Objective This study aims to characterize pathogenic somatic mutations in patients with autoinflammatory or autoimmune diseases lacking disease-causing germline mutations, explore their contribution to disease pathogenesis and progression, and evaluate their implications for diagnosis and targeted therapy.Methods We performed a systematic analysis of somatic mutations in a selected panel of 185 immune-related genes in 2,912 patients with autoinflammatory or autoimmune diseases, recruited from 41 medical centers across China, who were previously negative for germline mutations based on whole-exome sequencing.Results We identified both previously reported and novel somatic mutations in genes such as UBA1, KRAS, and NLRP3. Pathogenic somatic mutations in TNFAIP3 were discovered first in patients with autoinflammatory diseases. The pathogenic somatic mutation detection rate was 1.35% in adults and 0.97% in children, emphasizing the importance of genetic diagnosis and novel gene discovery for somatic mutations. In addition, somatic mutations in Ras-related genes were identified in seven patients, and 39 clonal hematopoiesis-associated mutations were identified in 36 adult patients. Moreover, myeloid cells harboring somatic mutations expanded during disease flare and reduced during remission. Disregarding the dynamic elevation of the variant allele fraction during disease progression led to therapeutic failure.Conclusion This study delineated the genetic landscape of pathogenic somatic mutations underlying autoinflammatory and autoimmune diseases, offering valuable insights for genetic diagnosis and targeted therapies.

Objective To characterize malignancy patterns in Chinese patients with idiopathic inflammatory myopathies (IIM) and evaluate the real-world applicability of the International Myositis Assessment and Clinical Studies Group (IMACS) cancer screening guideline. Methods This multi-centre retrospective study included adult patients with IIM from five tertiary referral centers in China between January 2010 and December 2024. Cancer-associated myositis (CAM) was defined as malignancy diagnosed within 3 years before or after IIM onset. Logistic regression analyses were performed to identify factors associated with malignancy, and a simplified refinement score was developed to assess its incremental value beyond the IMACS guideline. Results Among 1980 eligible patients with IIM, 176 (8.9%) had CAM. Lung cancer (18.2%), breast cancer (14.8%), and thyroid cancer (11.9%) were the most common malignancies. Overall, 76.1% of cancers occurred within 1 year before or after IIM onset. According to the IMACS guideline, 65.9% of CAM patients were classified as high-risk, whereas 65.4% of non-CAM patients were also assigned to the moderate-risk category. Multivariable analysis identified anti-TIF1γ antibody positivity, anti-SAE antibody positivity, elevated C-reactive protein, and elevated CA125 as independent risk factors, whereas interstitial lung disease was inversely associated with malignancy. A refinement score incorporating anti-SAE antibody positivity, elevated C-reactive protein, elevated CA125, and absence of interstitial lung disease further stratified malignancy risk within IMACS categories and improved discrimination compared with IMACS alone (AUC 0.762 vs. 0.699, P < 0.001). Conclusion The IMACS guideline effectively identifies patients at increased malignancy risk, and a simple refinement score may further improve risk stratification.

BACKGROUND AND OBJECTIVE:The treatment of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (MDA5+DM-ILD) remains a significant clinical challenge. To compare the effectiveness and safety of upadacitinib (UPA) versus tofacitinib (TOFA) upon 6-month lung transplantation-free survival in newly diagnosed MDA5+DM-ILD patients. METHODS:This multi-centre cohort study in China enrolled MDA5+DM-ILD patients treated from January 2020 to February 2025. Prevalent/incident new users and non-inferior design along with inverse probability treatment weighting (IPTW) were implemented to emulate randomized controlled trial. RESULTS:In the eligible cohort, a total of 106 patients were treated with UPA and 328 with TOFA. The crude 6-month lung transplantation-free survival rates were 71.7% (76/106) in the UPA group and 67.4% (221/328) in the TOFA group. In the IPTW-adjusted cohort, UPA showed a trend toward higher survival than TOFA (p = 0.067), with a weighted risk difference of 10.3% (95% confidence interval -0.4% to 20.2%) meeting the non-inferiority margin (non-inferiority p = 0.003). Sensitivity and subgroup analyses showed consistent results, with potentially greater benefit of UPA in incident JAK inhibitor users (as first-line treatment), monotherapy recipients (without combination with other immunosuppressants except steroid), and those with rapidly progressive ILD. Safety profiles were comparable between groups. CONCLUSION:UPA was found to be non-inferior to TOFA in improving 6-month lung transplantation-free survival among patients with MDA5+DM-ILD, with comparable safety.

