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摘要： Lynch syndrome is rarely associated with rectal cancer (RC) and thus, metachronous RC has been scarcely investigated. This study aimed to analyze the mucosal immune microenvironment in sporadic and metachronous RC. We analyzed the mucosal immune microenvironment in the 25 metachronous RCs present in the IMMUNOREACT 1 and 2 multicentre observational studies (624 patients). A panel of immune markers was retrospectively investigated at immunohistochemistry: CD3, CD4, CD8, CD8b, Tbet, FoxP3, PD-L1, MSH6, and PMS2 and CD80. Single-cell suspensions were subjected to flow-cytometry to determine the proportion of epithelial cells (pan-cytokeratin) acting as antigen-presenting cells (expressing CD80, CD86, HLA-ABC) and the proportion of activated CD8 + T cells (CD8 + positive for CD28, CD38), inhibitory T cells (CD3 + CTLA-4+) of activated CD4 + T helper cells (CD4 + CD25+) and activated T regulatory cells (CD4 + CD25 + FoxP3+). No mismatch repair gene deficiencies were observed in the patients. The previous history of colorectal adenoma was significantly more frequent in metachronous RC. In healthy epithelial cells, HLA-ABC expression was significantly higher in patients with metachronous RC. In therapy-na & iuml;ve metachronous RC patients, a significantly lower level of circulating lymphocytes and CD3 + T-cell infiltration in the healthy mucosa surrounding the RC was observed compared to patients with non-metachronous cancer. Our study supports the hypothesis that metachronous RC can occur in a cancerization field in patients with weak systemic and local immune systems. The peculiar site of RC makes the mismatch-repair genes deficiency in metachronous cancer onset less relevant.

关键词： Seawater drowning induced acute lung injury (SWD-ALI)   epithelial-mesenchymal transition (EMT)   mesenchymal stem cells (MSCs)   pulmonary function   tumor necrosis factor alpha (TNFα)  

摘要： Background:Seawater drowning (SWD) has been an escalating hazard in recent years. It can not only cause immediate death but can also inflict severe complications, such as acute lung injury (ALI), which greatly increases the mortality rate. Thus, investigating the mechanism of SWD induced lung injury and discovering effective treatments is of great importance. The aim of this study was to minimize the lethality and disability of SWD-ALI. Methods:Using male C57BL/6 mice, we established a SWD induced ALI (SWD-ALI) model via the oral laryngoscopy endotracheal injection (LEI) of artificial seawater. We then administered mesenchymal stem cells (MSCs) via laryngoscopy endotracheal nebulized inhalation. We tested our hypotheses using pulmonary function tests, micro-computed tomography (Micro-CT), hematoxylin and eosin (HE) staining, Masson staining, immunofluorescence, immunoblotting, flow cytometry, transcriptome sequencing, quantitative real-time polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). Results:We successfully established the SWD-ALI model via LEI method of seawater. The results indicated that SWD induced severe ALI by activating the Snail-mediated epithelial-mesenchymal transition (EMT) pathway through the tumor necrosis factor alpha (TNFα) inflammatory response. Further, we administered transoral laryngoscopy endotracheal nebulization to the SWD mice treated with inhaled MSCs. Non-invasive pulmonary function tests revealed that the respiratory symptoms and respiratory function of the mice were significantly alleviated. Additionally, the histological injury and air-blood barrier, and inflammatory response were significantly mitigated, and TNFα-mediated Snail expression was significantly down-regulated. Importantly, we used Masson staining to examine mouse lung tissue after 28 days of drowning and found that the SWD mice suffered from significant long-term pulmonary fibrosis injury, and MSCs treatment significantly attenuated the de

关键词： Immunobiological treatment   Precision medicine   Autoimmunity   Polymorphisms   Prediction  

