Biology subjects

Rasouli, S.

Publications and source records attributed to Rasouli, S..

5 recordsLinked to original sources

bioRxiv2026

CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease

Epstein-Barr virus (EBV) reprograms autoreactive B cells into activated antigen-presenting cells that drive pathogenic T- and B-cell responses in autoimmune disease. Whether eliminating these cells contributes to durable remission after CD19 chimeric antigen receptor (CAR) T-cell therapy is unknown. Here, using EBV B-cell sequencing (EBV-seq), we profiled EBV+ B cells from patients treated with CD19-CAR T cells (systemic lupus erythematosus, n=6; inflammatory myopathy, n=3; systemic sclerosis, n=3) or rituximab (n=15) and recombinantly expressed their antibodies to define antigen specificity. At baseline, EBV+ B cells were enriched relative to healthy donors, class-switched and hypermutated, expressed the latency III program with heightened antigen-presentation signatures, and encoded autoantibodies. CAR T cells, but not rituximab, depleted EBV+ B cells and shifted the reconstituted repertoire towards IgM+, minimally mutated, largely non-autoreactive cells, consistent with infection of newly generated B cells. After rituximab, EBV+ B cells retained a class-switched, hypermutated and autoreactive with an activated antigen-presenting phenotype. Sustained drug-free remission occurred in 8/12 CAR T-cell-treated versus 0/15 rituximab-treated patients. In vitro, EBV+ B cells resisted anti-CD20 and anti-CD19 antibodies but were killed by CAR T cells and a CD19 T-cell engager. Our findings suggest resetting the EBV+ autoreactive B-cell repertoire contributes to sustained drug-free remission.

immunology↗

bioRxiv2026

EBV reprograms autoreactive B cells as antigen presenting cells in multiple sclerosis

Summary paragraphMultiple sclerosis (MS) is a chronic autoimmune disease targeting the central nervous system (CNS). MS develops almost exclusively in individuals previously infected with Epstein-Barr virus (EBV)1, yet the mechanisms linking EBV infection to MS pathogenesis remain incompletely defined. Here we characterized EBV-infected B cells in MS and demonstrated that EBV directly infects autoreactive anti-CNS antigen B cells and reprograms them into pro-inflammatory antigen-presenting cells (APCs). EBV B cells in MS were enriched within the CD27CD21low memory B-cell subset and exhibited upregulated B cell activation and APC transcriptional programs. Recombinant antibodies derived from MS blood and cerebrospinal fluid (CSF) EBV B cells bound brain tissue, and several cross-bound both MS-associated autoantigens and Epstein-Barr virus nuclear antigen-1 (EBNA1). In vitro, EBV B cells functioned as APCs that stimulated T peripheral helper cells, with associated activation of EBV- anti-CNS antigen B cells. Collectively, these findings support a mechanistic framework in which EBV infects and transcriptionally reprograms autoreactive anti-CNS antigen B cells into APCs that drive pathogenic anti-CNS antigen T cell and EBV- B cell responses in MS.

immunology↗

bioRxiv2025

Whole-brain chemosensory responses of both C. elegans sexes

Sexually-dimorphic neural circuits play a critical role in shaping sex-specific animal behaviors. Maps of the structural dimorphisms in these circuits have been explored by analyzing "synaptic connectomes", electron micrograph reconstructions of synaptic connectivity. Nevertheless, recent studies in the model organism C. elegans have shown little to no correlation between the synaptic connectome and dynamic neural activity. Therefore, the extent of sexual dimorphism in functional neural activity remains unknown. To determine the extent of functional sexual-dimorphisms in C. elegans we compared activity, neuron-by-neuron, across all neurons in the heads of both sexes. To sample a broad view of responses to different sensory modalities, we tested a diverse panel of ethologically-relevant olfactory, gustatory, and chemical stimuli, representing both attractive and aversive cues. We found that nearly every sensory neuron responded dimorphically to at least one cue and monomorphically to other cues, indicating that sexually-dimorphic circuits are pervasive and stimulus dependent. This dimorphic and monomorphic activity was present to a lesser extent in downstream interneurons and even less so in motoneurons, implicating sensory neurons as the primary source and location of sexually-dimorphic activity. Comparing the functional activity we measured to the published synaptic connectomes of both sexes revealed that sexual dimorphism in functional connectivity was distinct from and complementary to sexual dimorphism in synaptic connectivity. Our results provide a first-of-its-kind comparison of whole-brain dynamics between sexes at the level of single neurons, serving as an extensive resource for further investigations of functional sex differences.

neuroscience↗

bioRxiv2024

Identification of stable reference genes for quantitative real-time PCR in human fibroblasts from lymph nodes and synovium

Real-time quantitative PCR (RT-qPCR) has emerged as an accurate and widely used technique for measuring gene expression levels. However, its reliability depends on the selection of appropriate reference genes to normalize for sample input. Accordingly, the identification of reference genes characterized by stable expression in cells and conditions of interest is essential for ensuring accurate expression values. To date, no study has specifically identified suitable reference genes for primary human cultured fibroblast-like synoviocytes (FLS) and lymph node stromal cells (LNSCs) within the context of rheumatoid arthritis (RA). These stromal cells play a critical role in the pathogenesis of disease. In this study, we evaluated the suitability of 15 candidate reference genes for normalizing transcript expression in FLS and LNSCs subjected to various in vitro stimuli. We included traditional reference genes often used for transcript normalization in fibroblasts as well as candidate genes identified as suitable reference genes via GeneVestigator analysis of publicly available transcriptomic data. RefFinder algorithms were used to identify the most stable reference genes for transcript normalization across the cell types and different experimental conditions. We determined that the optimal number of reference genes for every experimental condition tested was two; RPLP0 and POLR2G exhibited the greatest stability across different experimental conditions for LNSCs. However, for FLS, we observed greater variability in the most stable reference genes across different experimental conditions. Although POLR2G and TBP emerged as the most stable reference genes under unstimulated conditions, our findings indicated that FLS require distinct reference genes for transcript normalization depending on the specific experimental conditions. Validation of the selected reference genes for normalizing the expression levels of metabolic genes in unstimulated FLS emphasized the importance of prior evaluation of potential reference genes, as arbitrary selection of reference genes could lead to data misinterpretation. This study constitutes the first systematic analysis for selecting optimal reference genes for transcript normalization in different types of human fibroblasts. Our findings emphasize the importance of proper selection of reference genes for each experimental condition separately when applying standard quantitative PCR technology for assessing gene expression levels.

molecular biology↗

bioRxiv2022

PRC2 clock: a universal biomarker of aging and rejuvenation

DNA methylation (DNAm) is one of the most reliable biomarkers for aging across many mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, age-dependent DNAm gain is less specified. Multiple studies have demonstrated that polycomb repressive complex 2 (PRC2) targets are enriched among the CpG sites which gain methylation with age. However, a systematic whole-genome examination of all PRC2 targets in the context of aging methylome as well as whether these associations are pan-tissue or tissue-specific is lacking. Here, by analyzing DNAm data from different assays and from multiple young and old human and mouse tissues, we found that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells gain methylation with age in all examined somatic mitotic cells. We also estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the "PRC2 clock," defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells. In addition, we demonstrate the application of this biomarker in the evaluation of different anti-aging interventions, including dietary restriction and partial epigenetic reprogramming.

genomics↗