JCI Insight

CD4+ T cell plasticity plays a pivotal role in immune homeostasis. However, evidence of T cell plasticity and its pathological role in human systemic lupus erythematosus (SLE) is missing due to the lack of a reporter system. Here we utilized T cell receptor (TCR) repertoire data as a molecular signatures alongside transcriptomic dataset. Using a large-scale ImmuNexUT database of autoimmune disease patients including 117 SLE cases, we quantified T cell plasticity across 13 fine-grained T cell-typ...

Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in lupus granulocytes over 4 years of follow up and across disease activity levels using 229 patient samples. We demonstrate that DNA methylation profiles in lupus are influenced by ancestry-specific genetic variants and are highly stable over time. DNA methylation levels in two CpG sites correlated significantly with changes in lupus disease activity. Pr...

Hypertension, vascular inflammation and renal inflammation are characteristic of systemic lupus erythematosus (SLE), a multisystem autoimmune disease that is complex and poorly understood. Oxidation products of arachidonic and other fatty acids, termed isolevuglandins (isoLG) lead to formation of post-translational protein modifications that are immunogenic. We demonstrate isoLG enrichment in dendritic cells (DCs), B cells, and plasma cells from juvenile female B6.SLE123 mice. In adult B6.SLE123...

GlycoRNA, newly identified RNA molecules bearing glycan modifications on cell membranes, is implicated in cell communication and immune regulation. However, current technological limitations impede a thorough elucidation of their biological roles and clinical significance. Here, we developed Nucleotides Hybridization and Aptamer-based Proximity Ligation (NHAPL), a homogeneous assay enabling sensitive and quantitative glycoRNA analysis from 160pg total cell RNA and 1{micro}l serum. NHAPL integrat...

Morphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. We first characterized which cells produce the CXCR3 lig...

Women with Systemic Lupus Erythematosus (SLE) show significantly increased cardiovascular risk compared to the general population. However, despite CVD being a major cause of morbidity and mortality for these women, this increased risk is not managed clinically and tools to dissect and predict their cardiovascular risk are lacking. Notably, this elevated CVD risk is not captured by traditional risk factors. To explore molecular programs underlying asymptomatic atherosclerosis in SLE we used a we...

BackgroundTissue inflammation is associated with organ dysfunction and death in Covid-19. The efficacy of dexamethasone in preventing mortality in critical Covid-19 suggests that inflammation has a causal role in death. Whether this deleterious inflammation is a direct response to the presence of SARS-CoV-2, or an independent immuno-pathologic process, is unknown. MethodsTissue was acquired from detailed post-mortem examinations conducted on 11 well characterised hospitalised patients with fata...

In the general human population, aging is associated with a rise in systemic inflammation, primarily involving innate immune pathways related to interferon (IFN), toll-like receptor, and cytokine signaling. In systemic lupus erythematosus (SLE), a prototypical systemic autoimmune disease, aging is distinctly associated with improvements in disease activity, suggesting a unique relationship between aging and inflammation in this disease. Using a multi-omic approach incorporating transcriptional p...

Genome-wide association studies have identified genetic polymorphisms at 11p15 associated with Systemic Lupus Erythematosus (lupus). Statistical fine mapping prioritizes a highly prevalent coding haplotype within the IRF7 gene. Analysis of ancient DNA confirms that this haplotype has persisted at high frequencies in the global population for millennia. The IRF7 risk haplotype is sufficient to increase nuclear localization of IRF7 and transcriptional activity downstream of pattern recognition rec...

ObjectiveSystemic lupus erythematosus (SLE) is characterized by persistent type I interferon (IFN) signaling and adaptive immune dysregulation. We previously identified hypomethylation of HLA-DRB1 and STAT1 in SLE CD8+ T cells, enabling aberrant IFN-driven HLA-DRB1 expression and expansion of a distinct CD8+ T cell subset. This study aimed to comprehensively characterize CD8+ HLA-DRB1+ T cells in lupus. MethodsPeripheral blood CD8+ T cells from SLE patients and healthy controls were analyzed by...

