TNF-beta Research Articles

The Impact of Acute Ammonia Nitrogen Stress on Serum Biochemical Indicators and Spleen Gene Expression in Juvenile Yellowfin Tuna (Thunnus albacares)

The presence of ammonia nitrogen in water has a significant impact on the serum and spleen of fish, potentially leading to changes in substances such as proteins in the serum while also causing damage to the immune function of the spleen. To investigate the effects of ammonia nitrogen (NH3-N) stress on juvenile yellowfin tuna (Thunnus albacares), this study established three NH3-N concentrations, 0, 5, and 10 mg/L, denoted as L0, L1, and L2, respectively. Serum and spleen samples were collected at 6, 24, and 36 h. The effects of different NH3-N concentrations and exposure times on the physiological status of juvenile fish were investigated by analyzing serum biochemical indices and splenic gene expression. The results indicate that in the L1 group, the serum high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), complement 3 (C3) and complement 4 (C4) levels, and acid phosphatase (ACP) activity showed a trend of initially increasing and then decreasing. In the L2 group, the serum low-density lipoprotein cholesterol (LDL-C), HDL-C, and C4 levels and ACP activity also displayed an initially rising and then declining trend, while TG, C3, and creatinine (CRE) levels and alkaline phosphatase (AKP) activity showed an upward trend. In the L1 group, glutathione peroxidase 1b (GPX1b), interleukin 10 (IL-10), interleukin 6 receptor (IL-6r), and tumor necrosis factor alpha (TNF-α) gene expression levels in the spleen exhibited a trend of first increasing and then decreasing. In the L2 group, IL-10, IL-6r, tumor necrosis factor beta (TNF-β), caspase 2 (casp2), and caspase 9 (casp9) gene expression levels in the spleen also showed an initial increase followed by a decrease. When NH3-N levels are below 5 mg/L, it is recommended to limit stress exposure to no more than 36 h for the juvenile fish. For concentrations ranging from 5 to 10 mg/L, stress should be strictly controlled to within 24 h. Exposure to high NH3-N levels may affect biochemical indicators such as serum lipid metabolism, immunity, and metabolism in juvenile fish, and may damage the expression of antioxidant, immune gene, and apoptosis factors in the spleen. This study aims to deepen our understanding of the effects of NH3-N on juvenile tuna, with the goal of establishing effective water quality monitoring and management strategies. This will ensure the quality of aquaculture water, reduce the harm caused by NH3-N to juvenile yellowfin tuna, and enhance aquaculture efficiency and product quality.

Searching for New Biomarkers of Neuroendocrine Tumors: A Comparative Analysis of Chromogranin A and Inflammatory Cytokines in Patients with Neuroendocrine Tumors.

Neuroendocrine neoplasms (NENs) present a diagnostic challenge due to their heterogeneous nature and non-specific clinical manifestations. This study aimed to explore novel biomarkers for NENs. Serum chromogranin A (CgA) levels and a panel of 48 inflammatory cytokines were analyzed in a cohort of 84 NEN patients and 40 healthy controls using enzyme-linked immunosorbent assay (ELISA) and multiplex ELISA. Significant alterations in cytokine levels were observed in the NEN patients compared to the controls, including elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), and reduced levels of angiogenic factors like platelet-derived growth factor-BB (PDGF-BB) and tumor necrosis factor beta (TNF-β). Notably, cytokines such as growth-regulated alpha protein (GRO-α) and TNF-β demonstrated strong potential as diagnostic markers, with receiver operating characteristic (ROC) curve analyses showing high sensitivity and specificity. Additionally, a positive correlation was found between CgA levels and several inflammatory cytokines, suggesting their synergistic role in tumor progression. These findings highlight the limited reliability of CgA alone as a diagnostic marker and underscore the importance of a multi-marker approach in diagnosing and monitoring NENs. Further research on a larger cohort is necessary to validate these biomarkers and their potential clinical applications.

