Biology subjects

Esser, D.

Publications and source records attributed to Esser, D..

4 recordsLinked to original sources

bioRxiv2025

CSF single-cell RNA sequencing reveals clonally expanded CD4+ stem cell-like memory T cells in GAD65-antibody associated neurological syndromes

BackgroundGlutamic acid decarboxylase (GAD) antibody-associated autoimmune neurological syndromes (AINS) are a spectrum of autoimmune-mediated CNS disorders. While antibodies targeting the 65 kDa isoform of GAD are of high diagnostic value, T cell mediated cytotoxicity has been identified as a key component of disease pathogenesis. The precise pathophysiological mechanisms by which the disease is triggered and maintained, however, remain incompletely understood. MethodsWe performed single-cell transcriptome and immune repertoire sequencing (sc-seq) in CSF and blood of 8 anti-GAD65 AINS patients compared to 8 non-inflammatory controls. Monoclonal antibodies (mAbs) were synthesized from B cell receptor (BCR) data to evaluate the B cellular immune response. FindingsWe identified an increase and expansion of activated CD4+ stem cell-like memory T cells (TSCM) in the CSF of anti-GAD65 AINS patients. Expanded T cells showed increased expression of proinflammatory genes. The mAb analysis revealed a high frequency of GAD65-reactive BCRs in the CSF of anti-GAD65 AINS patients with increased somatic hypermutations compared to non-GAD-reactive BCRs and BCRs from controls. ConclusionsSc-seq identified clonally expanded CD4+ TSCM in the CSF of anti-GAD65 AINS patients harboring cytotoxic properties likely contributing to disease pathogenesis. GAD-reactive B cells circulate in the CSF of anti-GAD65 AINS patients further supporting the concept of an antigen-specific intrathecal immune response. Future studies need to clarify the actual pathogenicity of these immune cells and the link between T and B cellular immune mechanisms in the pathogenesis of anti-GAD65 AINS. FundingGerman Research Foundation (ERARE18-202 UltraAIE), German Federal Ministry of Education and Research (CONNECT GENERATE (2.0); 01GM1908A and 01GM2208A).

immunology↗

bioRxiv2024

Metabolic modeling reveals the aging-associated decline of host-microbiome metabolic interactions in mice

Aging is the predominant cause of morbidity and mortality in industrialized countries. The specific molecular mechanisms that drive aging are poorly understood, especially the contribution of the microbiota in these processes. Here, we combined multi-omics with metabolic modeling in mice to comprehensively characterize host-microbiome interactions and how they are affected by aging. Our findings reveal a complex dependency of host metabolism on microbial functions, including previously known as well as novel interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome, which we attribute to reduced beneficial interactions in the microbial community and a reduction in its metabolic output. These microbial changes coincided with a corresponding downregulation of key host pathways predicted by our model to be dependent on the microbiome that are crucial for maintaining intestinal barrier function, cellular replication, and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes, focusing on microbial nucleotide metabolism as a pivotal factor in aging dynamics. These pathways could serve as future targets for the development of microbiome-based therapies against aging. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/587009v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@a8e7faorg.highwire.dtl.DTLVardef@115f35aorg.highwire.dtl.DTLVardef@1bbf32org.highwire.dtl.DTLVardef@1a58c7f_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2023

CSF plasma cell expansion in LGI1-/CASPR2-autoimmune encephalitis is associated with loss of regulatory MAIT cells

Anti-Leucine-rich glioma inactivated-1 (LGI1) and anti-contactin-associated-protein-2 (CASPR2) associated autoimmune encephalitis (AIE) variants are characterized by directly pathogenic autoantibodies present in serum and CSF. The dynamics and drivers of intrathecal and systemic autoantibody production are incompletely understood. We aimed to elucidate the immunologic basis of the LGI1-/CASPR2-associated AIE variants by performing multi-omic profiling of CSF/blood in untreated patients. We validated findings by flow cytometry in independent cohorts and confirmed functionality using rodent immunization. We identified clonal IgG2 and IgG4 plasma cell expansion and affinity maturation in the CSF together with clonally restricted, activated, antigen-experienced CD8 and CD4 T cells as a hallmark of these encephalitis variants. Using recombinant cloning, we confirmed that expanded CSF plasma cell clones almost exclusively bound the respective neuronal autoantigen. In addition, we found a loss of regulatory mucosa-associated invariant T (MAIT) cells and gamma delta T cells in the CSF and - to a lesser degree - in blood. We validated the functional role of these invariant T cells using a novel murine active immunization paradigm using both autoantigens: MAIT cells suppressed systemic formation of LGI1 and CASPR2-specific anti-neuronal antibodies. We propose that loss of systemic and intrathecal regulatory mechanisms mediated by innate-like T cells promote plasma cell expansion and autoantibody production as a shared mechanism in AIE. One sentence summaryCerebrospinal fluid (CSF) and peripheral blood (PB) single cell transcriptomics of patients with untreated anti-LGI1 and anti-CASPR2 autoimmune encephalitis demonstrated CSF specific expansion of autoantigen-specific plasma cell clones and systemic loss of invariant mucosa-associated T-cells (MAIT).

neuroscience↗

bioRxiv2023

Recurrent phases of strict protein limitation inhibit tumor growth and restore lifespan in a Drosophila intestinal cancer model

Diets that restrict caloric or protein intake offer a variety of benefits, including decreasing the incidence of cancer. However, whether such diets pose a substantial therapeutic benefit as auxiliary cancer treatments remains unclear. We determined the effects of severe protein depletion on tumorigenesis in a Drosophila melanogaster intestinal tumor model, using a human RAF gain-of-function allele. Severe and continuous protein restriction significantly reduced tumor growth but resulted in premature death. Therefore, we developed a diet in which short periods of severe protein restriction alternated cyclically with periods of complete feeding. This nutritional regime reduced tumor mass, restored gut functionality, and normalized the lifespan of oncogene-expressing flies to the levels observed in healthy control flies. Furthermore, this diet reduced the chemotherapy-induced stem cell activity associated with tumor recurrence. Transcriptome analysis revealed long-lasting changes in the expression of key genes involved in multiple major developmental signaling pathways. Overall, the data suggest that recurrent severe protein depletion effectively mimics the health benefits of continuous protein restriction, without undesired nutritional shortcomings. This provides seminal insights into the mechanisms of the transcriptomic memory effect required to maintain the positive effects of protein restriction throughout the phases of a full diet.

cancer biology↗