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Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5 + DM) is an autoimmune condition associated with rapidly progressive interstitial lung disease and high mortality. The aetiology and pathogenesis of MDA5 + DM are still largely unknown. Here we describe the immune signatures of MDA5 + DM via single-cell RNA sequencing, flow cytometry and multiplex immunohistochemistry in peripheral B and T cells and in affected lung tissue samples from one patient. We find strong peripheral antibody-secreting cell and CD8 + T cell responses as cellular immune hallmarks, and over-stimulated type I interferon signaling and associated metabolic reprogramming as molecular immune signature in MDA5 + DM. High frequency of circulating ISG15 + CD8 + T cells at baseline predicts poor one-year survival in MDA5 + DM patients. In affected lungs, we find profuse immune cells infiltration, which likely contributes to the pro-fibrotic response via type I interferon production. The importance of type I interferons in MDA5 + DM pathology is further emphasized by our observation in a retrospective cohort of MDA5 + DM patients that combined calcineurin and Janus kinase inhibitor therapy show superior efficacy to calcineurin inhibitor monotherapy. In summary, this study reveals key immune-pathogenic features of MDA5 + DM and provides a potential basis for future tailored therapies. Anti-melanoma differentiation-associated gene 5-positive dermatomyositis is a severe autoimmune disease with largely unknown aetiology. Here authors identify the key immune cell types that contribute to the disease phenotype and implicate type I interferons signalling in the patho-mechanism.

Abstract The remarkable efficacy of chimeric antigen receptor (CAR) T cell therapy in hematological malignancies has provided a solid basis for the therapeutic concept, wherein specific pathogenic cell populations can be eradicated by means of targeted recognition. During the past few years, CAR-based cell therapies have been extensively investigated in preclinical and clinical research across various non-tumor diseases, with particular emphasis in the treatment of autoimmune diseases (ADs), yielding significant advancements. The recent deployment of CD19-directed CAR T cells has induced long-lasting, drug-free remission in patients with systemic lupus erythematosus (SLE) and other systemic ADs, alongside a more profound immune reconstruction of B cell repertoire compared with conventional immunosuppressive agents and B cell-targeting biologics. Despite the initial success achieved by CAR T cell therapy, it is critical to acknowledge the divergences in its application between cancer and ADs. Through examining recent clinical studies and ongoing research, we highlight the transformative potential of this therapeutic approach in the treatment of SLE, while also addressing the challenges and future directions necessary to enhance the long-term efficacy and safety of CAR-based cell therapies in clinical practice.

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups. The presentation of systemic lupus erythematosus has been known to differ by ancestry, but the underlying genetic factors remain unclear. Here, the authors report ancestry-specific susceptibility loci and better risk prediction when using data from matched ancestral groups.

To investigate the clinical significance of the interferon (IFN) score, especially the IFN-I score, in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (anti-MDA5 DM). We enrolled 262 patients with different autoimmune diseases, including idiopathic inflammatory myopathy, systemic lupus erythematosus, rheumatoid arthritis, adult-onset Still's disease, and Sjögren's syndrome, as well as 58 healthy controls. Multiplex quantitative real-time polymerase chain reaction (RT-qPCR) using four TaqMan probes was used to evaluate type I IFN-stimulated genes (IFI44 and MX1), one type II IFN-stimulated gene (IRF1), and one internal control gene (HRPT1), which were used to determine the IFN-I score. The clinical features and disease activity index were compared between the high and low IFN-I score groups in 61 patients with anti-MDA5+ DM. The associations between laboratory findings and the predictive value of the baseline IFN-I score for mortality were analyzed. The IFN score was significantly higher in patients with anti-MDA5+ DM than in healthy controls. The IFN-I score was positively correlated with the serum IFN-α concentration, ferritin concentration, and Myositis Disease Activity Assessment Visual Analogue Scale (MYOACT) score. Compared with patients with a low IFN-I score, patients with a high IFN-I score showed a higher MYOACT score, C-reactive protein concentration, aspartate transaminase concentration, ferritin concentration, plasma cell percentage, and CD3+ T-cell percentage, as well as lower lymphocyte, natural killer cell, and monocyte counts. The 3-month survival rate was significantly lower in patients with an IFN-I score of >4.9 than in those with an IFN-I score of ≤4.9 (72.9% . 100%, respectively; P = 0.044). The IFN score, especially the IFN-I score, measured by multiplex RT-qPCR is a valuable tool to monitor disease activity and predict mortality in patients with anti-MDA5+ DM.