Association between the levels of toxic heavy metals and schizophrenia in the population of Guangxi, China: A Case-Control Study

The relationship between body levels of heavy metals and the risk of schizophrenia remains unclear. This study investigates the relationship between plasma levels of toxic heavy metals and the risk of schizophrenia among adults in Guangxi, China. Plasma concentrations of lead (Pb), cadmium (Cd), arsenic (As), and chromium (Cr) were measured using inductively coupled plasma mass spectrometry (ICP-MS). To evaluate both the single and combined effects of metal exposure on the risk of schizophrenia, we employed multivariate logistic regression, Bayesian Kernel Machine Regression (BKMR), and generalized Weighted Quantile Sum (gWQS) models. Additionally, we employed the Comparative Toxicogenomics Database (CTD) to analyze the mechanistic pathways through which metal mixtures may induce schizophrenia. Relative mRNA expression levels were measured using Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to predict potential biological functions. In logistic regression models, compared to the lowest exposure group (Q1), the odds ratios (ORs) for Pb in groups Q2, Q3, and Q4 were 2.18 (95% CI: 1.20 - 3.94), 4.74 (95% CI: 2.52 - 8.95), and 3.62 (95% CI: 1.80 - 7.28), respectively. Both BKMR and gWQS models indicated a positive correlation between the combined effects of toxic heavy metal mixtures and the risk of schizophrenia, with Pb demonstrating the most substantial impact, particularly in older adults and females. Elevated levels of tumor necrosis factor (TNF) and interleukin-1 beta (IL-1β) were observed in patients with schizophrenia, while the expression of tumor protein p53 (TP53) was significantly reduced. These findings underscore the critical need to avoid exposure to toxic heavy metals to prevent schizophrenia, highlighting significant public health implications.

A protocol for a single center, randomized, controlled trial assessing the effects of spectacles or orthokeratology on dry eye parameters in children and adolescents

BackgroundThe prevalence of myopia among adolescents is increasing precipitously in China, and the popularity of orthokeratology (OK) lenses as an effective treatment for controlling myopia progression is rising. This protocol assessed and compared the clinical dry eye parameters in children and adolescents with myopia treated with spectacles or OK lenses. Methods and analysisThis single-masked randomized control trial will include 300 participants (aged 8–17 years) with myopia treated with OK lens (study group) or spectacles (control group). We will record the ocular surface disease index, visual analog scale score, noninvasive tear breakup time, tear meniscus height, meibomian gland score, ocular redness score, visual acuity, tear Matrix Metalloproteinase-9 concentration, tear Lymphotoxin alpha levels at baseline, and after 1-, 3-, 6-, and 12-month. DiscussionThis study will be a standardized, scientific, clinical trial designed to evaluate the dry eye parameters in children and adolescents with myopia treated with OK lenses for myopia control. Ethics and disseminationThis study has been approved by the Ethics Committee of He Eye Specialist Hospital [ethics approval number: IRB(2023)K024.01]. Before participating in the trial, written informed consent will be obtained from all patient's parents or guardians. The findings of this study will be showcased at both local and international conferences and will also be submitted for publication in reputable peer-reviewed journals. Trial registration numberClinicaltrials.gov: NCT06023108 {2a, 2b}

LTβR Agonism Promotes Anti-Tumor Immune Responses via Modulation of the Tumor Microenvironment.

The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis and better responses to immune-checkpoint blockade (ICB) in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to anti-tumor responses may facilitate development of improved treatment strategies. Lymphotoxin beta receptor (LTβR) signaling is a critical regulator of lymph node organogenesis and can cooperate with antiangiogenic and ICB treatment to augment tumor-associated HEV formation. Here, we demonstrated that LTβR signaling modulates the tumor microenvironment via multiple mechanisms to promote anti-tumor T cell responses. Systemic activation of the LTβR pathway via agonistic antibody treatment induced tumor-specific HEV formation, upregulated the expression of TLS-related chemokines, and enhanced dendritic cell (DC) and T cell infiltration and activation in syngeneic tumor models. In vitro studies confirmed direct effects of LTβR agonism on DC activation and maturation and associated DC-mediated T cell activation. Single agent LTβR agonist treatment inhibited syngeneic tumor growth in a CD8+ T cell- and HEV-dependent manner, and the LTβR agonist enhanced anti-tumor effects of anti-PD-1 and CAR T cell therapies. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LTβR agonism and lymphotoxin alpha (LT⍺) expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA-4 treatment. Collectively, this study highlights crucial functions of LTβR signaling in modulating the tumor microenvironment and could inform future HEV/TLS-based strategies for cancer treatments.