What is already known on this topic O_LIAconitate Decarboxylase 1 (ACOD1) is an enzyme involved in the synthesis of itaconate, a metabolite generated during the Krebs cycle. C_LIO_LIItaconate has been identified as an immunomodulatory molecule C_LIO_LIACOD1/Itaconate has been studied in the context of various inflammatory and autoimmune diseases, including sepsis, inflammatory bowel disease and rheumatoid arthritis. In these conditions, dysregulation of itaconate metabolism has been associated ...

Systemic Lupus Erythematous (SLE) is a chronic autoimmune disorder, broadly characterized by systemic inflammation along with heterogeneous clinical manifestations, severe morbidity, moribund organ failure and eventual mortality. In our study, SLE patients displayed higher percentage of activated, inflamed and hyper polarized CD8+ T cells, dysregulated CD8+ T cell differentiation, significantly elevated serum inflammatory cytokines, higher accumulation of cellular ROS when compared to healthy co...

Gene expression signatures can stratify patients with heterogeneous diseases, such as Systemic Lupus Erythematosus (SLE), yet understanding the contributions of ancestral background to this heterogeneity is not well elucidated. We hypothesized that ancestry would significantly influence gene expression signatures and measured 34 gene modules in 1566 SLE patients of african (AA), european (EA) or native american (NAA) ancestry to determine the impact of ancestry on gene expression. Healthy subjec...

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by autoantibodies to nuclear antigens. SLE is highly heterogeneous, both clinically and immunologically, yet the molecular basis underlying this remains incompletely understood. To address this, we profiled the plasma proteome in 260 SLE patients and 86 healthy volunteers (HVs) using the SomaScan v4.1 platform, quantifying 7,288 analytes corresponding to 6,595 unique proteins. We identified 215 proteins that were r...

Systemic autoimmune rheumatic diseases (SARDs) are a heterogeneous group of autoimmune conditions characterized by immune system dysregulation leading to chronic inflammation and tissue damage. The overlapping clinical manifestations make differential diagnosis challenging, highlighting the need for novel biomarkers to facilitate early diagnosis, stratification, and personalized treatment. Five SARDs including idiopathic inflammatory myopathies (n=210), rheumatoid arthritis (n=84), systemic scle...

ObjectiveSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells, essential for immune surveillance, exhibit profound dysfunction in SLE, including impaired cytotoxicity and cytokine production. However, the mechanisms underlying these abnormalities remain poorly understood. This study investigates how the accumulation of dysfunctional mitochondria due to defective mitophagy contributes to NK ...

Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), has both a heterogeneous clinical and pathological presentation. For example, proliferative nephritis identifies a more aggressive disease class that requires immunosuppression. However, the current classification system relies on the static appearance of histopathological morphology which does not capture differences in the inflammatory response. Therefore, a biomarker grounded in the disease biology ...

Pulmonary arterial hypertension (PAH) is a serious complication of systemic lupus erythematosus (SLE) with increased mortality. A prothrombotic state may contribute to pathogenesis of SLE-PAH. Microvesicles (MVs) are known to be associated with thrombosis. Here, we investigated circulating MVs and their associations with SLE-PAH. Eighteen SLE-PAH patients, 36 SLE-non-PAH patients, and 36 healthy controls (HCs) were enrolled. Flow cytometry was used to analyze circulating MVs from leukocytes (LMV...

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies raised against nuclear antigens and whose production is promoted by autoreactive T follicular helper (TFH) cells. Basophils, by accumulating in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms to be defined. Here, we demonstrate that a functional relationship between TFH cells and basophils occurs in SLO during lupus pathogenesis. On SLE patient b...

ObjectiveAutoimmune diseases (ADs) markedly elevate venous thromboembolism (VTE) risk, yet the shared genetic architecture and tissue-specific regulatory mechanisms of this "Autoimmune-Thrombotic Axis" remain poorly defined. We aimed to characterize the genomic landscape of immunothrombosis to identify causal links and therapeutic targets. Approach and ResultsWe integrated large-scale GWAS data for VTE and 16 ADs using a multi-omics framework, including pleiotropy scanning, local genetic correl...