Dysregulation of the CARD11-BCL10-MALT1 (CBM) complex is associated with a group of inborn errors of immunity termed “CBM-opathies,” which encompass a spectrum of clinical manifestations including combined immunodeficiency, autoimmune inflammation, atopic disorders, and lymphoproliferation. In this study, we identified novel compound heterozygous variants in the CBM complex in a patient with a family history of immune dysfunction. The patient inherited the variants CARD11 p.K215N and MALT1 p.K543R/p.M732T from asymptomatic carrier parents. Phenotypically, the patient exhibited a developmental arrest of B lymphocytes at the transitional/naïve B cell stage, accompanied by activation of virus-response pathways. Impaired development of T follicular helper cells was linked to defective germinal center formation and agammaglobulinemia. Furthermore, the patient showed expansion of T peripheral helper cells and a deficiency in regulatory T cells, both associated with autoimmunity and colitis. In vitro studies confirmed an imbalance in Tph/Tfh cell differentiation. Single-cell RNA sequencing further revealed a deficiency in B cell development and an enriched population of pro-inflammatory CD3dimCD4−CD8−CD247+ T cells, functionally enriched in the MAPK signaling pathway. Mechanistically, the MALT1 K543R and M732T variants attenuated MALT1’s enzymatic activity and compromised its protein stability, while the CARD11K215N variant disrupted CARD11-mediated promotion of BCL10 filament formation. We demonstrated that these three variants act synergistically to impair NF-κB activation. Specifically, CARD11K215N cooperates with the co-pathogenic MALT1M732T and the modifier variant MALT1K543R to destabilize the functional integrity of the CBM complex, thereby driving the patient’s phenotype. In summary, our study provides new insights into the pathogenesis of autoimmune inflammatory disorders within the spectrum of CBM-opathies and reveals a potential role for the CBM complex in regulating the balance between T peripheral helper and T follicular helper cells. Identified three novel variants in the CBM complex in a patient with a family history of immune dysfunction. CARD11K215N/MALT1K543R/M732T variants impaired B cell development and CD4+T cell differentiation, especially T peripheral helper and T follicular helper cells, by destabilizing the functional integrity of CBM complex.

OBJECTIVE:Steroid-induced osteonecrosis of the femoral head (SONFH) is a refractory skeletal disorder influenced by genetic and environmental factors. However, conclusive pathogenic genetic evidence remains elusive due to the limited exploration of rare damaging variants. In this study, we aimed to identify rare variants associated with SONFH. METHODS:We conducted whole-exome sequencing in an SONFH case-control study comprising 174 patients with systemic lupus erythematosus (SLE) taking steroids, followed by comparing the cases with an ethnically matched healthy population and validation in an additional SONFH cohort of 246 patients without SLE. Rare damaging variants were identified via genetic burden analysis and confirmed by Sanger sequencing and pedigree studies. The functional assessments of the erythrocytes on target variants were performed. RESULTS:We identified 10 heterozygous ANK1 and EPB41 rare variants in 9 (10.8%) of 83 patients with SONFH compared with 0 of the 91 non-SONFH controls (0%). The burden effect of them remained robust after adjusted analysis (Firth's logistic regression-adjusted odds ratio [aOR]ANK1 11.3; aOREPB41 32.3; both P < 0.05). The variants were detected in 10 of the validated SONFH cohort (4.1%) with 246 non-SLE conditions. Functional analyses revealed that the variants result in membrane dysfunctions in the patients' erythrocytes, characterized by reduced ANK1 expression, abnormal morphology, and increased hypotonic hemolysis. CONCLUSION:These findings suggest that the rare variants in ANK1 and EPB41 are novel SONFH disease risk factors that compromise erythrocyte membrane integrity, exacerbating microcirculatory damage in the presence of glucocorticoid as a second hit.