Lymphotoxin β receptor and tertiary lymphoid organs shape acute and chronic allograft rejection.

Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLOs regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin αβ/lymphotoxin β receptor (LTαβ/LTβR) pathway, which is essential for TLO formation, to define the role of TLOs in transplantation. We showed that intragraft TLOs are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLOs in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLOs or LTα overexpression accelerated rejection. If the LTβR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival was prolonged. Intravital microscopy of renal TLOs demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLOs contributes to local immune responses, leading to earlier allograft failure. TLOs and the LTαβ/LTβR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases, such as autoimmune diseases or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.

Effects of circulating inflammatory proteins on spinal degenerative diseases: Evidence from genetic correlations and Mendelian randomization study.

Numerous investigations have suggested links between circulating inflammatory proteins (CIPs) and spinal degenerative diseases (SDDs), but causality has not been proven. This study used Mendelian randomization (MR) to investigate the causal associations between 91 CIPs and cervical spondylosis (CS), prolapsed disc/slipped disc (PD/SD), spinal canal stenosis (SCS), and spondylolisthesis/spondylolysis. Genetic variants data for CIPs and SDDs were obtained from the genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary method, analyzing the validity and robustness of the results through pleiotropy and heterogeneity tests and performing reverse MR analysis to test for reverse causality. The IVW results with Bonferroni correction indicated that beta-nerve growth factor (β-NGF), C-X-C motif chemokine 6 (CXCL6), and interleukin-6 (IL-6) can increase the risk of CS. Fibroblast growth factor 19 (FGF19), sulfotransferase 1A1 (SULT1A1), and tumor necrosis factor-beta (TNF-β) can increase PD/SD risk, whereas urokinase-type plasminogen activator (u-PA) can decrease the risk of PD/SD. FGF19 and TNF can increase SCS risk. STAM binding protein (STAMBP) and T-cell surface glycoprotein CD6 isoform (CD6 isoform) can increase the risk of spondylolisthesis/spondylolysis, whereas monocyte chemoattractant protein 2 (MCP2) and latency-associated peptide transforming growth factor beta 1 (LAP-TGF-β1) can decrease spondylolisthesis/spondylolysis risk. MR analysis indicated the causal associations between multiple genetically predicted CIPs and the risk of four SDDs (CS, PD/SD, SCS, and spondylolisthesis/spondylolysis). This study provides reliable genetic evidence for in-depth exploration of the involvement of CIPs in the pathogenic mechanism of SDDs and provides novel potential targets for SDDs.

The predictive value of TNF family for pulmonary tuberculosis: a pooled causal effect analysis of multiple datasets.

Despite extensive research on the relationship between pulmonary tuberculosis (PTB) and inflammatory factors, more robust causal evidence has yet to emerge. Therefore, this study aims to screen for inflammatory proteins that may contribute to the susceptibility to PTB in different populations and to explain the diversity of inflammatory and immune mechanisms of PTB in different ethnicity. The inverse variance weighted (IVW) model of a two-sample Mendelian Randomization (MR) study was employed to conduct causal analysis on data from a genome-wide association study (GWAS). This cohort consisting PTB GWAS datasets from two European and two East Asian populations, as well as 91 human inflammatory proteins collected from 14,824 participants. Colocalization analysis aimed to determine whether the input inflammatory protein and PTB shared the same causal single nucleotide polymorphisms (SNPs) variation within the fixed region, thereby enhancing the robustness of the MR Analysis. Meta-analyses were utilized to evaluate the combined causal effects among different datasets. In this study, we observed a significant negative correlation between tumor necrosis factor-beta levels (The alternative we employ is Lymphotoxin-alpha, commonly referred to as LT) (P < 0.05) and tumor necrosis factor receptor superfamily member 9 levels (TNFRSF9) (P < 0.05). These two inflammatory proteins were crucial protective factors against PTB. Additionally, there was a significant positive correlation found between interleukin-20 receptor subunit alpha levels (IL20Ra) (P < 0.05), which may elevate the risk of PTB. Colocalization analysis revealed that there was no overlap in the causal variation between LT and PTB SNPs. A meta-analysis further confirmed the significant combined effect of LT, TNFRSF9, and IL20Ra in East Asian populations (P < 0.05). Levels of specific inflammatory proteins may play a crucial role in triggering an immune response to PTB. Altered levels of LT and TNFRSF9 have the potential to serve as predictive markers for PTB development, necessitating further clinical validation in real-world settings to ascertain the impact of these inflammatory proteins on PTB.

