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关键词： Interleukin-37   Systemic lupus erythematosus   Gene polymorphisms   Ethnic variability   Meta-Analysis  

摘要： This study examined the association between circulating interleukin-37 (IL-37) levels and systemic lupus erythematosus (SLE), as well as the relationship between IL-37 gene polymorphisms and susceptibility to SLE. Relevant studies were identified through extensive searches of the Medline, Embase, and Web of Science databases up to December 2024. A meta-analysis was conducted to compare serum/plasma IL-37 levels in SLE patients with those in controls and to evaluate the association between IL-37 gene polymorphisms and SLE risk. Twelve studies comprising 1,229 SLE patients and 745 controls were analyzed. The meta-analysis revealed higher IL-37 levels in SLE patients compared to controls (SMD: 0.570, 95% CI-0.070-1.210, p = 0.0803), though the difference was not statistically significant. Subgroup analysis showed a significant association in Asians (SMD: 0.730, 95% CI: 0.151-1.310, p = 0.010), but not in Arabs (SMD: 0.410, 95% CI: -0.780-1.600, p = 0.500). Analysis of the original data indicated significant results (SMD: 1.026, 95% CI: 0.505-1.547, p < 0.001), while the re-calculated data did not. Studies conducted before 2019 revealed a significant association (SMD: 0.906, 95% CI: 0.438-1.374, p < 0.001), unlike more recent studies. Higher IL-37 levels were observed in patients with lupus nephritis, although these findings were not statistically significant. Genetic analysis of IL-37 rs3811047 polymorphism revealed no significant association in Arabs (OR: 1.432, 95% CI: 0.607-3.373, p = 0.413), whereas a significant association was noted in Asians (OR: 0.649, 95% CI: 0.448-0.941, p = 0.023). The meta-analysis demonstrated significantly elevated IL-37 levels in SLE patients among Asians, along with a significant association between IL-37 polymorphisms and SLE.

关键词： PAPA syndrome   PSTPIP1   IL-1 beta   Anakinra   Canakinumab   Neutrophilic dermatoses   Acne   Pyogenic arthritis   Pyoderma gangrenosum  

摘要： PAPA syndrome is a rare autosomal dominant autoinflammatory disorder characterized by sterile pyogenic arthritis, pyoderma gangrenosum (PG), and severe acne, driven by PSTPIP1 mutations that enhance IL-1 beta production. IL-1 inhibitors-anakinra and canakinumab-have been reported in small case series, but comparative effectiveness, safety, and optimal dosing remain unclear. A systematic review of ten original case-report studies (19 patients) was performed, following PRISMA guidelines. Data extracted included clinical manifestations, treatment regimens, therapeutic responses across arthritis, PG, and acne, and adverse events. Complete resolution of pyogenic arthritis occurred in 11/17 treatment courses, versus 3/11 for PG and 4/10 for acne. Partial improvements were noted in 2 arthritis, 4 PG, and 1 acne cases;non-responses were most frequent in PG (4/11) and acne (5/10). Canakinumab demonstrated improved patient compliance due to its less frequent dosing schedule (every 4-8 weeks), in contrast to daily injections of anakinra. This also correlated with a trend toward fewer injection-site reactions. Reported adverse events were primarily mild, including local reactions and occasional infections. Anti-IL-1 therapy appears most effective for arthritis manifestations in PAPA syndrome, with markedly lower efficacy for PG and acne. Canakinumab's dosing schedule offers practical advantages and potentially fewer adverse effects, but existing evidence is limited to case reports and small series. Well-designed randomized controlled trials are urgently needed to confirm efficacy, safety, and comparative benefits of anakinra versus canakinumab. Future studies should also explore genotype-phenotype correlations and extend investigation to adjunctive pathways to improve cutaneous outcomes.

关键词： TNF-alpha modulator   Ulcerative colitis (UC)   Deuteration   Fluorination   Metabolic stability  

摘要： Tumor necrosis factor-alpha (TNF-alpha) is an important target for the treatment of inflammatory diseases. Targeting TNF-alpha inhibition, such as antibody drug infliximab and adalimumab, has emerged as an effective therapeutic strategy for managing the most difficult-to-treat chronic ulcerative colitis (UC). So far, there are no small molecule TNF-alpha inhibitors available on the market for the treatment of UC. Previously, we reported an indanone analogue (R)-STU104 showed considerable inhibitory activity on TNF-alpha production in both acute and chronic mouse models of UC with a favorable safety profile. However, further development potential of this compound was greatly limited due to its poor metabolic stability in human liver microsomes and suboptimal pharmacokinetic profiles in mice. Herein, we discovered a deuterated TNF-alpha small molecule modulator (R)-104-6D-01, which demonstrated promising clinical potential for the treatment of UC. This new compound exhibited enhanced oral bioavailability and exposure in pharmacokinetic studies, as well as superior anti-UC efficacy in a DSS-induced mouse UC model, compared with (R)-STU104 at a dosage of 30 mg/kg/d. Collectively, (R)-104-6D01 proves to be a promising candidate of potential use in treating UC as an oral TNF-alpha small molecule modulator.

