Elderly-onset rheumatoid arthritis (EORA), defined as onset at ≥60 years, is a clinically distinct and increasingly prevalent subset of rheumatoid arthritis (RA). This review synthesizes evidence that EORA is not merely late-onset RA but a pathogenically unique entity, driven by immune aging, inflammaging, and other mechanisms like defective immunosuppressive system, age-related somatic mosaicism, and dysbiosis. It frequently presents with heterogeneous features such as acute large-joint involvement and polymyalgia symptoms, often leading to diagnostic delays. Despite similar initial activity to young-onset RA, EORA follows a more aggressive course with severe joint destruction and significant comorbidities. Treatment with conventional disease-modifying antirheumatic drugs is complicated by polypharmacy and high adverse event risks, often leading to undertreatment. A shift to geriatric-centered care, with comprehensive assessment and tailored treat-to-target strategies, is therefore imperative. This review underscores the need to recognize EORA's unique pathophysiology and clinical profile to improve diagnosis, therapy, and outcomes for this growing population.

Compared with anti-citrullinated protein autoantibody (ACPA)-positive RA, the etiology of ACPA-negative RA remains unclear, posing significant challenges to diagnosis. Recently, evidence has emerged that ACPA-negative RA is characterized by metabolic reprogramming, as well as dysregulated lipid metabolism. The remnant cholesterol inflammation index (RCII) is a comprehensive index of lipid burden and inflammation; this study evaluated the predictive value of RCII as a novel biomarker for ACPA-negative RA. In the Beijing Hospital (BJH) cohort, we first compared RCII across various autoimmune diseases and undifferentiated inflammatory arthritis versus healthy controls (HCs). Subsequently, we assessed the independent association between RCII and ACPA-negative RA in the BJH cohort and UK Biobank (UKB) cohort using multivariable logistic regression, adjusting for confounders including age, sex, BMI, and cardiovascular comorbidities. Diagnostic performance was evaluated via receiver operating characteristic (ROC) analysis, and optimal diagnostic RCII intervals were defined using a stratified 5-fold cross-validation framework. Furthermore, the possible underlying mechanisms were investigated using untargeted serum lipidomics in a matched subset. In the BJH cohort, RCII levels were significantly elevated in ACPA-negative RA, ACPA-positive RA, undifferentiated inflammatory arthritis, dermatomyositis, and systemic lupus erythematosus compared with HCs, with the highest levels observed in ACPA-negative RA. Dual-cohort analysis confirmed elevated RCII in ACPA-negative RA, with independent associations (BJH: OR = 26.11; UKB: OR = 5.59) even after adjusting for age, sex, BMI, and cardiovascular disease (CVD). In the ROC analysis, RCII demonstrated relatively high diagnostic accuracy, achieving an area under the curve (AUC) of 0.929 in the BJH cohort and 0.785 in the UKB cohort. Cross-validation established stable diagnostic intervals, effectively minimizing the indeterminate decision zone, or “gray zone” to less than 10