Background:Anti-MDA5 dermatomyositis is often complicated by interstitial lung disease and early mortality. Peripheral lymphopenia has been linked to poor outcomes, but the routinely measured lymphocyte compartments underlying this signal remain incompletely defined. We used hierarchical flow-cytometric immunophenotyping to characterize the mortality-associated lymphopenic pattern. Methods:In this exploratory retrospective cohort, we studied 64 adults with anti-MDA5 dermatomyositis who had baseline lymphocyte subset testing and 180-day follow-up. We compared major lymphocyte populations and T-cell differentiation subsets between survivors and non-survivors. Associations with mortality were assessed using ROC, Kaplan-Meier, and Cox regression analyses. Results:Thirteen of 64 patients died by day 180. Non-survivors showed T-cell-dominant lymphopenia, most marked in CD4+ central and effector memory T cells. Median-split Kaplan-Meier analysis showed lower 180-day survival with lower CD4+ memory T-cell counts (log-rank P = 0.00058). Each 1-SD increase in CD4+ memory T-cell count was associated with lower mortality after age adjustment (aHR 0.16, 95% CI 0.04-0.63, P = 0.008). CD4+ memory T-cell count had an AUC of 0.80 (95% CI 0.68-0.91), comparable to total CD4+ T-cell count (AUC 0.78, 95% CI 0.65-0.90). Findings were similar after separate adjustment for LDH or KL-6 and among patients with baseline RP-ILD. Conclusions:Reduced peripheral CD4+ memory T-cell counts characterized a T-cell-dominant immunophenotype associated with 180-day mortality in anti-MDA5 dermatomyositis. These exploratory findings refine the established CD4+ lymphopenia signal and require validation in independent cohorts.

ObjectiveMacrophage activation syndrome (MAS) is frequently secondary to rheumatic diseases, with features including a cytokine storm and hemophagocytosis. Emapalumab is a monoclonal antibody that targets interferon-γ and has the ability to precisely regulate cytokines. This study aimed to investigate the efficacy and safety of low-dose emapalumab for patients with refractory MAS in the Chinese population.MethodsFrom January 2022 to July 2024, 9 patients with MAS secondary to adult-onset Still’s disease (AOSD) or systemic lupus erythematosus (SLE) received low-dose emapalumab following no response to prior conventional therapies. The laboratory parameters, therapeutic response, and safety were assessed following low-dose emapalumab-based treatment.ResultsOf the nine MAS patients, 5 patients were secondary to AOSD and 4 patients were secondary to SLE. The overall response rate was 66.7% (6/9), 77.8% (7/9), 88.9% (8/9) and 88.9% (8/9) at week 1, 2, 4 and week 8, respectively. At the end of the follow-up period, up to 88.9% (8/9) of patients achieved complete remission. All patients demonstrated improvement or normalization of clinical manifestations and laboratory parameters. Notably, the median prednisone-equivalent dose for the patients was reduced by 85.5% during the treatment. Cytomegalovirus infection occurred in 33.9% (3/9) of patients, with no occurrence of serious adverse events reported.ConclusionOur findings suggest that low-dose emapalumab may be a promising salvage option for refractory MAS in the Chinese population, but confirmation in larger prospective studies is required.

Objectives:To describe the real-world efficacy and safety of obinutuzumab in a heterogeneous systemic lupus erythematosus (SLE) population, including severe or refractory manifestations. Methods:We retrospectively analyzed 56 SLE patients who received a single dose of obinutuzumab (1000 mg) at Renji Hospital, Shanghai Jiao Tong University School of Medicine between October 2021 and March 2024. Patients were followed for 48 weeks. Outcomes included the proportion of patients achieving definitions of remission in systemic lupus erythematosus (DORIS), Lupus Low Disease Activity State (LLDAS), clinical stable, and flare. Changes in SLEDAI-2K, anti-dsDNA, complement levels, B cell counts, glucocorticoid dose, and adverse events were assessed. Subgroup analyses were performed to address population heterogeneity. Results:At baseline, 35.7% of patients were newly diagnosed, 55.4% had relapsing/refractory disease, and 8.9% were on maintenance therapy. By week 48, 37.5% achieved DORIS remission, 32.1% LLDAS, and 19.6% remained clinically stable. Mean SLEDAI-2K decreased from 11.75 ± 9.31 (range: 0 to 46) to 1.45± 1.93 (range: 0 to 8). Among 15 lupus nephritis patients, 86.7% achieved complete renal response. Significant hematologic improvement was observed in autoimmune hemolytic anemia and thrombocytopenia. B cell counts declined rapidly and began to repopulate from week 36. Glucocorticoids tapered from 43.04 ± 18.19 (range: 0 to 60) to 8.95 ± 9.78 (range: 0 to 50) mg/day. Obinutuzumab was well tolerated, with infections observed in 14 cases (25.0%) and infusion reactions in 4 cases (7.1%). Conclusion:Obinutuzumab showed favorable efficacy and safety in SLE, including severe/refractory manifestations, suggesting potential benefits for difficult-to-treat patients.