摘要： Rheumatoid arthritis (RA) is a multifactorial autoimmune inflammatory disease that mainly affects the joints, on reducing functional capacity and impacting quality of life. Cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6) are crucial in the pathogenesis and treatment of this disease. Some patients using TNF inhibitors (TNFi) do not respond or lose their response to these medications. Clinical, sociodemographic, and genetic data were used to evaluate the associations of single nucleotide polymorphisms (SNP) in TNF, , TNFRSF1A, , and TNFRSF1B genes with the diagnosis of RA, standardized score results, laboratory tests, and response to TNFi. In one subsample, TNF and IL-6 serum levels cytokines were performed. A total of 654 subjects (360 healthy controls and 294 diagnosed with RA) were included in the analysis. Higher levels of TNF have been found in individuals diagnosed with RA. IL-6 levels were higher in individuals who did not respond to TNFi treatment, while responders had levels comparable to those without the disease. No associations were found between the SNPs studied and the diagnosis of RA;however, rs767455-C seems to play a role in the response to golimumab treatment, being related to better therapeutic response and lower mean serum leukocyte levels. In addition, rs1061622-G was associated with poorer functional capacity and rs1800629-A was associated with higher leukocyte values and serum transaminase levels. The rs1061622-G and rs767455-C may play a role in the response to TNFi treatment, especially for patients using golimumab, although they do not seem to be associated with the diagnosis of RA. Polymosphisms in the TNF pathway may impact baseline levels of immune cells and markers of renal and hepatic function in RA patients. Our results highlight the importance of evaluating the impact of these polymorphisms on TNFi response and safety, particularly in larger-scale studies.

关键词： Hyperammonemia   Hepatic encephalopathy   Motor incoordination   IL-17   Blood-brain barrier   Neuroinflammation   GABAergic neurotransmission   Anti-IL-17   Therapeutic treatment  

摘要： Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination which is reproduced in hyperammonemic rats. Hyperammonemia induces peripheral inflammation which triggers neuroinflammation and enhanced GABAergic neurotransmission in cerebellum and motor incoordination. The mechanisms involved remain unknown. The aims were to assess if the early increase of peripheral IL-17 triggers motor incoordination in hyperammonemic rats and to identify some underlying mechanisms. We assessed if blocking peripheral IL-17 with anti-IL-17 at 2-4 days of hyperammonemia prevents motor incoordination and analyzed underlying mechanisms. Hyperammonemia induces a transient blood IL-17 increase at days 3-4. This is associated with increased IL-17 receptor membrane expression and activation in cerebellum, leading to NADPH oxidase activation, increased superoxide production and MLCK that induce blood-brain barrier (BBB) permeabilization by reducing occludin and ZO-1. BBB permeabilization facilitates the entry of IL-17, which increases in cerebellum and activates microglia. This increases TNF alpha and the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway. This enhances GABAergic neurotransmission which impairs motor coordination. Blocking peripheral IL-17 with anti-IL-17 prevents all the above process and prevents motor incoordination. Early treatment to reduce blood IL-17 may be a useful treatment to reverse motor incoordination in patients with MHE.

关键词： IL-9 expression   Th9 cells   cytokines   human CD4(+) T cell differentiation   inborn errors of immunity  

摘要： BACKGROUND:CD4 T cells play essential roles in adaptive immunity. Distinct CD4 T cell subsets - Th1, Th2, Th17, Th22, T follicular helper and regulatory T cells - have been identified and their contributions to host defence and immune regulation are increasingly well-defined. IL-9 producing Th9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human Th9 cells remain incompletely defined. OBJECTIVE:Define signalling pathways that regulate IL-9 production by human CD4 T cells. METHODS:Human naive and memory CD4 T cells were cultured under different conditions and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4 T cells from a broad range of patients (n=92) with pathogenic variants in key immune genes (n=21) to differentiate into IL-9 cells. RESULTS:We identified two culture conditions that yielded IL-9-expressing cells from naïve CD4 T cells, and amplified IL-9 production by in vivo-generated memory CD4 T cells: TGFβ plus IL-4 (i.e. Th9 polarising condition), and the combination of IL-21, IL-23, IL-6, IL-1β and TGFβ (i.e. Th17 polarising condition). Combining these conditions had a synergistic effect in generating IL-9CD4 T cells. IL-9 induction required STAT3-activating cytokines as well as intact signalling via the TCR and STAT5. Importantly, IL-9 induction was restrained by IFNγ/STAT1 and IL-10. CONCLUSIONS:Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4 T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease.

