with BOS differed compared to patients without BOS, i.e. good outcome recipients. Here we found that four genes (Sox9, FAR2, LOC728855 and NDUFS5) were significantly higher expressed in MSC isolated from BOS patients Conclusions: This data demonstrates that lung resident MSC possess lung specific properties that should be taken into considerations when using MSC for cell-based therapy in severe lung disorders like BOS. These results also show that MSC isolated from lung-transplanted patients with BOS do not have an altered phenotype.
2016-08-01 | GSE74163 | GEO
Project description:Background: Mesenchymal stromal cells (MSC) have been proposed as a future cell based therapy for lung diseases like bronchiolitis obliterans syndrome (BOS). Theoretically, it might be beneficial to use lung resident MSC already adapted to the pulmonary environment. We therefore aimed to compare lung MSC with the well-characterized bone marrow MSC. Furthermore, MSC isolated from lung-transplanted patients with BOS were compared to MSC isolated from good outcome recipients. Methods: MSC were isolated from bone marrow (BM) and adult/fetal lung tissues and compared by a comprehensive panel of assays. Results:The gene expression profiles of adult lung derived and fetal lung derived MSC were very similar compared to BM derived MSC, with only 235 and 338 genes, respectively, being significantly differently expressed. Out of the 235 genes that were significantly different between adult lung derived and BM derived MSC, 90 genes were higher expressed in the lung derived MSC. In case of fetal lung derived MSC, 166 genes were higher expressed compared to the BM derived MSC. Interestingly, only, 89 genes were found to be expressed differently when comparing BM derived MSC to both, fetal and adult lung derived MSC, indicating that these genes are lung specific. Next, we went on to evaluate if MSC isolated from biopsies of lung-transplanted patients with BOS differed compared to patients without BOS, i.e. good outcome recipients. Here we found that four genes (Sox9, FAR2, LOC728855 and NDUFS5) were significantly higher expressed in MSC isolated from BOS patients Conclusions: This data demonstrates that lung resident MSC possess lung specific properties that should be taken into considerations when using MSC for cell-based therapy in severe lung disorders like BOS. These results also show that MSC isolated from lung-transplanted patients with BOS do not have an altered phenotype. Comparison of gene expression of MSC isolated from bone marrow, adult lung and fetal lung.
2016-08-01 | E-GEOD-74163 | biostudies-arrayexpress
Project description:We investigated the association between genetic variants in the histone modification regions and the prognosis of lung adenocarcinoma after curative surgery. Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The SNPs were analyzed in a discovery set (n=166) and a validation set (n=238). The associations of the SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. This study showed that genetic variants in the histone modification regions could predict the prognosis of lung adenocarcinoma after surgery.
2021-08-21 | GSE182384 | GEO
Project description:We investigated the association between genetic variants in the histone modification regions and the prognosis of lung adenocarcinoma after curative surgery. Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The SNPs were analyzed in a discovery set (n=166) and a validation set (n=238). The associations of the SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. This study showed that genetic variants in the histone modification regions could predict the prognosis of lung adenocarcinoma after surgery.
2021-08-21 | GSE182383 | GEO
Project description:Antiviral responses must be regulated to rapidly defend against infection while minimizing inflammatory damage, but the mechanisms for establishing the magnitude of response within an infected cell are not well understood. miRNAs are small non-coding RNAs that negatively regulate protein levels by binding target sequences on their cognate mRNA. Here we identify miR-144 as a negative regulator of the host antiviral response. Ectopic expression of miR-144 resulted in increased replication of three RNA viruses, influenza, EMCV, and VSV, in primary mouse lung epithelial cells. To elucidate the mechanism whereby miR-144 increases influenza replication within lung epithelial cells, immortalized murine Type I epithelial cells (Let1 cells) stably over-expressing miR-144 were infected with influenza A for 1 or 18 hours and the transcriptional profile was compared with those of infected control cells. This systems biology approach identified the transcriptional network regulated by miR-144 and demonstrated that it controls the TRAF6/IRF7 antiviral response by post-transcriptionally suppressing TRAF6 levels. In vivo ablation of miR-144 reduced influenza replication within the lung. 16 RNA samples from immortalized murine Type I airway epithelial cells (Let1 cells) were analyzed using Agilent microarrays. Cells expressing miR-144, miR-451, or a vector control (GFP) were analyzed after infection with PR8 influenza virus (MOI=5) for 1 or 18 hours.
2013-09-11 | E-GEOD-50742 | biostudies-arrayexpress
Project description:Deep sequencing of mRNA from 6 organs of yak (Bos grunniens) Analysis of ploy(A)+ RNA of brain,heart,liver,lung,spleen, and stomach of yak (Bos grunniens)
2012-05-18 | E-GEOD-33300 | biostudies-arrayexpress
Project description:Chronic lung allograft dysfunction (CLAD) limits the long term survival after lung transplantation. CLAD is diagnosed late on the decline in lung function, when any immuno-intervention is ineffective. Identification of early forerunners of CLAD is therefore essential to prevent the progression of the disease before irreversible damages to the allograft. We used large-scale gene expression profiling of whole blood cells to identify early biomarkers of Bronchiolitis Obliterans Syndrome (BOS), the main form of CLAD. Microarray experiments performed from 80 patients (40 stable (STA) and 40 BOS) identify 47 genes differentially expressed between STA and BOS recipients. An independent set of patients (13 STA, 11 BOS) was then used for external validation by qPCR. POU Class 2 Associating Factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A) and B-cell lymphocyte kinase (BLK) genes were identified and validated as predictive markers of BOS more than 6 months before diagnosis with AUCs of 0.83, 0.77 and 0.78 respectively. These genes allow stratifying upon CLAD risk (log-rank test p<0.01) and could provide clinicians with new tools to improve follow-up and adapt treatment of patients likely to develop BOS.
2018-02-23 | GSE94557 | GEO
Project description:Antiviral responses must be regulated to rapidly defend against infection while minimizing inflammatory damage, but the mechanisms for establishing the magnitude of response within an infected cell are not well understood. miRNAs are small non-coding RNAs that negatively regulate protein levels by binding target sequences on their cognate mRNA. Here we identify miR-144 as a negative regulator of the host antiviral response. Ectopic expression of miR-144 resulted in increased replication of three RNA viruses, influenza, EMCV, and VSV, in primary mouse lung epithelial cells. To elucidate the mechanism whereby miR-144 increases influenza replication within lung epithelial cells, immortalized murine Type I epithelial cells (Let1 cells) stably over-expressing miR-144 were infected with influenza A for 1 or 18 hours and the transcriptional profile was compared with those of infected control cells. This systems biology approach identified the transcriptional network regulated by miR-144 and demonstrated that it controls the TRAF6/IRF7 antiviral response by post-transcriptionally suppressing TRAF6 levels. In vivo ablation of miR-144 reduced influenza replication within the lung.
2013-09-11 | GSE50742 | GEO