OBJECTIVE:Systemic lupus erythematosus (SLE) is a complex autoimmune disease driven by neutrophil dysregulation and neutrophil extracellular trap (NET) formation, with unmet therapeutic needs. This study aimed to investigate the therapeutic potential of protein kinase CK2 inhibitor CX-4945 in SLE as well as to elucidate the underlying mechanisms. METHODS:CX-4945 was administered to multiple murine models, including MRL/lpr mice, imiquimod (IMQ)-induced lupus model, IMQ-induced psoriasis model, and cecal ligation and puncture-induced sepsis model. Renal function, histopathological changes, immune complex deposition, NET formation, and inflammatory cytokine levels were evaluated. RESULTS:CX-4945 significantly ameliorated renal damage in MRL/lpr and IMQ-induced lupus models, as evidenced by reduced urinary albumin-to-creatinine ratio, glomerular abnormalities, immune complex/complement C3 deposition, and neutrophil infiltration. The neutrophils from patients with SLE exhibited elevated CK2α expression and enzyme activity. Mechanistically, CX-4945 suppressed interferon-stimulated genes and reactive oxygen species-related pathways, induced mitochondrial metabolic rewiring, inhibited JNK/p38 MAPK phosphorylation, and modified NET protein composition to abrogate macrophage proinflammatory responses. CONCLUSION:CK2α is aberrantly up-regulated in SLE neutrophils, and targeting CK2 with CX-4945 exerts therapeutic effects in SLE. These findings identify CK2 as a novel therapeutic target for SLE and support the repurposing of CX-4945 for treating neutrophil-driven inflammatory and autoimmune diseases.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic joint inflammation and systemic immune dysregulation. Emerging evidence suggests that the gut microbiome plays an important role in immune modulation in RA, yet the role of the gut virome remains poorly understood. Here, using the K/BxN serum-transfer arthritis model, we systematically evaluated the potential role of fecal virome transplantation (FVT) in modulating gut ecology and innate inflammatory responses. Arthritic mice exhibited marked alterations in gut virome composition compared with healthy controls. Administration of purified virus-like particles (VLPs) from healthy donors correlated with reductions in paw swelling, histopathological inflammation, bone erosion, circulating proinflammatory cytokines, and myeloid cell infiltration in inflamed tissues. In parallel, 16S rRNA sequencing showed that FVT remodeled the gut bacterial community toward a composition more similar to that of healthy controls. Targeted serum metabolomics revealed increased levels of microbiota-derived tryptophan metabolites, including indole-3-lactic acid and related indole derivatives, suggesting a link between gut microbial remodeling and systemic immunometabolic regulation. Collectively, these findings indicate that FVT may attenuate inflammatory arthritis by remodeling gut microbial ecology, potentially involving virome-bacteriome interactions and immunometabolic pathways.

Systemic lupus erythematosus (SLE) is characterized by dysregulated immune responses. Paeoniflorin (PF), a highly purified monoterpene glycoside derived from Paeonia lactiflora, exhibits immunomodulatory activity, but its mechanisms in SLE remain unclear. This study investigated whether PF ameliorates SLE by modulating the gut microbiota–lipid metabolite axis and restoring Th17/Treg immune balance. Network pharmacology was applied to predict PF-related targets and pathways in SLE. MRL/lpr mice were treated with PF, and disease severity was assessed by clinical manifestations, autoantibody levels, renal function, and histopathology. Intestinal barrier integrity and motility were evaluated in vivo. Th17 and Treg cell populations in intestinal and peripheral immune tissues were analyzed by flow cytometry. Gut microbiota composition was profiled using 16S rRNA gene sequencing, and untargeted LC–MS/MS–based metabolomics of intestinal contents was performed to identify differential metabolites and enriched metabolic pathways. PF treatment significantly alleviated lupus-like manifestations in MRL/lpr mice, including reduced splenomegaly and lymphadenopathy, decreased serum anti-dsDNA, ANA, total IgG, and IL-17 levels, and improved renal function and histopathological injury. PF restored Th17/Treg balance by suppressing IL-17–producing CD4⁺ T cells and promoting Foxp3⁺ Treg cells across intestinal and peripheral immune compartments. PF also improved intestinal barrier integrity and reshaped gut microbial composition by reducing inflammation-associated taxa and enriching beneficial bacteria. Metabolomic analysis demonstrated that PF markedly downregulated glycerophospholipid metabolism, particularly reducing lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC), which have been reported to promote RORγt activity and Th17 differentiation. Correlation analyses linked microbial alterations with lipid metabolite changes and Th17/Treg-associated immune parameters. Paeoniflorin alleviates SLE by regulating a gut microbiota–lipid metabolite–immune axis, suppressing pro-Th17 lysophospholipid metabolism and restoring Th17/Treg immune homeostasis.

