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摘要： Patient stratification is crucial for improving immunotherapy effectiveness. Acha-Sagredo et al. identified an interferon (IFN)-high immunophenotype and CD74 overexpression as predictors for immunotherapy response in colorectal cancer (CRC). This signature, involving cytotoxic T cells and antigen-presenting macrophages, was found in both mismatch repair-deficient and -proficient CRCs. CD74 overexpression could serve as a biomarker, enabling personalized CRC treatment.

关键词： gout   IL-6   JAK2   STAT1   stat3   inflammation  

摘要： Background Interleukin-6 (IL-6) is a pleiotropic cytokine, with specific effects depending on the immune microenvironment. Extensive research has confirmed the pathological roles of the IL-6/JAK2/STAT1/3 signaling pathway in inflammation, autoimmunity, and cancer, as well as its involvement in the pathogenesis of various rheumatic diseases. However, the role and impact of IL-6 as an upstream regulator of the JAK2-STAT1/3 pathway in gout have seldom been reported. This study explores the influence and role of upstream IL-6 in regulating the JAK2-STAT1/3 signaling pathway on gout inflammation, offering new insights for targeted therapeutic interventions and drug development in gout *** and Results Clinical data and peripheral blood specimens were collected from gout patients and healthy individuals. In vitro and in vivo models of acute gout inflammation were established by stimulating PBMCs, THP-1 cells, and mice with MSU crystals. IL-6 expression was manipulated using IL-6 agonists and IL-6 knockout (KO) mouse technology to investigate the role and impact of the IL-6-mediated JAK2-STAT1/3 signaling pathway in gout models. RT-qPCR, WB, and ELISA were utilized to assess gene and protein expression levels. Paw swelling in mice was measured using a caliper gauge, while HE and IHC staining were conducted to evaluate the inflammatory status of mouse paw pad synovial tissues and detect the positive expression of relevant proteins. Serum IL-6 protein expression levels were significantly elevated in patients with gouty arthritis (GA) compared to healthy individuals, with multifactor logistic regression revealing an odds ratio (OR) of 2.175 for IL-6. In GA patients, mRNA expression of IL-6, JAK2, STAT1/3, and IL-1 beta was notably lower in the gout group compared to the healthy control (HC) group. Moreover, IL-6, JAK2, STAT1/3, p-JAK2, p-STAT1/3, and IL-1 beta proteins were markedly higher in the acute gout (AG) group compared to the intercritical gout (IG) and

摘要： The cGAS-STING pathway mediates the innate immune response to cytosolic DNA, contributing to surveillance against microbial invasion or cellular damage. Once activated, STING recruits TBK1 at the trans-Golgi network (TGN), which in turn phosphorylates IRF3 to induce type I interferon (IFN-I) expression. In contrast to STING, little is known about how TBK1 is transported to the TGN for activation. Here, we show that multiple TGN tethering factors, a group of proteins involved in vesicle capturing, are indispensable for STING-IFN-I signaling. Deletion of TBC1D23, a recently reported tethering factor, in mice impairs the STING-IFN-I signaling, but with insignificant effect on STING-NF-kappa B signaling. Mechanistically, TBC1D23 interacts with TBK1 via the WASH complex subunit FAM21 and promotes its endosome-to-TGN translocation. Furthermore, multiple TGN tethering factors were reduced in aged mice and senescent fibroblasts. In summary, our study uncovers that TGN tethering factors are key regulators of the STING-IFN-I signaling and suggests that their reduction in senescence may produce aberrant STING signaling.

关键词： Amyotrophic lateral sclerosis   MiR-223   Interleukin-1 beta   Inflammasome  

摘要： Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease identified by progressive motor neuron loss. NLRP3 inflammasomes induce inflammation and pyroptosis, which can lead to neurodegeneration, muscle atrophy, and respiratory decline. miR-223 targets NLRP3 and suppresses inflammasome formation. Here, miR-223, NLRP3 and IL-1 beta levels were evaluated as plasma biomarkers in the incidence and progression of ALS. Methods 32 ALS patients and 32 healthy subjects were assessed. In all patients, the functional disability was determined by Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the respiratory dysfunction was assessed by the percent predicted forced vital capacity (ppFVC) index in spirometry examination. Plasma levels of miR-223, NLRP3 and IL-1 beta were assessed in ALS and control groups. Results Compared to the healthy controls, ALS patients showed decreased miR-223 expression (P < 0.0001), increased NLRP3 expression (P = 0.0002) and increased IL-1 beta level (P = 0.0003). The areas under the ROC curves for miR-223, NLRP3 and IL-1 beta were 0.82, 0.76 and 0.75 respectively. The ALSFRS-R and ppFVC values were positively correlated with miR-223 and negatively correlated with NLRP3 and IL-1 beta levels. Conclusion Our results indicated that changes in miR-223, NLRP3 and IL-1 beta levels may correlate with the occurrence and functional progression of ALS. Additionally, therapeutic approaches based on miR-223 and inflammatory mediators can be proposed as effective strategies against disease progression.

