V-211.4: Single-cell RNA sequencing provides insights into intragraft B cell complexity in chronic lung allograft dysfunction (CLAD).
Bibliographic record
Abstract
Rationale: Chronic lung allograft dysfunction (CLAD) is the major factor limiting long-term survival in recipients of lung transplantation. CLAD has two clinical phenotypes – bronchiolitis obliterans syndrome (BOS) and the more severe restrictive allograft syndrome (RAS). We hypothesized that B cells in the CLAD lung allograft are a heterogeneous population with a unique composition and transcriptional signature, distinct from circulating B cells and from healthy lung B cells. Objective: We aimed to comprehensively define the transcriptomic landscape of B cells in CLAD lung allografts explanted at re-transplantation, and to further delineate B cell differences between BOS and RAS phenotypes. Methods: Single cell suspensions were made from CLAD lungs and matched peripheral blood mononuclear cells (PBMCs) (n = 13 comprising of 6 BOS and 7 RAS), and normal lungs (n = 6). All cells were subjected to single-cell RNA sequencing (scRNAseq) using the 10X Genomics 3’ assay. Furthermore, B and T cells were sorted from normal lungs (n = 4), CLAD lungs and matched PBMCs (n = 6 comprising of 3 BOS and 3 RAS); these underwent scRNAseq using the 10X Genomics 5’ assay. The 3’ data were utilized to calculate relative B cell proportions. The 5’ data were utilized to analyze B cell transcriptional heterogeneity using Seurat. Results: Immune cells (CD45+/Total) and B cells (CD20+ CD19+ CD79A+/Total) were increased in CLAD compared to normal lungs. Transcriptomic analysis revealed 11 distinct B cell clusters in CLAD and normal lungs, with pathways related to lymphocyte activation and antigen processing/presentation upregulated in CLAD lung B cells compared to normal lung B cells. We found that the relative proportion of a naive B cell cluster was increased, and a CD27- IgD- B cell cluster was decreased, in CLAD lungs compared to matched PBMCs. We found a non-statistically significant increase in the proportion of B cells (B cells/CD45+ cells in Lungs/PBMC) in RAS compared to BOS patients. Expansion of a specific memory B cell subpopulation was observed in RAS compared to BOS lungs (Figure 1). Conclusions: Our study deconvolutes B cell heterogeneity, the relative proportions of various B cell subpopulations, and the unique transcriptomic profiles of B cells in lung allografts of BOS and RAS patients. Our findings may help future identification of alloreactive B cell subsets, which could potentially be targeted for prevention or treatment of CLAD.CIHR Project Grant 173343 (SJ, TM), CME Fellowship in Respiratory Medicine (AB), Sanofi innovations award (TM, SJ).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".