Despite the success of targeted therapies in rheumatoid arthritis, the lack of predictive biomarkers of response leads to an empirical treatment approach, often delaying effective intervention due to non-response to the initially selected individualized medication regimens in approximately 40% of patients. Cellular and molecular deconvolution of synovial tissue heterogeneity reveals discrete disease phenotypes, enabling disease stratification and response prediction. Recent advances in single-cell RNA sequencing and mass cytometry have defined more refined synovial molecular signatures and cell-type abundance phenotypes, uncovering novel pathogenic cellular subsets and inflammatory crosstalk networks. These insights hold profound implications for treatment response prediction and novel target development. While progress is notable, the field remains in its infancy. The integration of synovial multi-omics with multi-modal arrays of clinical data using artificial intelligence holds promise for developing clinically actionable algorithms. Accordingly, innovative pathology-informed clinical trials are likely to be increasingly adopted, paving the way toward more precise and individualized therapy within a precision medicine framework.

Henoch-Schönlein purpura (HSP) is an inflammatory condition affecting the small blood vessels, leading to organ damage and symptoms across various body systems, including skin, joints, and kidneys. The disease's pathogenesis involves the deposition of immunoglobulin (Ig) A immune complexes in vessels, triggering inflammation and damage. Recent research highlights the role of T follicular helper cells (Tfh cells) in HSP. The review delves into Tfh cells' biological functions, emphasizing their involvement in the HSP's development by activating autoreactive B cells and inducing the production of autoantibodies through the secretion of interleukin (IL)-21, IL-4, and IL-6. Additionally, the roles of different Tfh cell subsets in the pathogenesis of HSP are also characterized by their unique features. We also highlight the relationship between Tfh cells and galactose-deficient IgA1 (Gd-IgA1) production, compare Tfh-mediated immune responses in HSP with those in IgA nephropathy (IgAN) and systemic lupus erythematosus (SLE), and discuss emerging therapeutic strategies targeting the Tfh-B-cell axis. It concludes by suggesting the need for further research on Tfh cells to understand HSP pathogenesis better and develop effective treatments.

Abstract Introduction In systemic lupus erythematosus (SLE), aberrant B cell activation is fueled by elevated oxidative phosphorylation (OXPHOS), yet checkpoints restraining this metabolic hyperactivity remain undefined. We identify mitochondrial carrier homolog 2 (MTCH2),as a critical metabolic gatekeeper that limits OXPHOS-driven autoreactive B cell expansion and maintains germinal center (GC) tolerance in autoimmunity. Methods We analyzed metabolic profiles of B cells from SLE patients and healthy controls using scRNA-seq. B cell-specific MTCH2-deficient mice (Mb1-Cre; Mtch2fl/fl) were subjected to pristane-induced lupus. GC responses, BCR repertoire, and somatic hypermutation (SHM) were assessed by flow cytometry, and BCR sequencing. Mechanistic studies employed immunoprecipitation and GTPase activity to define the MTCH2—FUNDC2 axis, and a high-throughput screen identified a pharmacological agonist. Results B cells from SLE patients exhibited an OXPHOS signature and concomitantly downregulated MTCH2. B cell-specific MTCH2 deletion in mice exacerbated lupus, with expanded GCs, elevated autoantibodies. Sc-metabolic profiling revealed profound metabolic reprogramming across B cell subsets, with dark-zone GC B cells exhibiting the highest OXPHOS activity. This metabolic rewiring skewed the BCR, promoting the clonal expansion of autoreactive cells with excessive SHM. Mechanistically, MTCH2 governed mitochondrial dynamics via the FUNDC2—MFN1/2 axis which led to dysregulated mitochondrial fusion and B cell activation threshold. Pharmacological upregulation of MTCH2 by agonist restored mitochondrial homeostasis and ameliorated lupus in vivo. Conclusion We establish MTCH2 as a pivotal metabolic checkpoint that restrains autoreactive B cell expansion. Loss of MTCH2 disrupts GC tolerance, driving clonal dominance of autoreactive B cells and accelerating systemic autoimmunity. Targeting the MTCH2 axis represents a clinically translatable strategy to reinstate metabolic control and restore immune tolerance in SLE. Funding Source National Natural Science Foundation of China ( 82230060, 32141004, 32430036, 32441093) Topic Categories Basic Autoimmunity (BA)

