Primary Sjögren’s syndrome (pSS) is a systemic autoimmune inflammatory disease mainly defined by T cell–dominated destruction of exocrine glands. Currently, CD8 ⁺ T cells are thought to be involved in the pathogenesis of pSS. However, the single-cell immune profiling of pSS and molecular signatures of pathogenic CD8 ⁺ T cells have not been well elucidated. Our multiomics investigation showed that both T cells and B cells, especially CD8 ⁺ T cells, were undergoing significant clonal expansion in pSS patients. TCR clonality analysis revealed that peripheral blood granzyme K ⁺ (GZMK ⁺ ) CXCR6 ⁺ CD8 ⁺ T cells had higher a proportion of clones shared with CD69 ⁺ CD103 ^– CD8 ⁺ tissue-resident memory T (Trm) cells in labial glands in pSS. CD69 ⁺ CD103 ^– CD8 ⁺ Trm cells featured by high expression of GZMK were more active and cytotoxic in pSS compared with their CD103 ⁺ counterparts. Peripheral blood GZMK ⁺ CXCR6 ⁺ CD8 ⁺ T cells with higher CD122 expression were increased and harbored a gene signature similar to Trm cells in pSS. Consistently, IL-15 was significantly elevated in pSS plasma and showed the capacity to promote differentiation of CD8 ⁺ T cells into GZMK ⁺ CXCR6 ⁺ CD8 ⁺ T cells in a STAT5-dependent manner. In summary, we depicted the immune profile of pSS and further conducted comprehensive bioinformatics analysis and in vitro experimental investigations to characterize the pathogenic role and differentiation trajectory of CD8 ⁺ Trm cells in pSS.

Background/Objectives: Constitutive activation of the PI3K/AKT/mTOR signaling cascade underlies the aggressive phenotype of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA); however, a quantitative synthesis of in vitro data on pathway inhibition remains lacking. This systematic review and meta-analysis aimed to (i) aggregate standardized effects of pathway inhibitors on proliferation, apoptosis, migration/invasion, IL-6/IL-8 secretion, p-AKT, and LC3; (ii) assess heterogeneity and identify key moderators of variability, including stimulus type, cell source, and inhibitor class. Methods: PubMed, Europe PMC, and the Cochrane Library were searched up to 18 May 2025 (PROSPERO CRD420251058185). Twenty of 2684 screened records met eligibility. Two reviewers independently extracted data and assessed study quality with SciRAP. Standardized mean differences (Hedges g) were pooled using a Sidik–Jonkman random-effects model with Hartung–Knapp confidence intervals. Heterogeneity (τ², I²), 95% prediction intervals, and meta-regression by cell type were calculated; robustness was tested with REML-HK, leave-one-out, and Baujat diagnostics. Results: PI3K/AKT/mTOR inhibition markedly reduced proliferation (to –5.1 SD), IL-6 (–11.1 SD), and IL-8 (–6.5 SD) while increasing apoptosis (+2.7 SD). Fourteen of seventeen outcome clusters showed large effects (|g| ≥ 0.8), with low–moderate heterogeneity (I² ≤ 35% in 11 clusters). Prediction intervals crossed zero only in small k-groups; sensitivity analyses shifted pooled estimates by ≤0.05 SD. p-AKT and p-mTOR consistently reflected functional changes and emerged as reliable pharmacodynamic markers. Conclusions: Targeted blockade of PI3K/AKT/mTOR robustly suppresses the proliferative and inflammatory phenotype of RA-FLSs, reaffirming this axis as a therapeutic target. The stability of estimates across multiple analytic scenarios enhances confidence in these findings and highlights p-AKT and p-mTOR as translational response markers. The present synthesis provides a quantitative basis for personalized dual-PI3K/mTOR strategies and supports the adoption of standardized long-term preclinical protocols.

The Leishmania homolog of receptors for activated C kinase (LACK) protein is derived from Leishmania parasites L. major. The polypeptide LACK_156–173 has been shown to confer protection against murine autoimmune arthritis. Fibroblast‐like synoviocytes (FLSs) play a pivotal role in the synovial invasion and joint destruction observed in rheumatoid arthritis (RA). The study reveals that LACK_156‐173 can inhibit the aggressive phenotype of RA‐FLSs by restoring dysregulated fatty acid synthesis metabolism. In RA‐FLSs, overexpression of fatty acid synthase (FASN) leads to excessive fatty acid accumulation, which in turn promotes mitochondrial fragmentation by enhancing phosphorylation at the ser616 site of dynamin 1‐like protein (DRP1). This process increases reactive oxygen species (ROS) production and activates the PI3K/mTOR/NF‐κB pathway, thereby facilitating the transition of RA‐FLSs to an aggressive inflammatory and bone‐damaging phenotype. LACK_156‐173 is internalized into the cytoplasm via CAPN2‐mediated endocytosis, where it directly binds to FASN and inhibits its activity. The findings suggest that targeting the restoration of fatty acid metabolism could potentially alleviate synovial invasion and joint damage in RA. LACK_156‐173 may therefore hold therapeutic promise for RA patients.