Objective:Rheumatic disease-associated macrophage activation syndrome (RD-MAS) is a rare and life-threatening complication of rheumatic diseases, with approximately 30% of cases being refractory to conventional therapeutic protocols. Ruxolitinib, a Janus kinase 1/2 inhibitor, has emerged as a potential therapy for refractory RD-MAS. This study aimed to evaluate its efficacy and safety in patients with refractory RD-MAS. Methods:A meticulous chart review was conducted on 20 refractory RD-MAS patients treated with ruxolitinib. Data from no ruxolitinib treatment RD-MAS patients served as historical controls. Clinical and laboratory parameters, therapeutic response, and survival outcomes were analyzed. Ruxolitinib's efficacy and safety were evaluated, and survival rates were compared to historical controls. Results:The cohort included 20 refractory RD-MAS patients (17 females, 3 males) with underlying conditions: adult-onset Still's disease (n = 13), systemic lupus erythematosus (n = 4), and other connective tissue diseases (CTDs) (n = 3). All patients displayed active disease at baseline. By week 8, 50% (10/20) of patients achieved partial remission, while 30% (6/20) attained complete remission. The ruxolitinib group had a significantly higher survival rate (19/20, 95%) compared to historical controls (13/21, 62%) (P = 0.011). By week 8, the median daily glucocorticoid dose dropped from 2.7 mg/kg to 0.5 mg/kg. Cytomegalovirus infection occurred in 20% (4/20) of patients. Conclusion:Ruxolitinib demonstrated substantial efficacy and tolerability in refractory RD-MAS, improving clinical outcomes and reducing glucocorticoid dependence. Although limited by its retrospective nature and small cohort size, this study suggests that ruxolitinib may serve as a potential therapy for refractory RD-MAS, warranting further investigation.

This study assessed the global, regional, and national burdens of psoriasis in adolescents and young adults (aged 10–24 years) from 1990 to 2021. Using Global Burden of Disease 2021 data, this study analyzed 1990–2021 global, regional, and national psoriasis burden trends through multidimensional methods, assessed cross-country disparities via WHO health equity frameworks, and projected disease burden projections through 2035. Psoriasis incidence and disability-adjusted life years (DALYs) among adolescents and young adults globally increased from 38.73 and 25.62 per 100,000 in 1990 to 41.57 and 27.74 per 100,000 in 2021, respectively. The average annual percentage change (AAPC) from 1990 to 2021 was 0.23 for incidence and 0.26 for DALYs. Joinpoint regression revealed significant changes in incidence in 1994, 2001, 2005, 2015, and 2019, while notable shifts in DALYs occurred in 1993, 2002, 2009, 2015, and 2019. Disparities in psoriasis burden varied significantly across regions and countries. High Socio-demographic Index (SDI) countries had a consistently high burden, while middle and low SDI regions saw significant increases, especially in females, driven by population growth. A nuanced change in SDI-related inequalities was detected. Disease burden for psoriasis in this population is projected to continue increasing from 2022 to 2035, with females continuing to bear a greater burden than males. Psoriasis burden among adolescents and young adults has risen sharply over three decades, with projections indicating accelerating trends, highlighting the urgent need for targeted interventions in high-SDI regions where prevalence peaks.

Follicular helper T cells (Tfh) are a Th cell subset that directly assists B cells in functioning, and their development is regulated by various factors. Among them, the initial regulation leads to phenotypic heterogeneity, while the regulation of their migration process results in spatial heterogeneity. The phenotypic heterogeneity is manifested by the presence of Tfh subsets with characteristics helper T cells (Th) of other lineages, namely Tfh1, Tfh2, and Tfh17, with different transcriptional programs and secrete distinct cytokines, potentially possessing different functions. The spatial heterogeneity is mainly manifested by the positional relationship between Tfh and germinal centers (GC), which are mainly divided into GC-Tfh, follicular mantle Tfh, and circulating Tfh, possibly reflecting the process of Tfh occurrence. This review summarizes the spatial and phenotypic heterogeneity of Tfh cells, and suggests a Tfh cell type framework with nodes of previous studied cell types and the edges of switching between specific celltypes, which is affected by the summation of imprinted plasticity part and de novo plasticity part in Tfh development, connecting the hypothesis Crotty et al. proposed in 2018. Discrete cell type is still eligible in qualifying the diseases state and quantifying the activity and severity of diseases, but it could also be beneficial to look Tfh from the view of cell states and expression programs, which, in the future studies, might better model the through process of Tfh development and unifying the contradiction caused by separate Tfh cell type view.

