Biology subjects

Sussman, J.

Publications and source records attributed to Sussman, J..

5 recordsLinked to original sources

bioRxiv2025

Imbalance of Tregs/B cells and elevated complement signalling are hallmarks of Refractory Myasthenia Gravis

BackgroundA significant proportion of patients with myasthenia gravis (MG) remain refractory to standard immunosuppressive therapy, and biomarkers to help guide treatment decisions are lacking. MethodsWe examined the circulating immune profile of patients with acetylcholine receptor antibody positive MG with differing treatment requirements and compared them to controls. FindingsRefractory patients displayed the highest frequency of memory B cells, and increased production of interleukin (IL)-6 and tumour necrosis factor (TNF)- upon toll-like receptor/ CD40 activation in vitro, mirrored by a dramatic loss of regulatory T cells (Tregs) and dendritic cells. Refractory MG was further characterised by elevated circulating complement proteins (C3, C5 and clusterin) and increased expression of complement receptors on lymphocytes. Following anti-CD20 therapy, residual plasmablasts persisted in circulation. Notably, a low baseline B cell frequency (<3%) was associated with poor clinical response to rituximab in refractory disease, although the sample size was limited. ConclusionOur findings define a distinct immune signature in refractory MG, identify potential biomarkers of treatment resistance, and highlight plasma cell depletion, IL-6 or complement inhibition, and Treg expansion as promising therapeutic avenues. FundingFunding was received from the NorthCare Charity, Myaware, Academy of Medical Sciences and the Neuromuscular Study Group. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/643341v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@13df9e2org.highwire.dtl.DTLVardef@1e086eborg.highwire.dtl.DTLVardef@1b9bb92org.highwire.dtl.DTLVardef@c9a164_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Mapping the Cellular Biogeography of Human Bone Marrow Niches Using Single-Cell Transcriptomics and Proteomic Imaging

The bone marrow is the organ responsible for blood production. Diverse non-hematopoietic cells contribute essentially to hematopoiesis. However, these cells and their spatial organization remain largely uncharacterized as they have been technically challenging to study in humans. Here, we used fresh femoral head samples and performed single-cell RNA sequencing (scRNA-Seq) to profile 29,325 enriched non-hematopoietic bone marrow cells and discover nine transcriptionally distinct subtypes. We next employed CO-detection by inDEXing (CODEX) multiplexed imaging of 18 individuals, including both healthy and acute myeloid leukemia (AML) samples, to spatially profile over one million single cells with a novel 53-antibody panel. We discovered a relatively hyperoxygenated arterio-endosteal niche for early myelopoiesis, and an adipocytic, but not endosteal or perivascular, niche for early hematopoietic stem and progenitor cells. We used our atlas to predict cell type labels in new bone marrow images and used these predictions to uncover mesenchymal stromal cell (MSC) expansion and leukemic blast/MSC-enriched spatial neighborhoods in AML patient samples. Our work represents the first comprehensive, spatially-resolved multiomic atlas of human bone marrow and will serve as a reference for future investigation of cellular interactions that drive hematopoiesis.

cell biology↗

bioRxiv2023

Physiological reprogramming in vivo mediated by Sox4 pioneer factor activity

Tissue damage elicits cell fate switching through a process called metaplasia, but how the starting cell fate is silenced and the new cell fate is activated has not been investigated in animals. In cell culture, pioneer transcription factors mediate "reprogramming" by opening new chromatin sites for expression that can attract transcription factors from the starting cells enhancers. Here we report that Sox4 is sufficient to initiate hepatobiliary metaplasia in the adult liver. In lineage-traced cells, we assessed the timing of Sox4-mediated opening of enhancer chromatin versus enhancer decommissioning. Initially, Sox4 directly binds to and closes hepatocyte regulatory sequences via a motif it overlaps with Hnf4a, a hepatocyte master regulator. Subsequently, Sox4 exerts pioneer factor activity to open biliary regulatory sequences. The results delineate a hierarchy by which gene networks become reprogrammed under physiological conditions, providing deeper insight into the basis for cell fate transitions in animals.

cell biology↗

bioRxiv2023

Evidence for in vitro extensive proliferation of adult hepatocytes and biliary epithelial cells

Over the last several years, a method has emerged which endows adult hepatocytes with in vitro proliferative capacity, producing chemically-induced liver progenitors (CLiPs). However, a recent study questioned the origin of these cells, suggesting that resident liver progenitor cells, but not hepatocytes, proliferate. Here, we provide lineage tracing-based evidence that adult hepatocytes acquire proliferative capacity in vitro. Unexpectedly, we also found that the CLiP method allows biliary epithelial cells to acquire extensive proliferative capacity. Interestingly, after long-term culture, hepatocyte-derived cells (hepCLiPs) and biliary-derived cells (bilCLiPs) become similar in their gene expression patterns, and they both exhibit differentiation capacity to form hepatocyte-like cells. Finally, we provide evidence that hepCLiPs can repopulate chronically injured mouse livers, reinforcing our earlier argument that CLiPs can be a cell source for liver regenerative medicine. Moreover, this study offers bilCLiPs as a potential cell source for liver regenerative medicine.

cell biology↗

bioRxiv2019

How delayed treatment benefits and harms would impact the optimal timing of statin initiation for cardiovascular primary prevention

BackgroundGenetic studies suggest that the relative risk reduction (RRR) of statins may increase over time, potentially resulting in much greater long-term benefit if statins are started before cardiovascular (CV) risk is high.\n\nMethodsWe used a nationally representative sample of American adults to estimate effects of initiating a statin when 10-year CV risk reaches 5%, 10% or 15%. We examined scenarios in which a statins initial RRR (30%) gradually doubles over 10 to 30 years of treatment.\n\nResultsInitiating a statin when 10-year CV risk is 5% resulted in a mean of 20.1 years on a statin before age 75 (8 years more than starting when CV risk reaches 10%). If a statins RRR doubles over 20 years, starting when CV risk is 5% would save about 5.1 to 6.1 additional QALYs per 1000 additional treatment years than starting when CV risk is 10%. Most of this additional benefit was accrued by those who reach a 5% risk at a younger age. Due to the prolonged treatment period, however, early treatment could also result in net harm if the treatment slowly increased a major complication of aging, such as muscular or neurological aging.\n\nConclusionsIn a thought experiment exploring the impact of delayed effects, we found that if the relative effectiveness of statin therapy gradually doubles over a 10 to 30 year period, starting a statin when 10-year CV risk is 5% could have much more long-term benefit than starting a statin when CV risk is 10%. Most of the additional benefit occurred in those at elevated age-adjusted CV risk. Unfortunately, given the long duration of treatment, substantial delayed statin harms, if present, could outweigh these potential benefits and result in substantial net harm.

epidemiology↗