Gene signatures common to allograft rejection are associated with lymphocytic bronchitis

Abstract

Lymphocytic bronchitis (LB) precedes chronic lung allograft dysfunction. The relationships of LB (classified here as Endobronchial or E‐grade rejection) to small airway (A‐ and B‐grade) pathologies are unclear. We hypothesized that gene signatures common to allograft rejection would be present in LB. We studied LB in two partially overlapping lung transplant recipient cohorts: Cohort 1 included large airway brushes (6 LB cases and 18 post‐transplant referents). Differential expression using DESeq2 was used for pathway analysis and to define an LB‐associated metagene. In Cohort 2, eight biopsies for each pathology subtype were matched with pathology‐free biopsies from the same subject (totaling 48 samples from 24 subjects). These biopsies were analyzed by multiplexed digital counting of immune transcripts. Metagene score differences were compared by paired t tests. Compared to referents in Cohort 1, LB demonstrated upregulation of allograft rejection pathways, and upregulated genes in these cases characterized an LB‐associated metagene. We observed statistically increased expression in Cohort 2 for this LB‐associated metagene and four other established allograft rejection metagenes in rejection vs paired non‐rejection biopsies for both E‐grade and A‐grade subtypes, but not B‐grade pathology. Gene expression‐based categorization of allograft rejection may prove useful in monitoring lung allograft health.

Telomere Dysfunction Drives Chronic Lung Allograft Dysfunction Pathology

“…We speculate that senescence reprogramming due to telomere dysfunction in club cells leads to release of an array of cytokines and chemokines that attract immune cells to the lung. Elevated numbers of T cells and NK cells could reflect a direct response to cell stress (37) or be due to T-cell attracting chemokines released by senescent club cells, such as CXCL-9, CXCL-10 and CXCL-11, that are commonly elevated in airway inflammation (38) and CLAD (39,40). Elevated levels of lymphocytes in lungs of SCGB1a1-cre TRF1 F/F transgenic mice suggests that telomere dysfunction in club cells could even contribute to the inflammatory changes seen in CLAD.…”

Chronic lung allograft dysfunction small airways reveal a lymphocytic inflammation gene signature

“…As our primary endpoint, we examined a previously-described LB metagene score in small airway brushing RNA, with a secondary comparison in transbronchial biopsy RNA. 10 LB-associated gene expression was increased in CLAD subjects compared with controls by 0.87 SDs (95% CI 0.34-1.40, Figure 2A). However, there was no statistically significant difference when this LB gene expression score was calculated on transbronchial biopsies (delta 0.40, 95%…”

“…However, the association between this LB gene signature with CLAD pathology and its performance in small airway brushings are unknown. 10 Here, we hypothesized that LB-associated gene expression would be increased in small airway brushings from subjects with CLAD.…”

Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation–Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation

“…After redundant and duplicate genes were removed, the list contained 1749 genes. Then the MDWG members identified overlap between these genes and genes described in the peer‐reviewed literature 2,8,12,29,32,33,38‐50,9,51,52,10,53‐56,11,57‐64,65 as being strongly associated with relevant clinical phenotypes and identified 1050 genes to be considered for inclusion. In the next step, a list including all genes with consensus expert opinion were selected and for which all Hugo duplicates were then combined, leaving 670 unique genes.…”