Biology subjects

Baron, J. L.

Publications and source records attributed to Baron, J. L..

4 recordsLinked to original sources

bioRxiv2026

Humoral Immune Dysregulation Defines High-Risk Cirrhotic Ascites

Fluid accumulates within serosal cavities in diverse disease states, where it creates biologically active and potentially pathologic niches. How these expanded microenvironments reflect and shape disease biology remains incompletely resolved. Here, we investigated human ascites fluid (n = 118), a hallmark of decompensated cirrhosis, to determine whether signatures of microbial exposure and local host response distinguish outcomes. Cirrhotic ascites was characterized by barrier remodeling, depletion of plasma cell-associated programs, and enrichment of oropharyngeal microbes. Surprisingly, detection of oropharyngeal microbes in ascites was not associated with adverse outcomes. Instead, the ascites of cirrhotic patients with poor outcomes was marked by profound plasma cell depletion and significantly reduced dimeric IgA, despite the presence of antigen-experienced B cells. Together, these findings identify local B cell dysregulation as a previously underappreciated component of cirrhosis-associated immune dysfunction. Impaired local humoral immunity, rather than microbial translocation alone, emerges as a feature of high-risk decompensated cirrhosis.

immunology↗

bioRxiv2025

Clinical cure of chronic hepatitis B is dependent on activation and perpetuation of robust CD4+ T cell responses

Chronic infection with hepatitis B virus (HBV), a major global pathogen, often leads to immune-mediated progressive liver injury and liver cancer. While seroclearance of the surface antigen (HBsAg) defines clinical cure and reduces disease-associated risks, HBsAg clearance is rarely observed and remains therapeutically elusive. Here we overcome some of the challenges to studying immune mechanisms of HBsAg clearance in chronic hepatitis B (CHB) using our mouse model of age-dependent HBsAg clearance and persistence, and samples from our BeNEG-DO clinical trial that provided longitudinal PBMCs from patients who either cleared HBsAg or retained stable HBsAg levels after stopping nucleos(t)ide analog therapy. We show that young mice fail to clear HBsAg and have impaired ability to efficiently initiate and sustain HBV-specific CD4+ T cell responses. We also demonstrate a role for CD4+ T cells in hepatic leukocyte organization and cytotoxicity, and in HBV-specific CD8+ T cell cytotoxicity and HBsAg clearance. Upstream of the CD4+ T cell response, we reveal that hepatic dendritic cells, particularly cDC2s, direct effective CD4+ T cell activation and differentiation. Studies in CHB patients identified immune features of HBsAg clearance that overlap with the mouse model, including TH1 and cytotoxic CD4+ T cell activation and CD8+ T cell cytotoxic effector function. These findings identify an essential role for potent CD4+ T cell activation in the clinical cure of CHB and illuminate potential immunotherapeutic targets for enhancing CD4+ T cell responses to achieve greater HBsAg clearance rates. One Sentence SummaryUsing a mouse model of hepatitis B and longitudinal PBMCs from patients with chronic hepatitis B, we identify shared mechanisms of HBsAg seroclearance.

immunology↗

bioRxiv2021

Hepatitis C Virus Infects and Perturbs Liver Stem Cells

Hepatitis C virus (HCV) is the leading cause of death from liver disease. How HCV infection causes lasting liver damage and increases cancer risk beyond viral clearance remains unclear. We identify bipotent liver stem cells as novel targets for HCV infection, and their erroneous differentiation as the potential cause of impaired liver regeneration and cancer development. We show 3D organoids generated from liver stem cells from actively HCV-infected individuals carry replicating virus and maintain low-grade infection over months. Organoids can be infected with a primary HCV isolate. Virus-inclusive single-cell RNA-sequencing uncovered extensive transcriptional reprogramming in HCV+ cells supporting hepatocytic differentiation, cancer stem cell development and viral replication while stem cell proliferation and interferon signaling are disrupted. Our data adds a pathogenesis factor - infection of liver stem cells - to the biology of HCV infection that explains persistent liver damage and enhanced cancer risk through an altered stem cell state.

microbiology↗

bioRxiv2021

Liver Organoid and T Cell Coculture Models Cytotoxic T Cell Responses against Hepatitis C Virus

Hepatitis C virus (HCV) remains a global public health challenge with an estimated 71 million people chronically infected, with surges in new cases and no effective vaccine. New methods are needed to study the human immune response to HCV since in vivo animal models are limited and in vitro cancer cell models often show dysregulated immune and proliferative responses. Here we developed a CD8+ T cell and adult stem cell liver organoid system using a microfluidic chip to coculture 3D human liver organoids embedded in extracellular matrix with HLA-matched primary human T cells in suspension. We then employed automated phase contrast and immunofluorescence imaging to monitor T cell invasion and morphological changes in the liver organoids. This microfluidic coculture system supports targeted killing of liver organoids when pulsed with a peptide specific for HCV nonstructural protein 3 (NS3) (KLVALGINAV) in the presence of patient-derived CD8+ T cells specific for KLVALGINAV. This demonstrates the novel potential of the coculture system to molecularly study adaptive immune responses to HCV in an in vitro setting using primary human cells.

immunology↗