Objective The shared and disease‐specific mechanisms across the immune‐mediated inflammatory diseases (IMIDs) spectrum remains incompletely characterized, despite the recognized role of autoantibodies as important indicators of immune tolerance breakdown and immune dysregulation. Methods Autoantibody reactome profiling of IgG and IgA autoantibodies was performed across eight IMIDs to delineate both shared and disease‐specific autoantibodies using autoantigen microarray. Results Widespread autoantibody signatures were observed, and 384 and 69 IgG and IgA autoantibodies were identified in IMID, predominantly targeting proteins involved in cytokine signaling and T cell‐related pathways. Notably, most IMIDs have the common pathways of cell apoptosis and proliferation, and each IMID has its unique pathways. The identified autoantibody signatures achieved area under the curve values of 0.6 to 1.0 for individual IMIDs and 0.996 for all IMIDs compared with healthy controls. The autoantibodies against SULF1 and HDAC3 were further validated in an independent rheumatoid arthritis cohort, and the overexpression of these two autoantigens was detected at the transcriptomic and protein levels. Conclusion These findings provide an exploratory autoantibody‐based resource for IMID and identify candidate signatures that may inform future studies of disease stratification, diagnostic refinement, and mechanistic investigation. Nevertheless, owing to the relatively small sample sizes for each disease subgroup, the observed predictive performances should be regarded as preliminary, necessitating further verification in larger independent patient cohorts.

This study aimed to develop and validate a biomarker-based prediction model for assessing the individual risk of coronary artery lesions (CAL) in Kawasaki disease (KD). A retrospective analysis was performed on 345 pediatric KD patients admitted between June 2018 and June 2022. Patients were randomly divided into training (n = 241) and validation (n = 104) sets. Univariate analysis identified candidate predictors, and Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for feature selection. Multivariable logistic regression and machine learning models—random forest (RF), support vector machine, and k-nearest neighbors—were developed. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis. A nomogram was constructed, and SHapley Additive exPlanations (SHAP) values were applied to interpret feature contributions. Seven biomarkers were significantly associated with CAL in univariate analysis (P < 0.05). LASSO and multivariable logistic regression analysis identified age, N-terminal pro-B-type natriuretic peptide, interleukin-6, calprotectin, endothelial microparticles, Matrix Metalloproteinase-9, and Galectin-3 as independent predictors. The RF model demonstrated superior performance, with AUCs of 0.888 (training) and 0.860 (validation). SHAP analysis confirmed these three variables as the top contributors to CAL prediction. The nomogram exhibited strong calibration and clinical utility. The machine learning-based prediction model incorporating novel biomarkers enables individualized risk assessment for CAL development in KD patients. This model exhibits excellent predictive performance and clinical applicability, facilitating early identification of high-risk patients and the implementation of targeted interventions, thereby optimizing healthcare resource allocation and improving long-term cardiovascular outcomes.

