Biology subjects

Karns, R.

Publications and source records attributed to Karns, R..

5 recordsLinked to original sources

bioRxiv2024

Cholestasis alters polarization and suppressor function of hepatic regulatory T cells.

Fibrosing cholangiopathies, including biliary atresia and primary sclerosing cholangitis, involve immune-mediated bile duct epithelial injury and hepatic bile acid (BA) retention (cholestasis). Regulatory T-cells (Tregs) can prevent auto-reactive lymphocyte activation, yet the effects of BA on this CD4 lymphocyte subset are unknown. Gene regulatory networks for hepatic CD4 lymphocytes in a murine cholestasis model revealed Tregs are polarized to Th17 during cholestasis. Following bile duct ligation, Stat3 deletion in CD4 lymphocytes preserved hepatic Treg responses. While pharmacological reduction of hepatic BA in MDR2-/- mice prompted Treg expansion and diminished liver injury, this improvement subsided with Treg depletion. A cluster of patients diagnosed with biliary atresia showed both increased hepatic Treg responses and improved 2-year native liver survival, supporting that Tregs might protect against neonatal bile duct obstruction. Together, these findings suggest liver BA determine Treg function and should be considered as a therapeutic target to restore protective hepatic immune responses.

immunology↗

bioRxiv2022

Comparative Analysis of Global Hepatic Gene Expression in Adolescents and Adults with Non-alcoholic Fatty Liver Disease

IntroductionTo gain insights into the mechanisms underlying distinct nonalcoholic fatty liver disease (NAFLD) histological phenotypes between children and adults, we compared hepatic gene expression profiles associated with NAFLD phenotypes between the two age groups. MethodsHistological characteristics of intra-operative liver biopsies from adolescents and adults undergoing bariatric surgery were assessed by the same pathologist using the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Hepatic gene expression was measured by microarray analysis. Transcriptomic signatures of histological phenotypes between the two groups were compared, with significance defined as p-value <0.05 and a fold change >1.5. ResultsIn 67 adolescents and 76 adults, distribution of histological phenotypes was: not-NAFLD (controls) 51% vs 39%, NAFL 39% vs 37%, and NASH 10% vs 24%, respectively. There were 279 differentially expressed genes in adolescents and 213 in adults with NAFLD vs controls. In adolescents, transcriptomes for NAFL vs controls, and borderline vs definite NASH were undifferentiable, whereas in adults, NAFL and borderline NASH demonstrated a transcriptomic gradient between controls and definite NASH. When applied to adolescents, significant adult genes discriminated borderline and definite NASH from control and NAFL, but the majority of significant pediatric genes were not portable to adults. Genes associated with NASH in adolescents and adults showed some ontological consistency but notable differences. ConclusionsThere is some similarity but major differences in the transcriptomic profiles associated with NAFLD between adolescents and adults with severe obesity. These data suggest different mechanisms contribute to the pathogenesis of NAFLD severity at different stages in life. Study HighlightsO_ST_ABSWHAT IS KNOWNC_ST_ABSO_LINonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adults C_LIO_LINAFLD histological features and severity differ between children and adults but reasons for these differences are not clear. C_LI WHAT IS NEW HEREO_LIComparison of hepatic gene expression profiles between adolescents and adults with severe obesity and NAFLD showed some similarities but major differences in expressed genes C_LIO_LIThe findings suggest the mechanisms driving different NAFLD severity and phenotypes are different at different stages in life. C_LI

genetics↗

bioRxiv2021

Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of ulcerative colitis (UC) patients require colectomy within five years of diagnosis, but polygenic risk scores (PRS) utilizing findings from GWAS are unable to provide meaningful prediction of this adverse status. By contrast, in Crohns disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a Transcriptional Risk Score (TRS). Here we demonstrate that both measured (TRS) and polygenic predicted gene expression (PPTRS) identify UC patients at 5-fold elevated risk of colectomy with data from the PROTECT clinical trial and UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with transcriptome-wide association studies to stratify risk of disease complications.

genetics↗

bioRxiv2021

Commensal bacterial-derived retinoic acid primes host defense to intestinal infection

Interactions between the microbiota and mammalian host are essential for effective defense against pathogenic infection; however, the microbial-derived cues that mediate this beneficial relationship remain unclear. Here, we find that the intestinal epithelial cell (IEC)-associated commensal bacteria, Segmented Filamentous Bacteria (SFB), promotes early protection against the bacterial pathogen, Citrobacter rodentium, independently of CD4+ T cells. Global analyses demonstrated that SFB induced histone modifications in IECs at sites enriched for the retinoic acid receptor (RAR) motif. Interestingly, SFB-colonized mice exhibited greater expression of RAR targets during infection relative to germ-free mice, suggesting SFB may enhance defense through retinoic acid (RA) signaling. Consistent with this, supplementing germ-free mice with RA decreased pathogen levels. Further, mice with impaired RA-responsiveness in IECs displayed increased susceptibility to C. rodentium infection. RA was elevated in the intestine of mice colonized with SFB, indicating that the presence of commensal bacteria can modulate intestinal RA levels. However, this regulation by SFB was not dependent on mammalian RA production. Sequence analyses suggested that RA-generating enzymes are expressed by a subset of commensal bacteria. Remarkably, RA was produced by intestinal bacteria including SFB, and inhibiting RA signaling blocked SFB-induced protection against C. rodentium infection. These data collectively reveal RA as an unexpected microbiota-derived metabolite that primes innate intestinal defense and suggests that pre- and probiotic approaches to elevate RA could prevent or combat pathogenic infection.

microbiology↗

bioRxiv2018

Ddx3x regulates B-cell development and light chain recombination in mice

The X chromosome gene, DDX3X, is an ATP-dependent RNA helicase with roles in transcription, splicing, nuclear export, and translation. Loss of function mutations in DDX3X are linked to a variety of neoplasms, including B-cell lymphoma. We find that conditional homozygous deletion (Mb1-Cre) of Ddx3x in developing mouse B cells in female mice results in a complete absence of mature peripheral B cells associated with an absolute block at the pro-B cell stage of development in the bone marrow. In male mice with Vav1-Cre or Mb1-Cre mediated hemizygous deletion of Ddx3x, there are less severe reductions in peripheral B-cell frequencies with skewing towards the marginal zone lineage, suggesting that the Y chromosome homolog Ddx3y or other male factors may partially compensate for loss of Ddx3x. Loss of Ddx3x in male mice is associated with perturbations at developmental time points linked to cell cycle arrest and immunoglobulin chain rearrangement. Mechanistically, loss of Ddx3x in pre-B cells is associated with reduced expression of the histone reader Brwd1, failure to curtail proliferation, and defective Igk rearrangement, which skews the peripheral B cell receptor repertoire toward lambda light chain usage. These data reveal that Ddx3x plays an essential role in B-cell development by supporting proliferative and epigenetic changes necessary for rearrangement of immunoglobulin genes.

immunology↗