OA02 Longitudinal high throughput proteomics identifies novel proteins associated with inflammation and future response in new-onset, treatment-naïve rheumatoid arthritis

Abstract Background/Aims Despite the availability of effective targeted therapies, only 20-30% achieve low disease activity and even fewer attain remission. There remains a pressing need to identify meaningful biomarkers and disease endotypes to enable precision medicine. We aimed to identify serum protein biomarkers that associate with RA inflammation and future remission in a treatment-naïve, new-onset RA trial cohort. Methods Serum from 105 patients from the ‘VEDERA’ trial (first-line tumour necrosis factor inhibitor + methotrexate [TNFi + MTX] versus methotrexate treat-to-target [MTX-TT]) at baseline, week 24 and 48 were analysed for 92 proteins using the Olink Target 96 Inflammation panel. Clinical and MSUS assessments completed at baseline, weeks 24 and 48 were used for the analyses. Clinical remission was defined as DAS28-ESR ≤ 2.6 and joint-level remission as absence of power Doppler ultrasound synovitis (PDUS). After adjusting for age, gender and seropositive status, Bayesian mixed effects regression (posterior estimates and 95% credible intervals reported) was used to identify association of (i) proteins with clinical disease activity (DAS28-ESR) and joint-level inflammation (total power Doppler ultrasound synovitis (PDUS) scores] and (ii) baseline proteins with future (week 24 or 48) clinical and joint-level remission. Results Longitudinally, out of 92 proteins, 10 and 14 were significantly associated with DAS28-ESR and total PDUS scores respectively, with 3 proteins in common: leukaemia inhibitory factor receptor (LIF-R); fractalkine (CX3CL1); interleukin-10 receptor alpha (IL-10RA). Baseline levels of 9 proteins were associated with future clinical remission (week 24 = 6 proteins; week 48 = 3 proteins) while 6 were associated with future PDUS status (week 24 = 4 proteins; week 48 = 3 proteins). Proteins that were associated with inflammation longitudinally and whose baseline levels associated with future remission included IL-17C, fibroblast growth factor 5 (FGF-5), lymphotoxin alpha and TNF. Posterior estimates and 95% credible intervals for above proteins are reported in Table 1. Conclusion Using longitudinal high-throughput proteomics in a treatment-naïve early onset RA cohort, this study sheds new light on known and novel protein associates of inflammation and future remission. With future validation, these biomarkers could provide mechanistic understanding and allow for individualised treatment strategies to improve outcomes. Disclosure R. Shukla: None. R. Wakefield: None. A. Tan: None. P. Emery: Consultancies; BristolMyersSquibb, AbbVie, Gilead, Galapagos, Eli Lilly, MSD, Pfizer, Novartis, Roche and Samsung. Grants/research support; AbbVie, Eli Lilly, Novartis, BristolMyersSquibb, Pfizer and Roche, outside the submitted work. D. Plant: None. M.H. Buch: Consultancies; AbbVie, Arxx Therapeutics, Boehringer Ingelheim, Galapagos, Gilead, and Pfizer; and speaker fees from AbbVie, CESAS Medical, Galapagos, Gilead, Medistream, and Pfizer. Grants/research support; grant support from Gilead.

The causal association between circulating cytokines with the risk of frailty and sarcopenia under the perspective of geroscience.

Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis. Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms. Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, P = 0.028, false discovery rate (FDR)-adjusted P = 1.000; OR = 1.03, 95% CI = 1.00-1.07, P = 0.042, FDR-adjusted P = 0.784; OR = 1.02, 95% CI = 1.00-1.05, P = 0.038, FDR-adjusted P = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, P = 0.003, FDR-adjusted P = 0.103). Monokine induced by interferon-γ (MIG) and tumor necrosis factor-beta (TNF-β) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, P < 0.0001, FDR-adjusted P= 0.012; OR = 1.01, 95% CI = 1.00-1.03, P = 0.013, FDR-adjusted P = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia. Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-β and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors.

The Prolonged Activation of the p65 Subunit of the NF-Kappa-B Nuclear Factor Sustains the Persistent Effect of Advanced Glycation End Products on Inflammatory Sensitization in Macrophages.

Advanced glycation end products (AGEs) prime macrophages for lipopolysaccharide (LPS)-induced inflammation. We investigated the persistence of cellular AGE-sensitization to LPS, considering the nuclear content of p50 and p65 nuclear factor kappa B (NFKB) subunits and the expression of inflammatory genes. Macrophages treated with control (C) or AGE-albumin were rested for varying intervals in medium alone before being incubated with LPS. Comparisons were made using one-way ANOVA or Student t-test (n = 6). AGE-albumin primed macrophages for increased responsiveness to LPS, resulting in elevated levels of TNF, IL-6, and IL-1beta (1.5%, 9.4%, and 5.6%, respectively), compared to C-albumin. TNF, IL-6, and IL-1 beta secretion persisted for up to 24 h even after the removal of AGE-albumin (area under the curve greater by 1.6, 16, and 5.2 times, respectively). The expressions of Il6 and RelA were higher 8 h after albumin removal, and Il6 and Abca1 were higher 24 h after albumin removal. The nuclear content of p50 remained similar, but p65 showed a sustained increase (2.9 times) for up to 24 h in AGE-albumin-treated cells. The prolonged activation of the p65 subunit of NFKB contributes to the persistent effect of AGEs on macrophage inflammatory priming, which could be targeted for therapies to prevent complications based on the AGE-RAGE-NFKB axis.

Associations between Th1-related cytokines and complicated pediatric appendicitis

The pathogenesis of appendicitis is not understood fully, and the diagnosis can be challenging. Previous research has suggested an association between a T helper (Th) 1-dependent immune response and complicated appendicitis. This prospective cohort study aimed to evaluate the association between serum concentrations of the Th1-associated cytokines interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-10, IL-17A and tumor necrosis factor beta (TNF-β) and the risk of complicated appendicitis in children. Appendicitis severity was determined through histopathological examination. A total of 137 children < 15 years with appendicitis were included with a median age of 10 years (IQR 8–12); 86 (63%) were boys, and 58 (42%) had complicated appendicitis. Children with complicated appendicitis had significantly higher concentrations of serum IL-6 and IL-10, and lower of TNF-β. After adjustment for age, symptom duration, and presence of appendicolith in a multivariable logistic regression, a higher concentration of IL-6 remained associated with an increased risk of complicated appendicitis (aOR 1.001 [95% CI 1.000–1.002], p = 0.02). Serum concentrations of IL-1α, IL-1β, IL-2, IL-10, IL-17A and TNF-β were not significantly associated with the risk of complicated appendicitis. In conclusion, our results suggests that the systemic inflammatory response in complicated appendicitis is complex and not solely Th1-dependent.

Alcohol and Caffeine Co-Administration Increased Acetylcholinesterase Activity and Inflammatory Cytokines in Sleep-Deprived Rats: Implications for Cognitive Decline and Depressive-Like Manifestations.

