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摘要： OBJECTIVES:Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterised by a primary pathogenic involvement of interleukin (IL)-1. Therefore, IL-1 blockers are currently considered the optimal therapeutic option for SchS patients. However, while IL-1 blockers are first-line for SchS, long-term real-world evidence is limited by the rarity of the disease. We assessed the long-term effectiveness and safety of the IL-1 inhibitors anakinra and canakinumab used in SchS, also looking for variables capable of affecting global effectiveness and drug retention over time. METHODS:Data analysed in this study were drawn from the international AutoInflammatory Disease Alliance (AIDA) Registry dedicated to SchS. RESULTS:28 SchS patients corresponding to 37 treatment lines were included in the study. Complete and partial responses occurred in 73.1% and 29.9% of anakinra-treated patients, and 66.8% and 33.3% with canakinumab. The overall anakinra and canakinumab drug retention rates at 12-, 36-, and 60-month follow-up were 85.6%, 81.7% and 64.7%, respectively; the probability of discontinuing IL-1 inhibitors at 12-, 36- and 60 months due to loss of effectiveness was 9.6%, 13.7% and 24.5%, respectively. The maximum IgG M-protein levels were found to be significantly higher in patients achieving partial response compared to those benefiting from complete response (p=0.032). Lymphadenopathy independently predicted anti-IL-1 discontinuation due to loss of effectiveness (HR 7.78, 95% CI: 1.27-47.9; p=0.027). CONCLUSIONS:The present study confirms the high effectiveness of IL-1 inhibitors in controlling SchS, including the complete and partial response rates and the long-term survival. Elevated IgG M-protein levels and the presence of lymphadenopathy should be considered as potential indicators for identifying patients more likely to exhibit a partial response and a possible loss of treatment efficacy.

关键词： Airway   Allergy   IL-4   Th2   Fibroblast  

摘要： center dot Airway fibroblasts in allergic asthma (AA) mice demonstrated a 2.3-fold increase in IL-4+ cell proportion (p < 0.01), indicating their dominant role in driving Th2 inflammation compared to CD4+ T cells (24.7 % contribution, p < 0.001). center dot Fibroblasts upregulated activation markers CD80/CD83/CD86 (p < 0.0001), which correlated with enhanced IL-4-dependent Th2 polarization (30.01 % Teffs vs. 8.89 % with naive fibroblasts, p < 0.0001), suggesting their capacity to amplify allergic responses. center dot Targeted FbNP therapy reduced pathological fibroblast frequency by 24.6 % and systemic IL-4 levels by 48.83 %, accompanied by significant suppression of Th2 cytokines (IL-5: 46.88 %;IL-13: 50.84 %, all p < 0.001), demonstrating dual anti-inflammatory and immunoregulatory effects. center dot Clinically, FbNP alleviated asthma symptoms (52-65 % reduction in airway resistance) and improved airway hyperresponsiveness (AHR, 41 % correction, p < 0.01), with sustained therapeutic efficacy for 14 days and no detectable toxicity.

关键词： Mammary adipose tissue   Breast cancer   Inflammation   NF-kappa B   Nuclear receptor coactivator 3  

摘要： In breast cancer, adipocytes are the predominant cell type in the microenvironment, and the continuous communication between these tissues alters the adipose phenotype. However, molecular mechanisms promoting these changes are still poorly understood. Previously, we demonstrated that NCoA3 expression is increased in adipose tissue adjacent to breast cancer and that this increase is associated with an inflammatory profile. This study aimed to investigate the mechanisms underlying NCoA3 expression in adipocytes within the breast tumor microenvironment. We demonstrated that breast cancer-secreted TNF increases NCoA3 expression in adipocytes, and this upregulation is dependent on NF-kappa B transcriptional activity. Furthermore, the use of a TNF blocker prevented both coactivator overexpression and macrophages recruitment, mimicking the effects observed when NCoA3 expression was downregulated using a short hairpin RNA. These findings shed light on the molecular mechanisms by which breast cancer cells modulate adipocyte behavior, identifying NCoA3 as a key mediator in the tumor-adipose tissue crosstalk. Targeting this pathway through TNF inhibition offers promising therapeutic strategy to attenuate tumor-associated inflammation and potentially improve outcomes in breast cancer patients.