Objectives:Rituximab (RTX) has been commonly used for the treatment of patients with severe or refractory systemic lupus erythematosus (SLE), yet real-world data concerning RTX as the first-line treatment in newly diagnosed moderate-to-severe SLE patients is lacking. Methods:We conducted a retrospective cohort study using a newly diagnosed (<3 months) hospitalized Systemic Lupus Inception Cohort (hSLIC) at our center between April 1, 2013 and September 1, 2022. All patients were followed up for at least 12 months or until death. The cohort included patients on RTX (n = 104) as the first-line treatment and those on conventional immunosuppressants (IS) (n = 154) as comparators. Propensity-score-based inverse probability of treatment weighting (IPTW) was used to minimize possible confounding factors. The primary outcome analyses included attainment of modified lupus low disease activity state (mLLDAS) and remission by 12 months. The secondary outcomes focused on mortality, major flare rates, and the incidence of adverse events of interest, i.e., major infections. Results:After IPTW, 76.0%/50.5% of RTX-treated patients achieved mLLDAS/remission versus 45.8%/9.7% in the conventional IS group during 12 months of follow-up, respectively (p = 0.005 and p < 0.001). The sensitivity analyses with renal or neuropsychiatric lupus removal and timeline breakout (pre- versus post-November 2019) confirmed the robustness of RTX's efficacy in achieving mLLDAS and remission outcomes. Additionally, the incidence of major infections was similar between the two groups (12.5% vs. 8.4%, p = 0.288). Conclusions:In patients with newly diagnosed moderate-to-severe SLE, upfront treatment with RTX was associated with improved clinical outcomes compared to conventional immunosuppressive therapy in terms of achieving low disease activity or remission by 12 months.

OBJECTIVES:Given the efficacy of B-cell depletion therapy in systemic lupus erythematosus (SLE) treatment and the capacity of engineered natural killer (NK) cells in B-cell elimination, we explored the potential of genetically modified NK cells to target CD19 for the treatment of SLE. METHODS:Peripheral blood-derived NK cells were engineered with CAR.CD19/interleukin (IL)-15 (XB-19.15) or CAR.CD19 alone. In vitro assays tested cytotoxicity, proliferation (Ki-67), and cytokine release (IL-15/interferon-gamma [IFN-γ]] against CD19+ cells (Raji, Nalm6, SLE B-cell). In vivo models included Nalm6-luc xenografts, humanised CD34+ mice, and SLE peripheral blood mononuclear cells xenografts to assess efficacy, persistence, and safety. A phase 1 trial enrolled 3 patients with refractory SLE receiving XB-19.15 as a proof-of-concept study. RESULTS:XB-19.15 showed superior cytotoxicity, sustained IL-15 secretion, and enhanced proliferation in vitro. In the mouse model, XB-19.15 showed significant dose-dependent tumour regression of Nalm-6 and B-cell depletion of humanised mice with long-term persistence in various lymphoid organs. The total levels of hIgG and anti-dsDNA antibodies were decreased in XB-19.15-treated groups with deep clearance of B-cell and plasma cells of bone marrow and spleen in the SLE xenograft model, indicating potential attenuation of SLE. Three patients received XB-19.15 achieved improvement in disease activity and reset of B-cell repertoires without severe adverse events. CONCLUSIONS:XB-19.15 enables potent, durable B-cell depletion and immune resetting in SLE with off-the-shelf utility and favourable safety. Preclinical and early clinical data support further trials to optimise dosing and confirm long-term efficacy.

