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关键词： Tissue regeneration  

摘要： Inflammatory cells are crucial regulators of infection and regeneration that actively migrate to affected tissues. NF-kB and TNF-alpha (TNF alpha) are master regulators of immune signalling, but their importance for immune cell migration is much less well understood. We have therefore investigated how NF-kB and TNF alpha regulate both macrophage function and behaviour in vivo using a zebrafish model of tissue repair. We show that NF-kB activity differentially regulates TNF alpha activity through Tnf receptors 1a and 1b to control macrophage responses to injury. Loss of NF-kB in macrophages results in elevated TNF alpha expression and results in more directional migration. Impaired NF-kB activity in macrophages perturbs tissue regeneration, causes increased proliferation, altered pro- and anti-inflammatory gene expression and delays fin regeneration. We identify a crucial role for NF-kB modulation of TNF alpha signaling to regulate macrophage responses to tissue injury, which are necessary for effective fin regeneration.

关键词： Dry eye disease   flow cytometry   inflammation   impression cytology   HLA-DR  

摘要： Purpose: To assess the association of HLA-DR on ocular surface conjunctival cells with the severity of signs and symptoms of dry eye disease (DED) in patients enrolled in the NORTHERN LIGHTS phase 2 trial. Methods: Patients with moderate to severe DED were recruited from 10 different countries in Europe. Symptoms of DED were assessed using the visual analog scale (VAS) global discomfort score, and signs via corneal fluorescein staining (CFS), lissamine green staining, Schirmer's test, and tear osmolarity. HLA-DR expression was evaluated via flow cytometry from impression cytology of conjunctival cells using the EyePrim (TM) device sampled from 205 DED patients. Results: HLA-DR expression was detected in a mean of 3.4% of cells at baseline. HLA-DR expression was significantly associated with corneal staining severity at baseline (p < 0.01). HLA-DR expression was not significantly associated with DED symptoms (VAS global discomfort score), nor lissamine green staining, Schirmer's test, tear osmolarity, or Sjogren's syndrome. Conclusion: HLA-DR was present in a wide range of percentages among DED patients indicating the heterogeneous nature of DED. HLA-DR was significantly associated with corneal fluorescein staining suggesting a correlation of the biomarker with ocular surface damage.

关键词： Mycosis fungoides   s & eacute   zary syndrome   Cutaneous T-cell Lymphoma   IL-4/13 inhibitors   microenvironment  

摘要： IntroductionDupilumab is a monoclonal antibody that inhibits the IL-4 receptor alpha, preventing the binding of IL-4 and IL-13 and the subsequent signal transduction. Mycosis fungoides (MF) and S & eacute;zary syndrome (SS) are the most common form of cutaneous T-cell lymphoma (CTCL). Several cases of MF have been reported following the initiation of dupilumab in patients previously diagnosed with atopic dermatitisAreas coveredThis article is a narrative review of the current state of knowledge regarding the correlation between dupilumab and the development of CTCL. Clinical studies on this topic are reviewed, with a particular focus on the pathogenetic theories proposed to date. Finally, we present a new theory, previously undescribed, regarding the potential role of the cytokine microenvironment in triggering CTCL in patients treated with dupilumabExpert opinionDupilumab could unmask CTCLs by inhibiting IL-4. In fact, a recent study observed that IL-4 plays a key role in maintaining the 'equilibrium phase' between tumor and microenvironment cells. Disruption of this balance could promote the escape of tumor cells and lead to the unmasking of CTCLs.

摘要： Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and frequently has mutations in the transcription factor p53. TAp63 alpha is a member of the p53 protein family that is generally tumor suppressive in various other p53-mutant or p53-deficient cancers. Here, we found that TAp63 alpha inhibited cell proliferation, epithelial-mesenchymal transition (EMT), and migration in several p53-mutant PDAC cell lines. TAp63 alpha transcriptionally repressed IL20RB (which encodes a subunit of the interleukin-20 receptor), potentially by inducing the methylation of its promoter. However, mutations in p53 or KRAS that are common in PDAC increased the abundance of the E3 ligase TRIM21, which promoted the ubiquitin-dependent degradation of TAp63 alpha. Thus, the degradation of TAp63 alpha enabled increases in IL20RB expression and formation of IL-20 receptors, resulting in the activation of downstream JAK1-STAT3 signaling that stimulated the proliferation, EMT, migration, and in vivo metastatic seeding of PDAC cells. Our findings identify a signaling axis involving TRIM21, TAp63 alpha, and IL-20RB in PDAC progression.

关键词： Interferon gamma (IFN-gamma)   tumor necrosis factor alpha (TNF-alpha)   granzyme B   vitiligo   Meta-analysis  

摘要： Background: Vitiligo is a chronic autoimmune skin depigmenting condition. IFN-gamma, TNF-alpha and granzyme B play key roles in vitiligo pathogenesis, some findings suggest their roles may be contradictory. Objective: We aimed to assess IFN-gamma, TNF-alpha and granzyme B levels in blood and skin of vitiligo patients using a meta-analysis approach. Additionally, we evaluated their association with disease activity. Methods: A Meta-analysis was conducted using Review Manager 5.4 software. A total of 55 studies including 3,023 vitiligo patients and 2,534 controls were included in the study. Results: Pooled results from our meta-analysis indicated significantly elevated IFN-gamma protein and transcript levels in blood and skin of vitiligo patients (p < 0.05). TNF-alpha protein levels were also significantly increased in blood and skin of vitiligo patients (p < 0.05). IFN-gamma and TNF-alpha levels were significantly higher in the lesional skin as compared to non-lesional skin (p < 0.05). Furthermore, elevated levels of IFN-gamma and TNF-alpha were observed in patients with active vitiligo (p < 0.05). Additionally, our study suggested a significant increase in granzyme B levels in vitiligo patients (p < 0.05). Conclusion: Overall, the meta-analysis suggests that IFN-gamma, TNF-alpha and granzyme B play a crucial role in vitiligo pathogenesis and progression and may serve as potential therapeutic targets for managing the disease. The PROSPERO registration no. for meta-analysis is CRD42024620274