关键词： Takayasu arteritis   baricitinib   JAK-STAT pathway   TNF-alpha   inhibitor-refractory   glucocorticoid-sparing therapy   clinical trial  

摘要： Objective This study aimed to assess the efficacy and safety of baricitinib in Takayasu arteritis (TAK) refractory to TNF-alpha inhibitors. Methods We conducted a multicentre, single-arm trial between February 2021 and August 2023. Patients with TAK unresponsive to at least 6 months of TNF-alpha inhibitors were treated with baricitinib 4 mg daily for up to 48 weeks, while continuing of immunosuppressants and glucocorticoids. Clinical features, inflammatory parameters, imaging changes and treatment data were collected during follow-up. The primary end point was the overall response (ORR) (complete response [CR] plus partial response [PR]) at 24 weeks. Results A total of 10 patients (nine female and one male) patients were enrolled, with median age of 29 years (26.0, 35.3) and a median disease duration of 56.5 months (31.8, 88.5). The ORR at 24 weeks was 80%, with six patients achieving CR and two achieving PR. Disease progression was noted in the remaining two patients. Disease activity, ESR and CRP at 24 weeks were significantly decreased compared with those at baseline. The median glucocorticoid dosage decreased from 20.0 mg/day (15.0, 26.3) at baseline (P < 0.001) to 6.3 mg/day (4.4, 10.6) at 24 weeks. No relapse was observed in the eight patients who achieved a response. The adverse effects (AEs) included upper respiratory tract infection (n = 2) and diarrhoea (n = 1), with no serious AEs reported. Conclusion Baricitinib is effective in patients with TAK resistant to conventional treatments and anti-TNF-alpha therapy and demonstrates a notable steroid-sparing effect. Trial registration ***;NCT06662721.

关键词： Syphilis   pregnancy   IL-10   serological response   immunology  

摘要： Background Approximately 50% of pregnant individuals treated for syphilis do not achieve a decline in non-treponemal titers by delivery. The serological response in pregnant persons is significantly slower compared to non-pregnant individuals, with unclear pathogenesis and clinical significance. This study aimed to determine the association between the host immune response and serological outcome in pregnant individuals with syphilis. Methods Twenty-four females with early syphilis, including 14 pregnant individuals, were included. Pro-inflammatory and regulatory cytokines (IFN-gamma, TNF-alpha, IL-4, IL-1 beta, IL-10, TGF-beta) were measured before treatment and 6 months after penicillin injection. Results The median time to serological cure was 5 months for pregnant individuals and 2 months for non-pregnant females. Pregnant individuals had significantly higher serum levels of IL-10 and TGF-beta at baseline and at 6 months post-treatment compared to non-pregnant individuals (p < .05). Conclusions A robust regulatory immune response to syphilis may be associated with a slower serological response to therapy during pregnancy.

关键词： cGAS   cGASL   Sting   IFN   Snakehead  

摘要： In mammals, cyclic GMP-AMP synthase (cGAS) senses cytosolic dsDNA to trigger type I interferon (IFN) response via the sting signalling, but its regulatory role in fish remains unclear. In the present study, cGAS and cGAS-like (cGASL) were identified in the snakehead (Channa argus), but they differ in the organization of two domains, NTase domain, MAB21 domain, with an additional transmembrane domain in cGASL. It is further revealed that cGAS can bind with Sting to enhance the production of type I IFN and IFN-stimulated genes (ISGs), such as viperin, mx, and its entire molecule with all domains is necessary for its functioning. However, the co-transfection of cGAS or cGASL with tbk1 and mda5 inhibited the expression of ISGs in EPC cells. It is notable that cGAS may exhibit dual functionality either by promoting sting-dependent IFN response or by suppressing RLR pathway activation, whereas cGASL solely acted as an RLR pathway inhibitor. These findings reveal complexed, pathwayspecific immunoregulatory roles of cGAS/cGASL in fish antiviral immunity.

关键词： Hypoimmune iPSCs   B2M knockout   Endothelial differentiation  

摘要： Background: Induced pluripotent stem cells (iPSCs) represent a promising source for regenerative therapies, yet allogeneic transplantation is limited by immune rejection. While strategies for generating hypoimmune iPSCs have been proposed, their efficacy after differentiation into lineage-specific cell types remains underexplored. Methods: A human iPSC line (36A) from peripheral blood mononuclear cells using a Sendai virus-based reprogramming protocol. Hypoimmune properties were conferred via CRISPR-Cpf1-mediated B2M knockout, combined with lentiviral overexpression of HLA-E and CD47. Immune evasion was validated using NK cell cytotoxicity assays. Endothelial differentiation was induced using a defined, stepwise protocol, and in vivo functionality was evaluated in humanized NSG mice. Results: The hypoimmune iPSCs retained pluripotency, exhibited stable karyotype, and demonstrated > 99% expression of HLA-E/CD47. NK cell-mediated lysis was significantly reduced in edited cells, although IFN-gamma levels remained elevated. Upon differentiation, the hypoimmune iPSCs yielded > 98% CD31(+)CD144(+) endothelial cells, which showed enhanced survival in vivo compared to wild-type controls. Conclusion: Multiplex gene editing successfully conferred durable immune evasion in both undifferentiated and endothelial-differentiated iPSCs. These findings support the clinical potential of hypoimmune iPSC-derived cell therapies for allogeneic transplantation without immunosuppression.