关键词： HLA-DR+ regulatory T cells   immune tolerance   systemic lupus erythematosus  

摘要： Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems. A key element in maintaining immune tolerance and preventing autoimmunity is the role of regulatory T cells (Treg cells). Among these, HLA-DR+ Treg cells represent a distinct subset, and their altered expression and functionality in SLE are closely associated with the progression of the disease. This review explores the biological characteristics of HLA-DR+ Treg cells, their mechanisms of action in SLE, as well as their potential and the challenges they pose as therapeutic targets. Methods and results This review offers a comprehensive analysis of the mechanisms by which HLA-DR+ Treg cells regulate immune responses. It highlights their direct interactions with autoreactive T cells and antigen-presenting cells, which contribute to the suppression of autoimmunity. Additionally, the review explores the critical role of these cells in maintaining immune tolerance and their promising potential in the context of antigen-specific immunotherapy. Discussion The potential of HLA-DR+ Treg cells in the treatment of systemic lupus erythematosus (SLE) is considerable, particularly due to their capacity to generate antigen-specific Tregs. The development of Treg-based therapies, including the expansion of both polyclonal and antigen-specific Tregs, is an area of active investigation. Nonetheless, several challenges persist, such as the need to optimize protocols for Treg generation and expansion, ensure the stability of the Treg phenotype, and address potential safety concerns associated with cellular *** research is essential to fully harness the potential of HLA-DR+ Treg cells in the treatment of SLE and other autoimmune diseases.

关键词： Acute kidney injury (AKI)   double- negative (DN T cells)   IL-7   renal tubular epithelial cells (RTEC)   gamma-chain cytokines  

摘要： BackgroundPrevious studies have demonstrated that double-negative (DN) alpha beta T cells play an important role in immune responses during ischemic acute kidney injury (AKI). Here, we investigate the role of gamma-chain cytokines in driving DN T cell proliferation in steady state and AKI, focusing on IL-2, IL-7, and *** assessed DN T cell proliferation in vitro in response to IL-2, IL-7, and IL-15, with co-culture experiments using renal tubular epithelial cells (RTECs) and IL-7 blockade. In vivo, wild-type and IL-7r knockout mice were studied to evaluate the impact of IL-7 on DN T cell expansion and kidney function during AKI. Human RTECs confirmed the relevance of these *** three cytokines promoted DN T cell proliferation in vitro, with IL-7 inducing the most robust expansion. Co-culture experiments showed RTECs as a key IL-7 source, and blockade reduced DN T cell expansion. In vivo, IL-7 complexes administered to wild-type mice increased DN T cells and selectively expanded the PD-1+ subset. IL-7 deficiency worsened renal outcomes during AKI. Human RTECs activated peripheral human DN T cells in *** results establish IL-7 as pivotal for DN T cell expansion and highlight RTECs' role in DN T cell homeostasis.

关键词： psoriasis   epidermal keratinocyte   betulinic acid   ursolic acid   interleukin 17   C-C motif chemokine ligand 20  

摘要： Psoriasis is a chronic inflammatory skin disease characterized by erythema, infiltration, and scaling, which is mainly caused by interleukin (IL)-17. The use of molecular targeted drugs in specific therapies offers high efficacy;however, high medical costs and a significant risk of side effects highlight the need for novel therapeutic agents. We previously observed that Morus alba extract (MAE) suppressed IL-17-induced CCL20 mRNA expression in normal human epidermal keratinocytes (NHEKs). In this study, we focused on the IL-17 signaling pathway and investigated the effects of pentacyclic triterpenoids, betulinic acid (BA), and ursolic acid (UA), which are present in MAE, on NHEK cells. Real-time reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) revealed that both BA and UA suppressed CCL20 expression, while only UA alone inhibited CCL20 release. ELISA using specific inhibitors demonstrated that both the p38 and extracellular-signal-regulated kinase 1/2 (ERK1/2) pathways were crucial for IL-17-induced CCL20 release in NHEK. UA effectively suppressed ERK1/2 nuclear localization and moderately affected p38 phosphorylation. These results indicated that UA is a potential seed compound for psoriasis treatment through its targeting of the IL-17 pathway.