Hani S. Mousa

CNS oligodendrocytes generate myelin, an RNA-containing proteolipid substance that enhances axonal transmission. In multiple sclerosis (MS), myelin debris is phagocytosed by microglia (MG), and prior studies have detected myelin-derived mRNA in MG nuclei, suggesting a retrograde transport pathway. We report myelin basic protein (MBP) is a nucleic acid binding and trafficking protein. We found that retro-transport of myelin RNA into the MG nucleus was phagocytosis and importin dependent. Transcriptomic and proteomic analyses of MG nuclei revealed enrichment of myelin mRNAs and proteins, with MBP singularly detected in soluble and chromatin associated fractions. MBP bound mRNA with high affinity (Kd ≈ 0.30 nM) and was sufficient to facilitate MG RNA nuclear import in vitro and in vivo. Functionally, MBP mediated the delivery of small interfering RNAs for targeted knockdown of toll-like receptor 4. These findings indicate MBP as an RNA binding protein capable of MG nuclear import, providing insight into neuroinflammatory pathology of MS.

Inflammatory Bowel Disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is an umbrella term used to describe a group of autoimmune conditions characterized by chronic, relapsing inflammation of the gastrointestinal tract. The tumour necrosis factor superfamily member 14 (TNFSF14), also known as LIGHT, is a pleiotropic cytokine with diverse roles in immune regulation. Here, we review the multifaceted involvement of LIGHT in intestinal inflammation, particularly its dual capacity to both promote immune activation and facilitate inflammation resolution in the context of IBD. We explore the molecular mechanisms of LIGHT signalling through its receptors, Herpes Virus Entry Mediator (HVEM) and Lymphotoxin-β Receptor (LTβR), and how these distinct interactions dictate its pro-inflammatory or regulatory functions. Finally, we review the therapeutic potential of targeting this pathway, highlighting the results of recent clinical trials and exploring future strategies aimed at restoring immune homeostasis in patients with IBD.

Inflammatory Bowel Disease (IBD) is a term used to describe a group of disorders characterized by chronic inflammation of the gastrointestinal tract, with Crohn’s Disease (CD) and Ulcerative Colitis (UC) being the most common. While still not fully understood, pathogenesis is believed to be multifactorial – the result of an interplay between genetic susceptibility, immune dysregulation and environmental factors that all lead to chronic inflammation and tissue remodeling. Innate immune cells, which orchestrate the initial defense mechanisms and modulate the subsequent immune response, play a central role in disease initiation and progression. This review examines the complex involvement of innate immune cells in IBD, emphasizing their interactions with environmental factors and the gut microbiome. We highlight the importance of microbial dysbiosis and impaired intestinal barrier function in disease pathogenesis, and the role that innate immune cells play not only as first responders, but also as key players in maintaining intestinal barrier integrity and gut microbiome. This review provides a comprehensive summary of the role that innate immune cells play in IBD pathogenesis with emphasis on the increasingly recognized role of the gut microbiome. A better understanding of innate immune cell mechanisms and of microbiome-immune interactions is key for the development of novel targeted therapies.

For decades, regulatory T cell (Treg) research has focussed on CD4+FOXP3+ Tregs, while characterisation of CD8+FOXP3+ Tregs has been limited due to their scarcity in blood. Here, by analysing 95 tissue samples from 26 deceased transplant organ donors we show that, despite representing less than 5% of circulating Tregs, CD8+ Tregs are enriched in human tissue, particularly in non-lymphoid tissues and bone marrow. We further show that they are fully demethylated at the FOXP3 TSDR, indicating lineage stability, and demonstrate their presence in human thymic tissue and cord blood. Transcriptomic profiling revealed strong similarities to CD4+ Tregs, however at the protein level, they reside in tissue as surface CD25 ^lo /-CD8+CD69+CD103+TLR9+HELIOS+FOXP3+ cells, expressing CD25 intracellularly. Surface CD25 was rapidly regained ex-vivo , allowing us to sort and expand them, and to subsequently demonstrate their therapeutic potential in a humanised mouse model of graft-vs-host disease. Additionally we report increased circulating CD8+Tregs in individuals with SLE and patients early following traumatic brain injury (TBI), underscoring their functional importance. We conclude that these under-studied cells likely play an essential but previously unappreciated role in maintaining peripheral tolerance. One Sentence Summary: FOXP3+CD8+ Tregs, expressing tissue residency markers and intracellular CD25, are enriched in human non-lymphoid tissues.

As the dimensionality, throughput, and complexity of cytometry data increases, so does the demand for user-friendly, interactive analysis tools that leverage high-performance machine learning frameworks. Here we introduce FlowAtlas.jl: an interactive web application that bridges the user-friendly environment of FlowJo and computational tools in Julia developed by the scientific machine learning community. We demonstrate the capabilities of FlowAtlas using a novel human multi-tissue, multi-donor immune cell dataset, highlighting key immunological findings.

Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.

While neurology remains the best‐represented specialty, it was Hematology and Rheumatology cases that were more often reported by non‐specialists. The overall distribution by country has also changed, reflecting recent outbreaks of infectious agents.

Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6–12 mo), and long-term (6–13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.

Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by chronic inflammation of the intrahepatic bile ducts, causing progressive ductopenia, cholestasis and fibrosis, and leading to liver failure. Ursodeoxycholic acid (UDCA) is the first-line therapy for the treatment of PBC patients. This is effective in majority of patients; however, up to 20 percent of patients have an incomplete response to UDCA therapy and have a reduced prognosis as compared to healthy individuals. Obeticholic acid (OCA) has been recently registered as second-line therapy for patients with incomplete response to UDCA, with plans to demonstrate the long-term clinical efficacy. Areas covered: Recent evolution in our understanding of disease mechanisms is leading to the advent of new and re-purposed therapeutic agents targeting key processes in the etiopathogenesis. Several therapeutic targets have been proposed which can be categorized into three compartments: immune, biliary and fibrosis. In this review we describe the main biological mechanisms underpinning disease development and progression in PBC and the new targeted therapies on the horizon. Expert commentary: Testing new drugs towards hard clinical endpoints is challenging in PBC due to its low prevalence and the slow progression of the disease. Novel promising biomarkers are under study and should be evaluated as surrogate endpoints in clinical trials.