JCI Insight

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...

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...

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...

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...

Sjogrens disease (SjD) is a chronic autoimmune disorder characterized by inflammation of the exocrine glands, leading to dry mouth and dry eyes. This study investigates the role of interleukin-9 (IL-9) and T helper 9 (Th9) cells in the pathogenesis of SjD. We found that serum IL-9 levels were significantly elevated in SjD patients and correlated with clinical laboratory parameters, including autoantibody production. In a mouse model of SjD, IL-9 and Th9-associated cytokines were also elevated, a...

ObjectivesTo investigate genetic architecture and identify novel risk loci shared between juvenile idiopathic arthritis (JIA) and other human leukocyte antigen (HLA)-associated autoimmune diseases (AIDs) by leveraging genome-wide association studies (GWAS) data. MethodsWe analyzed GWAS summary statistics from over two million participants (123,997 cases and 1,843,249 controls) of European ancestry across multiple AIDs including JIA, autoimmune thyroid disease (AITD), celiac disease, inflammator...

In this study, we provide a comprehensive characterization of the alveolar immune landscape in patients suffering from severe acute respiratory failure, predominantly caused by pneumonia or acute respiratory distress syndrome, conditions defined by intense pulmonary inflammation and immune dysregulation. Despite diverse underlying causes, the overall composition of alveolar immune cells was largely consistent, with neutrophils and macrophages comprising the majority of cells. However, the matura...

Individuals who have serum elevations of anti-cyclic citrullinated protein (anti-CCP) antibodies are at risk for developing rheumatoid arthritis (RA), yet immunologic factors that lead to a transition from pre- to clinical RA remain unclear. Here, we used materials from anti-CCP antibody-positive individuals enrolled in a clinical trial that evaluated the efficacy of hydroxychloroquine to prevent clinical RA, and performed multi-modal single-cell profiling (transcriptome, surface proteins, T/B-c...

Autoantibody internalization has been implicated in autoimmune disease pathogenesis, yet its mechanisms, and generality across different diseases, cell types, and affected tissues remain poorly defined. Using bulk RNA sequencing, we identified reproducible, autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction in muscle biopsies from patients with anti-Mi2 dermatomyositis and anti-PM/Scl scleromyositis across independent cohorts. Electroporation of purified pati...

BackgroundInfluenza vaccination and bacterial colonization both shape immunity in the respiratory tract, yet their combined impact on the human lung mucosa remains poorly understood. Secondary bacterial pneumonia following influenza infection is a leading cause of mortality, underscoring the need to define how vaccines and microbes intersect at the airway interface. MethodsUsing the Experimental Human Pneumococcal Challenge (EHPC) model, we examined how intramuscular inactivated (TIV) and nasal...

Ethiopian cutaneous leishmaniasis (CL) shows remarkably heterogeneous clinical presentations, but the underlying immunopathological mechanisms driving this heterogeneity in disease presentation remains poorly understood. To characterise the local immune response in Ethiopian CL, we performed spatial transcriptomics on paired lesional and non-lesional skin punch biopsies from five Ethiopian CL patients. We used reference-free deconvolution, morphology-guided regional analyses, and immunohistochem...

ObjectivesCardiovascular risk excess in rheumatoid arthritis (RA) cannot be explained by traditional risk factors alone. Recent experimental data have identified ALDH4A1 as a mitochondrial self-antigen implicated in atherosclerosis, yet its clinical significance in human autoimmunity remains unexplored. We aimed to characterize ALDH4A1 and anti-ALDH4A1 antibody levels in early RA, and evaluate their associations with atherosclerosis burden and lipoprotein traits. MethodsALDH4A1 and anti-ALDH4A1...

ObjectivesBehcets disease (BD) is a multisystem inflammatory disorder with diverse phenotypes and incompletely defined immune mechanisms. This study aimed to map immune dysregulation in BD at high resolution, comparing active versus remission states and identifying pathways linked to clinical phenotypes. MethodsWe performed single-cell RNA sequencing on 247,028 peripheral blood mononuclear cells (PBMCs) from 34 BD patients and 12 healthy controls. Transcriptomic profiling, differential gene exp...

BackgroundHuge neutrophilic infiltrates within lesional and perilesional tissue in hidradenitis suppurativa (HS) give rise to the hypothesis that neutrophil extracellular trap (NET) formation may further drive systemic immune activation in HS. As intrinsic constituents of NETs, nucleosomes-particularly circulating nucleosome containing Histone H3.1 (H3.1-nucleosomes)-serve as reliable indicators of NETosis in the blood. ObjectivesTo investigate whether plasma H3.1-nucleosomes, fluctuate with HS...

Acute respiratory failure causes millions of deaths worldwide each year, highlighting the need for a better understanding of its pathophysiology and approaches to identify treatment-responsive subphenotypes of patients. Although subphenotypes of acute respiratory failure have been described using peripheral blood biomarkers, it remains unclear whether lung-specific molecular profiles can define biologically and clinically meaningful subphenotypes. In this study, we identified four distinct subph...

Fanconi anemia (FA) is an inherited disorder classically characterized by childhood-onset bone marrow dysfunction and lifelong cancer predisposition. FA is caused by pathogenic variants in any one of 23 genes identified so far. Of these, FANCA is the most frequently mutated and accounts for disease in two-thirds of all patients with FA. The spectrum of FANCA pathogenic variants (mutations) is broad, and genotype-phenotype correlation is often unclear. Here we describe the natural history of cyto...

Vitiligo is an autoimmune disorder characterized by melanocyte destruction. We performed a rank-based meta-analysis of six independent transcriptomic studies (115 samples) spanning microarray, bulk and single-cell RNA-seq platforms to identify consensus signatures of lesional skin. Robust Rank Aggregation identified 114 differentially expressed genes (FDR < 0.05) with striking asymmetry: 108 downregulated versus 6 upregulated. Downregulated genes were dominated by melanocyte markers (MLANA, TYR...

BK polyomavirus (BKPyV) is a major complication in kidney transplant recipients (KTR), for whom no specific antiviral therapy is available. Modulation of immunosuppressive therapy results in virus clearance in most KTR with BKPyV DNAemia (controllers), but a significant minority fail to clear the virus (non-controllers). Here, we adapt LIBRA-seq, which links antibody sequence data to antigen specificity, to intact viral capsids of the four BKPyV genotypes to study and compare BKPyV-specific B-ce...

Allogeneic hematopoietic cell transplantation (allo-HCT) hinges on a delicate trade-off between graft-versus-tumor control and graft-versus-host disease (GvHD), mediated by donor T-cell recognition of antigens presented by recipient human leukocyte antigen (HLA) molecules. We hypothesized that, beyond allele-level matching, sequence divergence at peptide-binding grooves across donor and recipient HLA loci shapes these responses. To this end, we evaluated the effect of HLA evolutionary divergence...