Biology subjects

Pribitzer, S.

Publications and source records attributed to Pribitzer, S..

3 recordsLinked to original sources

bioRxiv2025

Infants who develop BPD have an airway endotype defined by vimentin expression and ciliary loss

RationaleBronchopulmonary Dysplasia (BPD) results from abnormal lung development after preterm birth, with structural deficits at every respiratory tree level. BPD with lower airway disease is emerging as a clinically significant phenotype with increased mortality, and there is a significant knowledge gap in the molecular mechanisms whereby preterm birth disrupts normal airway development. ObjectivesTo develop a human model of lower airway disease after preterm birth and to characterize a molecular endotype of evolving BPD (eBPD) at baseline and in response to injury. MethodsWe used a combination of an ex vivo organotypic Airway Epithelial Cell (AEC models) and well-characterized pathologic and transcriptomic patient samples for quantitative immunohistochemistry and RNA sequencing analyses. Measurements and Main ResultsCompared to AECs from healthy patients, eBPD- derived AECs have a molecular endotype of reduced proliferation, impaired differentiation to ciliated epithelium, and an expanded vimentin-positive population with a transcriptional shift toward stromal cell-associated genes. With hyperoxia exposure, eBPD-derived AECs exhibited a pronounced vimentin response ex vivo, which parallels the increased vimentin expression of airway cells observed in lung tissue from human infants with BPD. ConclusionsIn this organotypic model of neonatal airway differentiation, we find that infants with eBPD have impaired differentiation, increased expression of vimentin, and concomitant loss of cilia, with an exaggerated increase in vimentin expression after hyperoxia injury, findings that mimic the effects of prematurity in airway cells in human patients. These data provide a foundation for future mechanistic studies interrogating the role of intermediate filaments in epithelial differentiation and repair.

cell biology↗

bioRxiv2024

Linking candidate causal autoimmune variants to T cell networks using genetic and epigenetic screens in primary human T cells.

Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4+ T cells, suggesting that they alter disease risk via changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. We tested >18,000 autoimmune disease-associated variants for allele-specific expression using massively parallel reporter assays in primary human CD4+ T cells. The 545 expression-modulating variants (emVars) identified greatly enrich for likely causal variants. We provide evidence that many emVars are mediated by common upstream regulatory conduits, and that putative target genes of primary T cell emVars are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis-regulatory elements modulate both known and novel target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.

genetics↗

bioRxiv2024

Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis

OBJECTIVESWe aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system. DESIGNIn two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH. Eight deceased patients defined as COVID-sHLH underwent genomic sequencing in order to identify variants in immune-related genes. SETTINGTwo tertiary care hospitals in Seattle, Washington (Virginia Mason Medical Center and Harborview Medical Center). PATIENTS186 patients with COVID-19 INTERVENTIONSNone MEASUREMENTS AND MAIN RESULTSNine percent of enrolled COVID-19 subjects met our defined criteria for sHLH. Using broad serum proteomic approaches (O-link and SomaScan), we identified three biomarkers for COVID-19 associated sHLH (soluble PD-L1, TNF-R1, and IL-18BP), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and sTNF-R1). We also identified novel biomarkers and pathways of COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected variants in several genes involved in immune responses in individuals with COVID-sHLH, including in DOCK8 and in TMPRSS15, suggesting that genetic alterations in immune-related genes may contribute to hyperinflammation and fatal outcomes in COVID-19. CONCLUSIONSBiomarkers of COVID-19 associated sHLH, such as soluble PD-L1, and pathways, such as the syntaxin pathway, and variants in immune genes in these individuals, suggest critical roles for the immune response in driving sHLH in the context of COVID-19. Key PointsO_ST_ABSQUESTIONC_ST_ABSTo define biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system. FINDINGSIn two independent cohorts using two different platforms, we identified sPD-L1, IL-18BP, and sTNF-R1 as COVID-sHLH biomarkers. We identified the syntaxin pathway as important in COVID-sHLH and variants in immune-related genes in a subset of deceased COVID-sHLH subjects. MEANINGImmune related proteins and pathways are dysregulated in COVID-sHLH.

immunology↗