Extrafollicular age-associated B cells (ABCs) excessively expand and produce autoantibodies in systemic lupus erythematosus (SLE), and the regulatory mechanism remains elusive. We found that the m ⁶ A demethylase fat mass and obesity-associated protein (FTO) was highly expressed in ABCs from patients with SLE, which was positively associated with renal immune damage. FTO overexpression in murine and human B cells facilitated ABC expansion and exacerbated SLE in lupus-prone mice, whereas FTO ablation ameliorated ABC-driven autoimmunity. FTO expression was up-regulated upon activation of the toll-like receptor 7–myeloid differentiation primary response protein 88 (TLR7-MyD88) signaling pathway. FTO, in turn, promoted TLR7-driven ABC differentiation by targeting ATPase H ⁺ transporting V1 subunit G1 (ATP6V1G1), a subunit of the vacuolar H ⁺ -ATPase (V-ATPase), in an m ⁶ A-dependent manner. Mechanistically, FTO deficiency impaired lysosomal autophagy by reducing ATP6V1G1-mediated V-ATPase activity. The accumulation of damaged mitochondria led to mitochondrial dysfunction in human and murine B cells, characterized by reduced oxidative phosphorylation and elevated reactive oxygen species. This dysfunction limited cell proliferation and blocked ABC differentiation by dampening cellular responsiveness to interleukin-12. Thus, TLR7-FTO-ATP6V1G1 signaling metabolically shapes extrafollicular ABCs in SLE, providing a potential therapeutic target.

This investigation aimed to evaluate the efficacy and safety of belimumab and telitacicept in active systemic lupus erythematosus (SLE) and to explore potential predictors within a treat-to-target paradigm. 101 individuals were retrospectively enrolled at Guangdong Provincial People’s Hospital between January 2021 and December 2023, receiving either belimumab (n = 50) or telitacicept (n = 51) in conjunction with standard therapy for more than 24 weeks. Key clinical endpoints were evaluated, with lupus low disease activity state (LLDAS) as the primary outcome. Multivariate analysis was employed to investigate factors associated with failure to attain LLDAS. Baseline characteristics were balanced in both groups after propensity score-based inverse probability of treatment weighting. At 24 weeks, the rates of attainment of LLDAS were 54.86% in the telitacicept group and 33.13% in patients receiving belimumab (p = 0.048). A larger proportion of patients receiving telitacicept attained prednisone dosages of ≤ 7.5 mg/day (p = 0.012). Improvements in complement C4 levels and the occurrence of severe hypogammaglobulinemia were more pronounced among patients receiving telitacicept, with no differences in SLE Responder Index 4, DORIS remission, and renal response. Treatment with telitacicept (OR = 0.80, p = 0.032) and elevated levels of complement C3 (OR = 0.63, p = 0.003) were associated with a decreased risk of failing to achieve LLDAS. No severe adverse events were documented in both groups. Both belimumab and telitacicept displayed satisfactory effectiveness and safety profiles. Our findings imply telitacicept may offer potential benefits associated with the early attainment of LLDAS and reduced glucocorticoid exposure. Restricted by the observational design, the findings require further validation in prospective studies.

Anxiety and depression in patients with systemic lupus erythematosus (SLE) complicate clinical treatment and can seriously affect prognosis. The present study aims to investigate the effects of the anti-ribosomal P protein antibody (anti-RibP) in the peripheral blood and insomnia on the severity of anxiety and depression in case of SLE. The study compared both the results of the investigation on the objective perceptions of physicians concerning mood changes in patients with SLE and the results of self-rating scales that were completed by the enrolled patients. The conclusion of the comparation is used to determine the probability of the accurate detection of anxiety and depression by physicians. The study aims to assist in the early detection in clinical practice of abnormal emotions in patients with SLE and to summarize common clinical interventions for anxiety and depression. The relationship between anxiety and depression was evaluated by the Zung self-rating anxiety/depression scale (SAS/SDS). Basic information (e.g., blood type, smoking history, drinking history, educational background, duration of illness), the insomnia severity index (ISI) results, and anti-RibP in the peripheral blood, were investigated in 107 patients with SLE in northeastern China to further analyze the correlation between the severity of depression and anti-RibP, together with the consistency between results of the questionnaire for physicians and the self-rating scale for patients. Gender, smoking history, drinking history, educational background, and duration of illness were correlated with the SAS/SDS scores (P < 0.05). Family history had a significant effect on the SAS score (P = 0.031), while the SDS score was significantly correlated with blood type (P = 0.021). The ISI score was significantly and positively correlated with the SAS/SDS score (P < 0.001). The titer of anti-RibP showed a correlation with the SDS score (P < 0.05) but not with the SAS score (P = 0.198). The titer of anti-RibP was significantly higher in patients with major depression compared with those with no depression, patients with mild depression, and those with moderate depression (P < 0.001). Anxiety and depression in patients with SLE were correlated with sleeping, educational background, blood type, smoking history, and alcohol consumption. Although anti-RibP was not significantly correlated with anxiety, it indicated a significant correlation with major depression. Clinicians were more accurate in assessing anxiety compared with depression.