This study aimed to evaluate the clinical and immunological significance of anti-Ro52/TRIM21 and anti-Ro60/SSA antibodies in rheumatoid arthritis (RA), particularly the association of dual antibody positivity with disease severity, systemic manifestations, and therapeutic resistance. We conducted a cohort study involving 670 RA patients, stratified into four groups according to anti-Ro52 and anti-Ro60 antibody status: Ro52+/Ro60+, Ro52+/Ro60-, Ro52-/Ro60+, and Ro52-/Ro60-. Clinical characteristics, disease activity scores (DAS28-ESR, DAS28-CRP), systemic complications, and treatment responses were compared among groups. Multivariate logistic regression models identified independent predictors of difficult-to-treat RA (D2T-RA). Patients with dual Ro52+/Ro60+ positivity exhibited significantly higher disease activity (median DAS28-ESR: 4.97 . 4.39, p = 0.002), worse functional status (median HAQ-DI: 0.88 . 0.63, p = 0.001), and increased systemic complications, notably interstitial lung disease (OR = 4.14, 95% CI: 1.71-10.68, p = 0.002) and hematologic involvement (OR = 2.50, 95% CI: 1.02-6.19, p = 0.044), compared to antibody-negative patients. Dual antibody positivity independently predicted an increased risk of developing D2T-RA (OR = 4.05, 95% CI: 1.58-11.09, p = 0.004). Conversely, patients with isolated Ro60 positivity exhibited lower IgG levels, fewer systemic complications, and reduced reliance on biological therapies, indicating a less severe disease phenotype. Anti-Ro antibody subtyping effectively identifies distinct clinical and immunological RA subgroups. Patients with isolated Ro60 antibody positivity display a relatively less severe clinical profile compared to those with dual antibody positivity, highlighting the importance of specific antibody profiles in guiding personalized clinical management and therapeutic decision-making.

ObjectiveTo identify the effects of Sirtuin 1 (Sirt1) on gouty arthritis and investigate the underlying mechanisms.MethodsA gouty arthritis model was established by intra-articular injection of monosodium urate (MSU, 1 mg) crystal solution into the left foot pad of C57BL/6 mice. After pretreating the gouty arthritis mice with intra-articular injection of Sirt1 agonist (Resveratrol, RSV, 20 mg/kg) or peroxisome proliferator-activated receptor γ (PPARγ) inhibitor (T0070907, 1 mg/kg), the degree of joint inflammation of the gouty arthritis mice was evaluated by clinical integration of joint inflammation and hematoxylin and eosin (H&E) staining. The mRNA expression of Sirt1 and PPARγ were determined by real-time polymerase chain reaction (PCR). The expression profiling of inflammatory cytokines and chemokines in mouse joint tissues were determined by multi-factor assay kits. Peritoneal macrophages were isolated from mice and tested the effects of RSV and/or PPARγ on pro-inflammatory cytokines secretion by PCR.ResultsSirt1 agonist significantly suppressed the onset of gouty arthritis induced by MSU and reduced the infiltration of inflammatory cells in the joints. Sirt1 agonist significantly promoted the expression of PPARγ, while decreased the expression of interleukin (IL)-1β, IL-1α, IL-6, interferon-γ (IFN-γ), monocyte chemotactic protein 1(MCP-1), tumor necrosis factor a (TNF-α), and chemokines (CXCL-1, CXCL-5, CCL-22) induced by MSU in joint tissues. After blocking PPARγ with T0070907 or by siRNA, the anti-inflammatory effect of Sirt1 agonist on gouty arthritis disappeared and the expression of pro-inflammatory molecules were not significantly reduced.ConclusionsSirt1 may control the acute onset of gouty arthritis in mice by inhibiting the infiltration of inflammatory cells and the secretion of pro-inflammatory molecules through PPARγ.Key Points• Sirt1 and its activator, RSV, attenuate the severity of gouty arthritis in mice.• Sirt1 inhibits the infiltration of inflammatory cells and the secretion of pro-inflammatory molecules in MSU-induced arthritis.• Sirt1 inhibits inflammation partially dependent on PPARγ.

Objective Human adipose-derived mesenchymal progenitor cells (haMPCs) are stem cells with multiple differentiation potential and immunomodulatory function. Re-Join® comprises in vitro expanded haMPCs from adipose tissue of patients combined with cell suspension solution. This study was undertaken to evaluate the efficacy and safety of Re-Join® in patients with symptomatic knee osteoarthritis (OA). Methods Patients with Kellgren–Lawrence grade 1–3 knee OA were recruited from two centers and randomized to receive intra-articular injection of Re-Join® or HA. Pain and function were assessed by using WOMAC score, VAS, and SF-36. Magnetic resonance imaging (MRI) analysis was performed to measure cartilage repair. Adverse events (AEs) were collected. Results Fifty-three patients were randomized. Significant improvements in WOMAC, VAS, and SF-36 scores were observed in both groups at months 6 and 12 compared with baseline. Compared with the HA group, significantly more patients achieved 50% improvement of WOMAC and a trend of more patients achieved a 70% improvement rate in Re-Join® group after 12 months. Meanwhile, there was notably more increase in articular cartilage volume of both knees in the Re-Join® group than in the HA group after 12 months as measured by MRI. AEs were comparable between two groups. Most AEs were mild and moderate except one SAE of right knee joint infection in the HA group. Conclusions Significant improvements in joint function, pain, quality of life, and cartilage regeneration were observed in Re-Join®-treated knee OA patients with good tolerance in a period of 12 months. Trial registration ClinicalTrials.gov Identifier: NCT02162693 . Registered 13 June 2014.

A defining feature of successful vaccination is the ability to induce long-lived antigen-specific memory cells. T follicular helper (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5 + memory Tfh cells in human blood are divided into Tfh1, Tfh2, and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17, respectively. Here, we developed a new method to induce Tfh1, Tfh2, and Tfh17-like (iTfh1, iTfh2, and iTfh17) mouse cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7 + central memory Tfh cells with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.