Objective To compare the effectiveness and safety of tofacitinib (TOF) versus calcineurin inhibitor (CNI) as initial immunosuppressive regimen for anti-melanoma differentiation-associated gene 5-positive dermatomyositis with interstitial lung disease (MDA5+DM-ILD). Methods Adult Chinese patients with newly-diagnosed MDA5+DM-ILD (ILD course<3 months) from five tertiary referral centres between April 2014 and January 2023 were included for this retrospective cohort study. The primary effectiveness endpoint was lung transplantation-free survival within 1 year. Propensity score-based inverse probability of treatment weighting (IPTW) was applied for adjustment in this real-world study. Results : In the eligible cohort, a total of 94 (32.4%) and 105 (46.7%) patients died or underwent lung transplantation within 1 year in the TOF group (n=290) and the CNI group (n=225), respectively. After adjustment by IPTW, patients’ lung transplantation-free survival rate within 1 year was significantly higher in the TOF group compared to the CNI group (log-rank p=0.013). Multivariable Cox analysis performed in the IPTW dataset revealed the hazard ratio of TOF versus CNI for 1-year survival was 0.72 (95% CI, 0.56 to 0.94, p=0.013). The adjusted difference of survival rate was 9.3% (95%CI 2.8% to 15.8%). Alternative analytic strategies yielded consistent results in sensitivity analyses. Patients less than 60 years old, without RPILD, or with baseline PaO 2 /FiO 2 ≥300 mmHg might benefit more from TOF. Opportunistic infection was the major treatment-related serious adverse event, with generally comparable incidence (42.4% versus 45.3%). Conclusion In this large multi-centre cohort study, tofacitinib showed significantly more benefits for 1-year lung transplantation-free survival than calcineurin inhibitors in MDA5+DM-ILD.

Objective: To compare the effectiveness and safety of tofacitinib versus calcineurin inhibitor (CNI) as initial immunosuppressive regimen for anti-melanoma differentiation-associated gene 5-positive dermatomyositis with interstitial lung disease (MDA5(+)DM-ILD). Methods: Adult Chinese patients with newly diagnosed MDA5(+)DM-ILD (ILD course <3 months) from five tertiary referral centres between April 2014 and January 2023 were included in this retrospective cohort study. The primary effectiveness end-point was lung transplantation-free survival within 1 year. Propensity score-based inverse probability of treatment weighting (IPTW) was applied for adjustment in this real-world study. Results: In the eligible cohort, a total of 94 (32.4%) and 105 (46.7%) patients died or underwent lung transplantation within 1 year in the tofacitinib group (n=290) and the CNI group (n=225), respectively. After adjustment by IPTW, patients' lung transplantation-free survival rate within 1 year was significantly higher in the tofacitinib group compared to the CNI group (log-rank p=0.013). Multivariable Cox analysis performed in the IPTW dataset revealed that the hazard ratio of tofacitinib versus CNI for 1-year survival was 0.72 (95% CI 0.56-0.94; p=0.013). The adjusted difference of survival rate was 9.3% (95% CI 2.8-15.8%). Alternative analytic strategies yielded consistent results in sensitivity analyses. Patients aged <60 years, without rapidly progressive ILD, or with baseline arterial oxygen tension/inspiratory oxygen fraction >= 300 mmHg might benefit more from tofacitinib. Opportunistic infection was the major treatment-related serious adverse event, with generally comparable incidence (42.4% versus 45.3%). Conclusion: In this large multicentre cohort study, tofacitinib showed significantly more benefits for 1-year lung transplantation-free survival than calcineurin inhibitors in MDA5(+)DM-ILD.

OBJECTIVES:Despite expanding regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) therapy shows variable clinical efficacy in systemic lupus erythematosus (SLE). Here, we investigated whether previously unrecognised effects of IL-2 on age-associated B cells (ABCs) explain this therapeutic heterogeneity. METHODS:Integrated transcriptomic analysis was used to identify the prevalent signalling pathways associated with lupus pathogenic ABCs. The effects of IL-2 on ABCs were examined. TLR7-driven lupus-prone mice were administered to assess the efficacy of IL-2 therapy. IL-2 responsiveness of ABC was further evaluated in patients with SLE through bioinformatic analysis. RESULTS:Transcriptomic and single-cell analyses revealed elevated IL-2 signalling in ABCs, with a more pronounced IL-2 signature in patients with SLE than in healthy controls. IL2RB, a subunit of the IL-2 receptor, was significantly enriched in ABCs and showed increased chromatin accessibility at its promoter. IL-2 promoted ABC survival and differentiation in a stage-dependent manner. Prior IL-2 administration to recipient mice promoted the persistence of adoptively transferred ABCs. In lupus-prone mice, IL-2 administration increased both ABC and Treg populations without ameliorating disease manifestations with ABC's promotion being more dependent on the disease condition. Additionally, ABCs showed elevated expression of IL-2 receptor correlating with ABC frequency in our cohorts, and activation of IL-2 signalling was further observed in B cells and ABCs from patients with SLE. CONCLUSIONS:This study identified ABCs as a novel target of IL-2, expanding the understanding of IL-2's role in SLE beyond the traditional Treg-centric view and offering insights into the variable therapeutic efficacy of IL-2 in this context.