关键词： Atherosclerosis   C1q/TNF-related protein-1   Mendelian randomization   Coronary artery disease   Ischemic stroke   Multivariate  

摘要： Aims: To investigate the causal relationship between C1q/TNF-related protein-1 (CTRP1) and atherosclerosis across various vascular sites, informed by studies connecting CTRP1 to coronary artery disease. Methods: Summary statistics of CTRP1 from the available genome-wide association studies and atherosclerosis in classic vascular sites (including cerebral, coronary, and other arteries) from the FinnGen biobank were extracted for a primary MR analysis, and the analysis was replicated using Ischemic Stroke cohort (large artery atherosclerosis) for validation. The inverse variance-weighted method was used for primary assessment. Sensitivity analysis was performed by Cochrane's Q test and leave-one-out analysis. Potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to investigate the independent effect of CTRP1 on atherosclerosis after removing confounding factors. Results: Reliable causal evidence was found for CTRP1 involvement in three atherosclerosis endpoints: causal effects of CTRP1 on cerebral atherosclerosis (OR =1.31, CI:1.04-1.66;FDR_P=0.0222)], coronary atherosclerosis (OR=1.13, CI: 1.08-1.19;FDR_P=2.86e-07), and atherosclerosis at other sites (OR=1.06, CI:1.02-1.11;FDR_P=0.0125). The validation cohort further confirmed its causal effect on large-artery atherosclerosis (OR=1.10, CI:1.03-1.18;FDR_P=0.0115). The reverse MR analysis did not support the causal effect of atherosclerosis on CTRP1. Moreover, the MVMR analysis, adjusting for confounders (CTRP3, CTRP5, and CTRP9A), highlighted a significant independent causal effect of CTRP1 remaining on atherosclerosis. Conclusion: CTRP1 may represent a promising target for preventing and treating systemic atherosclerosis.

关键词： 溃疡性结肠炎   电针   黏液屏障   IL-4/STAT6/SPDEF通路   杯状细胞   小鼠  

摘要： 目的 观察电针对溃疡性结肠炎（UC）模型小鼠IL-4/STAT6/SPDEF通路相关蛋白表达的影响，探讨其改善肠黏液屏障的作用机制。方法 48只BALB/c小鼠随机分为空白组12只和造模组36只，造模组采用3%葡聚糖硫酸钠自由饮用建立UC模型，造模成功后随机分为模型组、电针组、柳氮磺吡啶组（SASP组），每组12只。电针组针刺“关元”“天枢”“足三里”“上巨虚”，每日20 min,SASP组每日予SASP混悬液（500 mg/kg）灌胃，空白组不干预，模型组仅捆绑，连续7 d。观察小鼠一般状况并进行疾病活动指数（DAI）评分，HE染色观察结肠组织形态，进行结肠黏膜损伤指数（CMDI）评分，AB-PAS染色观察结肠组织杯状细胞数量，免疫荧光染色检测结肠组织黏蛋白2(MUC2)蛋白表达，ELISA测定血清肿瘤坏死因子-α(TNF-α)、γ干扰素（IFN-γ）含量，Western blot检测结肠组织白细胞介素（IL）-4、信号转导与转录激活因子（STAT）6、上皮特异性ETs转录因子（SPDEF）蛋白表达。结果 与空白组比较，模型组小鼠出现黏液便、便血，饮食饮水量减少，体质量下降，DAI、CMDI评分明显上升（P<0.01），肠绒毛脱落坏死，结肠隐窝-绒毛结构破坏，伴有严重中性粒细胞浸润，黏液层变薄，杯状细胞萎缩、数量减少（P<0.01），结肠组织MUC2表达明显降低（P<0.01），血清TNF-α、 INF-γ含量明显升高（P<0.01），结肠组织IL-4、 STAT6、SPDEF蛋白表达明显降低（P<0.01）；与模型组比较，电针组与SASP组小鼠黏液便、便血减轻，体质量升高，DAI、CMDI评分明显降低（P<0.05），肠上皮形态基本正常，腺体结构改善，少量炎性细胞浸润和轻微水肿，黏液层厚度有所恢复，杯状细胞萎缩减轻、数量增加（P<0.05），结肠组织MUC2表达明显升高（P<0.05），血清TNF-α、IFN-γ含量明显降低（P<0.05），结肠组织IL-4、STAT6、SPDEF蛋白表达明显升高（P<0.05）。结论 电针可促进UC模型小鼠肠黏液屏障修复，其机制可能与激活IL-4/STAT6/SPDEF通路相关蛋白表达有关。