关键词： MHC Class I   ProteinMPNN   direct preference optimization   protein deimmunization   protein design  

摘要： ProteinMPNN is widely used in protein design workflows due to its ability to identify amino acid sequences that fold into specific 3D protein structures. In our work, we adjust ProteinMPNN to design proteins for a given 3D protein structure with reduced immune-visibility to cytotoxic T lymphocytes that recognize proteins via the MHC-I pathway. To achieve this, we developed a novel framework that integrates Direct Preference Optimization (DPO)-a tuning method originally designed for large language models-with MHC-I peptide presentation predictions. This approach fosters the generation of designs with fewer MHC-I epitopes while preserving the protein's original structure. Our results demonstrate that DPO effectively reduces MHC-I visibility without compromising the structural integrity of the proteins. Source code: https://***/hcgasser/CAPE_MPNN.

关键词： immunoproteasome   IL-4RA   type 2 inflammation   precision-cut lung slices   airway hyperresponsiveness  

摘要： Introduction Immunoproteasome (IP) is induced by pro-inflammatory stimuli such as interferon gamma to regulate inflammation and immunity. Asthma patients with airway type 2 high inflammation (e.g., IL-13) demonstrate more eosinophils and airway hyperresponsiveness (AHR) with less interferon gamma. The role of IP in regulating airway eosinophilic inflammation and AHR has not been *** This study was aimed to determine how IP regulates type 2 inflammation and AHR using LMP7 (a subunit of IP) deficient mouse lungs, precision-cut lung slices (PCLS), and cultured human airway epithelial cells treated with IL-13 in the absence or presence of an IP inhibitor ONX-0914 or exogenous *** LMP7 KO mouse lungs had significantly more IL-4R alpha protein expression than the wildtype (WT) mice. Following IL-13 treatment in PCLS, LMP7 KO mice had significantly more airway contraction than WT mice, which was coupled with increased eotaxin-2 levels. IP inhibition by ONX-0914 in IL-13 treated human airway epithelial cells resulted in significantly more IL-4R alpha protein expression and eotaxin-3 release. IP inhibition in human PCLS significantly increased *** Collectively, these data demonstrated that IP promotes degradation of IL-4R alpha, while inhibits type 2 inflammation and AHR. Enhancement of IP expression or activity may serve as an alternative approach to reduce the severity of type 2 inflammation and AHR.

关键词： SARS-CoV-2   Omicron   cellular immune response   CD8 T-cell epitope   conserved epitope  

摘要： Introduction Recent surveillance has identified the emergence of the SARS-CoV-2 Omicron ariant, which exhibits the ability to evade multiple neutralizing antibodies generated by prior infection or vaccination. However, significant knowledge gaps remain regarding the CD8 T-cell immune reactivity to the Omicron variant. This study aims to evaluate the characteristics of HLA-A2-restricted CD8 T-cell epitopes from the Omicron variant and analyze epitope-specific CD8 T-cell responses to SARS-CoV-2 inactivated vaccines. Methods We conducted a comprehensive analysis of CD8 T-cell responses to SARS-CoV-2 inactivated vaccines, focusing on HLA-A2-restricted epitopes derived from the Omicron variant. Mutant epitopes were evaluated for their impact on antigen presentation and CD8 T-cell immune reactivity. Additionally, we screened for epitopes that exhibited reduced CD8 T-cell responses following the emergence of the Omicron variant. Results Our findings revealed that mutant epitopes in the Omicron variant led to escape from antigen presentation and diminished CD8 T-cell immune responses. We identified two epitopes associated with decreased CD8 T-cell reactivity post-Omicron variant emergence. Notably, we discovered an S protein epitope, 67A>V, which demonstrated similar proportions of CD8 T-cell specificity between the ancestral and mutant strains, suggesting its conservation and potential immunogenicity for vaccine development. Furthermore, the third dose of the inactivated vaccine significantly increased the number of epitope-specific CD8 T cells, underscoring the importance of booster doses in enhancing cellular immune responses against the Omicron variant. Discussion This study highlights the ability of the Omicron variant to evade CD8 T-cell immune responses through epitope mutations, while also identifying conserved epitopes with potential utility in vaccine design. The observed increase in epitope-specific CD8 T cells following a booster dose emphasizes the critical rol