关键词： antibody   protein engineering   immunology   delivery  

摘要： Interleukin (IL)- 23 is a validated therapeutic target in inflammatory bowel disease. While antibodies targeting IL23 demonstrate clinical efficacy, they face challenges such as high costs, safety risks, and the necessity of parenteral administration. Here, we present a workflow to simultaneously enhance the affinity and protease stability of an anti- IL23R VHH employs both CDR and framework residues to achieve picomolar affinity for IL23R. The engineered VHH remains stable for over 8 h in intestinal fluid and 24 h in fecal samples. Oral administration of this VHH achieves deep pathway inhibition in nonhuman primate blood for over 24 h. With high potency, gut stability, high production yield, and favorable drug- like properties, oral VHHs offer a promising approach for inflammatory bowel diseases.

关键词： egg layer chickens   Marek's disease   MHC   genetic resistance  

摘要： Mortality from Marek's disease virus (MDV) infection results in economic loss for the poultry industry. It is controlled by vaccination, but the virus mutates and becomes more virulent. Variation within the MHC is well known to impact the outcomes following MDV infection from research performed utilizing the White Leghorn breed, with laboratory strains of the virus. The effect of the MHC haplotype following MDV challenge was determined from six lines of commercial elite (White Plymouth Rock (two), White Leghorn (three), and Rhode Island Red (one)) egg layer lines, challenged with vv+ virus. Mortality was recorded as sire daughter averages at 16-18 weeks of age from 19 generations of data. Sires were genotyped using a set of MHC-specific SNPs, encompassing 210,000 bp. Across all lines, there was a total of 23 unique MHC haplotypes, of which 15 were found at a frequency greater than 5% and used for further analysis. A significant impact on mortality was found for 16 of the haplotypes, with 9 haplotypes associated with decreased mortality and 7 haplotypes with increased mortality. There were three haplotypes identified in more than one line, allowing cross-line comparisons. The effect of these common haplotypes was consistent (either negative, positive or neutral) between lines.

关键词： anti-TNF failure   biological therapy   sequential therapy   ulcerative colitis   inflammatory bowel diseases  

摘要： Background: Many ulcerative colitis (UC) patients require the use of second-line agents after the failure of anti-TNF therapy. Research design and methods: We conducted a multicenter, retrospective study including 683 chronically active, moderate-to-severe UC patients who failed first-line anti-TNFs. The rate of treatment persistence and colectomy-free survival was assessed up to 3 years after the initiation of second-line therapy. Predictors for colectomy and persistence were investigated. Results: After the failure of the first-line anti-TNF, ustekinumab had superior persistence and colectomy-free survival rates compared to tofacitinib (p = 0.05;p = 0.001) and vedolizumab (p = 0.02;p = 0.05), but significant difference was only found in persistence rates in comparison with anti-TNFs (p < 0.001). Regardless of the number of prior anti-TNFs, significantly higher persistence (p = 0.05) and colectomy-free survival rates (p = 0.01) were observed over 2 years with ustekinumab than with vedolizumab or tofacitinib, whereas ustekinumab's superiority over tofacitinib seemed to disappear by the third year. Hypoalbuminaemia (p = 0.002) and shorter disease duration at second-line initiation (p = 0.03) increased, while concomitant immunomodulators (p = 0.05) reduced the risk for colectomy. Shorter disease duration (p = 0.01) and primary non-response to the previously used anti-TNF (p < 0.001) negatively influenced persistence with second-line non-TNF-targeted agents. Conclusion: After first-line anti-TNF failure, switching to a non-anti-TNF agent is worth considering in moderate-to-severe UC.

关键词： Herbicides   RAW 264.7   TNF   immunomodulatory activity   mitochondria   oxidative stress   clomazone   sulfentrazone   glyphosate  

摘要： Weeds are a concern in agriculture and the use of herbicides constitutes an effective, efficient, and economical way to control their growth. Recent discoveries of herbicides are promising for the management of resistant weeds. However, there is a gap in the knowledge of the toxic effects of some herbicides previously reported on immune cells. The present study aimed to examine cellular immunotoxicity of three herbicides (clomazone, glyphosate, and sulfentrazone) after 96 hr incubation utilizing RAW 264.7 BALB/c mouse monocyte/macrophage-like cell line to elucidate the role of some toxicological pathways. Data demonstrated the herbicides clomazone, glyphosate, and sulfentrazone initiated a cytotoxic effect as evidenced by EC50 values of 429.2;53.7;866.6 mg/L, respectively. Clomazone and sulfentrazone, at all concentrations, induced excess production of reactive oxygen (ROS) and reactive nitrogen (RNS) free radicals. An immunosuppression was observed in RAW 264.7 cells after incubation with 50 or 100 mg/L glyphosate and 500 or 1000 mg/L sulfentrazone. In addition, all herbicides produced mitochondrial depolarization and decreased tumor necrosis factor-alpha (TNF-alpha) levels. This constitutes the first report of the effects of clomazone and sulfentrazone on RAW 264.7 cells, including reduced TNF-alpha levels, indicating the adverse influence of herbicides on the immune system.