关键词： AHUO   acute hepatitis of unknown origin   AAV2   adeno-associated virus 2   HBV   hepatitis B virus   HLA   human leukocyte antigen   PAHUO   pediatric acute hepatitis of unknown origin  

关键词： wound healing   granulation tissue   myofibroblasts   cancer-associated fibroblasts   IL-6  

摘要： Wound healing represents a complex and evolutionarily conserved process across vertebrates, encompassing a series of life-rescuing events. The healing process runs in three main phases: inflammation, proliferation, and maturation/remodelling. While acute inflammation is indispensable for cleansing the wound, removing infection, and eliminating dead tissue characterised by the prevalence of neutrophils, the proliferation phase is characterised by transition into the inflammatory cell profile, shifting towards the prevalence of macrophages. The proliferation phase involves development of granulation tissue, comprising fibroblasts, activated myofibroblasts, and inflammatory and endothelial cells. Communication among these cellular components occurs through intercellular contacts, extracellular matrix secretion, as well as paracrine production of bioactive factors and proteolytic enzymes. The proliferation phase of healing is intricately regulated by inflammation, particularly interleukin-6. Prolonged inflammation results in dysregulations during the granulation tissue formation and may lead to the development of chronic wounds or hypertrophic/keloid scars. Notably, pathological processes such as autoimmune chronic inflammation, organ fibrosis, the tumour microenvironment, and impaired repair following viral infections notably share morphological and functional similarities with granulation tissue. Consequently, wound healing emerges as a prototype for understanding these diverse pathological processes. The prospect of gaining a comprehensive understanding of wound healing holds the potential to furnish fundamental insights into modulation of the intricate dialogue between cancer cells and non-cancer cells within the cancer ecosystem. This knowledge may pave the way for innovative approaches to cancer diagnostics, disease monitoring, and anticancer therapy.

摘要： OBJECTIVES:Human T follicular helper (Tfh) cells are classified into three subsets: Tfh1, Tfh2, and Tfh17 cells. Among them,Tfh2 cells are defined as CXCR3-negative and CCR6-negative, and may contain diverse cell populations. We examined whether CCR4 serves as a marker for identifying Tfh2 cells that produce interleukin (IL)-4 and its involvement in IgG4-related disease (IgG4-RD). METHODS:Single cell analysis of IL-4-producing Tfh subset was performed using multi-colour flow cytometry and t-SNE method. Blood samples were obtained from 23 treatment-naïve patients with active IgG4-RD. CCR4+Tfh2 cells were also assessed in affected tissues of IgG4-RD by flow cytometry and immunohistochemical staining. RESULTS:Tfh2 cells expressing CCR4 were identified as Tfh cells that specifically produce IL-4. CCR4+Tfh2 cells showed higher expression of GATA-3 and ICOS than CCR4-Tfh2 cells, while there was no difference in the expression of BCL-6 and FOXP3. The proportion of CCR4+Tfh2 cells in peripheral blood was increased in IgG4-RD compared to healthy controls, and even more CCR4+Tfh2 cells infiltrated into the affected lesions. CCR4+GATA-3+Tfh2 cells diffusely infiltrated tertiary lymphoid tissues and storiform fibrosis lesions. The proportion of CCR4+Tfh2 cells showed a significant correlation specifically with serum IgG4 levels among clinical indicators. Glucocorticoid therapy did not correct the increased proportion of CCR4+Tfh2 cells. CONCLUSIONS:CCR4 serves as a marker for identifying Tfh2 cells that specifically produce IL-4. CCR4+Tfh2 cells are a widely present T cell population that infiltrates tertiary lymphoid tissues and storiform fibrosis of IgG4-RD. Glucocorticoid fails to effectively target CCR4+Tfh2 cells that may contribute to a high relapse rate during glucocorticoid tapering in this disease.