关键词： 重组慢病毒载体   淋巴细胞激活基因   免疫抑制性受体   慢性病毒感染  

摘要： 目的 构建人淋巴细胞激活基因3(lymphocyte activation gene 3,LAG3)慢病毒重组表达载体,并转染小鼠成纤维细胞3T3以获得LAG3优势表达的单克隆细胞株.方法 提取人外周血单核细胞总RNA并逆转录为cDNA,以高保真DNA聚合酶PCR扩增LAG3胞外区和跨膜区基因序列.PCR产物采用限制性内切酶Eco RⅠ和NotⅠ双酶切后,与慢病毒载体pTSB-copGFP连接构建重组表达载体pTSB-LAG3-copGFP,并转化大肠埃希菌DH5α.PCR法筛选出阳性克隆菌,提取质粒DNA测序验证.pTSB-LAG3-copGFP重组载体与包装质粒psPAX2、pMD2.0G共同转染人胚肾293T细胞以包装、分泌病毒,收集病毒感染3T3细胞,采用嘌呤霉素筛选的同时有限稀释法获取LAG3稳定表达的3T3单克隆细胞.实时荧光定量PCR、免疫荧光法和流式细胞术分别检测细胞中LAG3 mRNA的转录及LAG3蛋白的表达.结果 重组pTSB-LAG3-copGFP慢病毒载体测序结果显示,扩增LAG3基因序列与GenBank中LAG3标准序列(序列号NM_002286.6)比对仅在跨膜区1 697 bp碱基位存在一处His氨基酸密码子同义突变.pTSB-LAG3-copGFP包装病毒感染3T3细胞经嘌呤霉素筛选,共获得20株LAG3+copGFP+-3T3单克隆细胞,均可检测出LAG3 mRNA的转录,其中MC-6单克隆细胞株LAG3转录水平最高.免疫荧光法与流式细胞术检测结果提示LAG3蛋白在MC-6中有效表达并分布于细胞膜和胞质细胞器膜上.结论 成功构建pTSB-LAG3-copGFP慢病毒载体,筛选获得淋巴细胞激活因子3高效表达的LAG3+copGFP+-3T3单克隆细胞株.为后续开展LAG3与乙型肝炎等慢性病毒感染性疾病发展的关系以及LAG3干预治疗等实验研究打下基础.

关键词： comparative effectiveness   multidisciplinary care   perianal fistula   setons  

摘要： Background and Aims: We aimed to assess the impact of setons on perianal fistula outcomes in patients with perianal fistulising Crohn's disease (PFCD) treated with anti-TNF therapy. Methods: We included patients treated with their first anti-TNF therapy for PFCD after undergoing a pelvic MRI between 2005 and 2022 from 6 North American centres. Our exposure was one or more setons at the time of anti-TNF therapy. Our primary outcome was major adverse fistula outcome (MAFO), a composite of repeat local surgical intervention, hospitalisation, or faecal diversion for PFCD, and our secondary outcome was fistula remission defined clinically. We used 1:1 cardinality matching and propensity score weighting to control for fistula severity based on centrally read MRIs, luminal characteristics, and concomitant therapies. Results: Our analysis included 221 patients: 81 with setons and 140 without setons. After cardinality matching, our cohorts were balanced (standardised difference < 0.1 for all covariates). Patients with setons had similar rates of MAFO (HR 1.23;95% CI, 0.68-2.21) and fistula remission at 6 months (OR, 0.81;95% CI, 0.41-1.59) and 12 months (OR, 0.63;95% CI, 0.31-1.27) compared to patients without setons. Our results remained stable when analysed by propensity score weighting and in a sensitivity analysis of patients who underwent an exam under anaesthesia. In patients with abscesses, there were lower rates of MAFO (HR, 0.49;95% CI, 0.19-1.25) but not statistically significant in patients with setons. Conclusions: In this multicentre, setons were not associated with improved fistula outcomes. Future prospective controlled studies are warranted.

关键词： Breast Cancer   Immunosuppression   Major histocompatibility complex - MHC  

摘要： Background Breast cancer (BC) continues to be a major health concern with 250,000 new cases diagnosed annually in the USA, 75% of which are hormone receptor positive (HR+), expressing estrogen receptor alpha (ER) and/or the progesterone receptor (PR). Although ER-targeted therapies are available, 30% of patients will develop resistance, underscoring the need for new non-ER/estrogen-based treatments. Notably, HR+BCs exhibit poor lymphocyte infiltration and contain an immunosuppressive microenvironment, which contributes to the limited efficacy of immunotherapies in HR+BC. In this study, we demonstrate that PR/progesterone signaling reduces major histocompatibility complex (MHC) Class I expression, facilitating immune evasion and escape from immune-based clearance of PR+*** To determine the effect of PR/progesterone on MHC Class I expression, we treated human and mouse mammary tumor cell lines with progesterone and/or interferon (IFN) and measured expression of genes involved in antigen processing and presentation (APP), as well as surface MHC Class I expression. We used the OT-I/SIINFEKL model antigen system to measure the impact of progesterone on immune cell-mediated killing of modified tumor cells. We also analyzed two large BC clinical cohorts to determine how PR expression correlates with APP gene expression and MHC Class I expression in ER-positive *** In vitro, we show that PR/progesterone signaling reduces APP gene expression and MHC class I expression in human and breast mammary tumor cell lines. PR-mediated attenuation of APP/MHC Class I expression is more pronounced in the presence of IFN. In immune cell killing assays, PR-expressing mammary tumor cells treated with progesterone are protected from immune-mediated cytotoxicity. We demonstrate that PR expression in vivo prevents immune-mediated rejection of xenoantigen-modified mammary tumor cell lines through mechanisms involving MHC Class I expression and CD8 T cells. Data analysis of