Current therapies for autoimmune diseases largely rely on broad-spectrum immunosuppressants and biologics, which indiscriminately deplete T or B cells. These approaches are largely constrained by systemic immunosuppression and off-target toxicities. Achieving durable, antigen-specific immune tolerance while preserving protective immunity against pathogens remains a long-standing goal in clinical practice. Here, we present a modular red blood cell (RBC)-based platform that induces antigen-specific tolerance through strain-promoted azide-alkyne cycloaddition (SPAAC)-mediated surface conjugation of disease-relevant peptides. We demonstrated that RBCs engineered by such approach retain their biophysical integrity and biocompatibility across a broad range of conjugation concentrations in vitro. Critically, when conjugated with single or multiple autoantigenic epitopes, these engineered RBCs elicited robust antigen-specific tolerance and drove durable disease remission in two well-established preclinical models, experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). Further mechanistic investigations revealed that the engineered RBCs reprogram antigen-presenting cells (APCs) toward a tolerogenic phenotype. This reprogramming, in turn, induces anergy in autoreactive T cells and suppresses the activation of autoreactive B cells. Collectively, this work establishes a versatile and clinically translatable platform, offering a path toward personalized, antigen-specific therapy for autoimmune diseases.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, whose progression is intimately linked to the complex dynamics of the tumor microenvironment (TME). Exosomes, once considered mere cellular waste, have emerged as pivotal mediators of intercellular communication within the TME, actively participating in the multistep development of HCC. These nanoscale vesicles play crucial roles in the initiation of precancerous lesions and, by transporting drug resistance-related molecules such as proteins and non-coding RNAs, facilitate the acquisition of resistance to chemotherapy and targeted therapies by tumor cells. Moreover, exosomes contribute to the establishment of pre-metastatic niches by remodeling distant organ microenvironments—inducing hypoxia, metabolic reprogramming, and angiogenesis—which collectively create favorable conditions for tumor cell colonization. They also modulate immune responses by inducing T-cell exhaustion, promoting macrophage polarization, and disrupting normal stromal cell functions, thereby constructing an immunosuppressive microenvironment that enables tumor immune evasion. Given their inherent biocompatibility and targeting capabilities, engineered exosomes have shown promise in cancer therapy, serving as carriers for therapeutic molecules and enabling precise drug delivery through surface modifications. Despite significant advancements, challenges remain in elucidating the in vivo regulatory mechanisms of exosomes, standardizing their isolation and purification processes, and evaluating their clinical efficacy. This review examines the multifaceted roles of exosomes in HCC, aiming to bridge mechanistic insights with precision diagnostics and pave new avenues for liver cancer treatment.

OBJECTIVES:Immune thrombocytopenia (ITP) is a haematological manifestation secondary to connective tissue disease (CTD). Many patients with CTD-ITP are refractory to glucocorticoids (GCs) plus immunosuppressant agents (ISAs); rituximab (RTX) is the recommended second-line therapy. Belimumab (BLM) shows efficacy against CTD. We compared the efficacy and safety of RTX and BLM. METHODS:Data of patients with CTD-ITP refractory to GCs plus ISAs administered were collected. The data of 11 patients with refractory CTD-ITP who received BLM were compared with those of 15 patients treated with RTX. RESULTS:At week 2, BLM resulted in a better overall response (OR) than RTX (72.7% vs 26.7%, p=0.045). The OR rate was 60.0% (9/15), 66.7% (10/15) and 73.3% (11/15) at week 4, 8 and 12, respectively, in the RTX group. It remained at 72.7% (8/11) during week 4-12 in the BLM group. Excluding the data of three deceased patients, the OR rate dropped at week 24 in both groups (RTX vs BLM, 61.5% (8/13) vs 70.0% (7/10), p=1.000). At week 24, four patients with OR in both groups successfully withdrew GCs to <15 mg prednisone (RTX vs BLM, 40% (4/10) vs 66.7% (4/6), p=0.608). The serum C3 level did not significantly change, whereas the serum immunoglobulin G level significantly decreased at week 4, 8 and 12 in both groups. There were three patients with serious adverse effects who died of severe pneumonia during weeks 12-24. CONCLUSIONS:BLM may be a safe and effective alternative to RTX for CTD-ITP refractory to GCs plus ISAs.

OBJECTIVES:There is continuous need to identify novel biomarkers that can provide early and accurate diagnosis of systemic lupus erythematosus (SLE) due to its highly heterogenous nature and lack of specific clinical manifestations. METHODS:A total of 316 subjects comprising 127 patients with SLE, 129 patients with other autoimmune diseases as disease controls (DCs) and 60 healthy controls (HCs) were enrolled to determine the clinical relevance of the surface expression levels of CD169 on monocytes, CD317 on B cells and CD177 on neutrophils by flow cytometry for the diagnosis of SLE. RESULTS:The flow cytometric assay based on the combination of three molecules displayed a favorable diagnostic performance with an area under curve (AUC) of 0.9243. The sensitivities and specificities for this assay were 79.2 % and 96.2 % in the training cohort, and 82.1 % and 97.3 % in the validation cohort, respectively. Importantly, the diagnostic performance of this assay was independent of anti-double stranded DNA (dsDNA) antibodies with an AUC of 0.9329. The clinical performance of this assay was validated in an independent test cohort with a sensitivity and a specificity of 88.9 % and 95.9 %, respectively. CONCLUSION:Our findings may have important clinical relevance in the diagnosis of SLE, especially when the suspects were tested negative for anti-dsDNA antibodies. Our study may shed light on a new direction other than detection of autoantibodies for the diagnosis of SLE in clinical settings.

Much remains unknown regarding T follicular helper 17 (T(FH)17) cells commonly found in autoimmune patients. We previously showed that (and here ask why) egress of gut segmented filamentous bacteria (SFB)-induced T-FH cells from Peyer's patches (PP) to systemic sites promotes arthritis. We found splenic T(FH)17 cells are gut derived. Functional analyses using fate-mapping mice revealed a c-Maf-dependent and SFB-induced T(H)17-to-T-FH cell reprogramming that dominantly occurs in PPs. Unlike conventional T-FH cells, T(H)17-derived T-FH cells are highly migratory and atypically concentrated in the dark zone of germinal centers (GCs). Compared to conventional T-FH cells, T(H)17-derived T-FH cells express higher levels of T-FH-associated functional molecules and more robustly conjugate with B cells. Gain- and loss-of-function studies demonstrated their dominance in promoting GC B cells and arthritis. Notably, murine gut T(H)17-derived T-FH signatures exist in rheumatoid arthritis patients. Thus, gut T cell plasticity generates atypical, potent T-FH cells promoting systemic autoimmunity.

BACKGROUND:Globally, atopic dermatitis (AD) is highly prevalent; however, there is a paucity of research focusing on its burden and trends. OBJECTIVE:To understand the current epidemic situation of AD and to suggest measures that may help reduce its global burden. METHODS:Global trends of AD, including prevalence, incidence, and disability-adjusted life-years, were analyzed using data from the Global Burden of Disease Study database 2021. RESULTS:In 2021, the global prevalence of AD reached 129 million cases, reflecting a 20% increase since 1990. However, the age-standardized prevalence rate decreased slightly during the same period, measuring 1728.5 per 100,000 individuals in 2021. The highest burden of AD was observed in high-income regions, with a notable prevalence among females and children under 5 years of age. However, the burden decreased across all sociodemographic index regions, with the most significant decline in high sociodemographic index countries. Regionally, South Asia reported the highest prevalence, while globally, India, China, and the United States exhibited the highest number of cases. LIMITATIONS:Variations in data sources and quality, and the absence of data regarding severity and environmental factors. CONCLUSION:The global burden of AD prevalence was highest in high-income countries and among females and young children.

Metabolic reprogramming is important in primary biliary cholangitis (PBC) development. However, studies investigating the metabolic signature within the liver of PBC patients are limited. In this study, liver biopsies from 31 PBC patients and 15 healthy controls were collected, and comprehensive metabolomics, lipidomics, and proteomics analysis were conducted to characterize the metabolic landscape in PBC. We observed distinct lipidome remodeling in PBC with increased polyunsaturated fatty acid levels and augmented fatty acid β-oxidation (FAO), evidenced by the increased acylcarnitine levels and upregulated expression of proteins involved in FAO. Notably, PBC patients exhibited an increase in glucose-6-phosphate (G6P) and purines, alongside a reduction in pyruvate, suggesting impaired glycolysis and increased purines biosynthesis in PBC. Additionally, the accumulation of bile acids as well as a decrease in branched chain amino acids and aromatic amino acids were observed in PBC liver. We also observed an aberrant upregulation of proteins associated with ductular reaction, apoptosis, and autophagy. In conclusion, our study highlighted substantial metabolic reprogramming in glycolysis, fatty acid metabolism, and purine biosynthesis, coupled with aberrant upregulation of proteins associated with apoptosis and autophagy in PBC patients. Targeting the specific metabolic reprogramming may offer potential targets for the therapeutic intervention of PBC.