Sleep deprivation is a major health problem in modern society; it has been worsened by alcohol and caffeine intake to stay awake and improve bodily activities, an experience common among night-shift workers. For the present study, 50 adult male Wistar rats weighing between 150 g and 200 g were randomly selected and divided into 5 groups of 10 rats each (n = 10). Group 1 was the control group; group 2 was the group of sleep-deprived (SD) rats; group 3 was composed SD rats submitted to the administration of 20% alcohol; group 4 comprised SD rats submitted to the administration of 200 mg/kg of caffeine; and Group 5 was composed of SD rats who underwent the co-administration of 20% alcohol and 200 mg/kg of caffeine. At the end of 28 days, the animals were euthanized, and blood samples were collected for biochemical analysis. Memory, anxiety, social behavior and locomotive activity were assessed using the Y-maze, the elevated plus maze, the hole-board and three-chambered social approach tests, and the open field test. The plasma levels of the acetylcholinesterase (AChE) enzyme and inflammatory cytokines (interleukin 6 [IL-6], interleukin 10 [IL-10], and tumor necrosis factor beta, [TNF-β]) were also measured. Data was expressed as mean ± standard error of the mean [SEM] values, and the data were analyzed through analysis of variance (ANOVA) followed by the Tukey post hoc test, with significance set at p < 0.05 . The results revealed that sleep deprivation, and the co-administration of alcohol and caffeine impair memory in rats. Sleep deprivation also caused a significant increase in anxiety and anxiety-related behavior, with decreased social interaction, in rats. Locomotive activity was improved in SD rats, especially in those to which alcohol was administered. Sleep deprivation significantly reduced acetylcholinesterase activity among SD rats and those to which alcohol was administered when compared with the controls. The plasma levels of IL-6, IL-10 and TNF-β were significantly increased in SD rats when compared with the controls. The administration of alcohol and caffeine separately, as well as their co-administration, significantly increased cytokine levels in rats.

Decreased expression of IL-4 Gene and Exploring of mutable lymphotoxin alpha (TNF-β) gene in Patients with Systemic Lupus Erythematosus

Rapid genetic system identification characterizes the complex illness known as systemic lupus erythematosus (SLE). The classic cytokine, IL-4, is known to stimulate the Th2 route of differentiation and to effectively inhibit the Th1 response. The pathogenesis of systemic lupus erythematosus (SLE) has been linked to immunological and genetic variables. Therefore, this study aimed to characterize the gene expression of IL-4 in peripheral blood mononuclear cells (PBMC) and explore potential links between the functional Interleukin-4 gene and SLE. Additionally, lymphotoxin alpha (LTA) is a key cytokine in the pathogenesis of SLE. In SLE, cytokines have a significant role in controlling lymphocyte function.

Circulating inflammatory cytokines and sarcopenia-related traits: a mendelian randomization analysis.

To explore the causal relationships between 91 circulating inflammatory cytokines and sarcopenia-related traits (low hand grip strength, appendicular lean mass, and usual walking pace) by Mendelian randomized analysis. Independent genetic variations of inflammatory cytokines and sarcopenia-related traits were selected as instrumental variables from publicly available genome-wide association studies (GWAS). The MR analysis was primarily conducted using the inverse variance-weighted (IVW) method. Sensitivity analyses included Steiger filtering and MR PRESSO, with additional assessments for heterogeneity and pleiotropy. The IVW method indicated a causal relationship between Vascular Endothelial Growth Factor A (VEGF-A) and low hand grip strength (OR = 1.05654, 95% CI: 1.02453 to 1.08956, P = 0.00046). Additionally, Tumor Necrosis Factor-beta (TNF-β) was found to have a causal relationship with appendicular lean mass (ALM) (β = 0.04255, 95% CI: 0.02838 to 0.05672, P = 3.96E-09). There was no evidence suggesting a significant causal relationship between inflammatory cytokines and usual walking pace. Our research substantiated the causal association between inflammatory cytokines, such as VEGF-A and TNF-β, and sarcopenia. This finding may provide new avenues for future clinical treatments.

Retinal response to systemic inflammation differs between sexes and neurons.

Neurological dysfunction and glial activation are common in severe infections such as sepsis. There is a sexual dimorphism in the response to systemic inflammation in both patients and animal models, but there are few comparative studies. Here, we investigate the effect of systemic inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) on the retina of male and female mice and determine whether antagonism of the NLRP3 inflammasome and the extrinsic pathway of apoptosis have protective effects on the retina. A single intraperitoneal injection of LPS (5 mg/kg) was administered to two months old C57BL/6J male and female mice. Retinas were examined longitudinally in vivo using electroretinography and spectral domain optical coherence tomography. Retinal ganglion cell (RGC) survival and microglial activation were analysed in flat-mounts. Retinal extracts were used for flow cytometric analysis of CD45 and CD11b positive cells. Matched plasma and retinal levels of proinflammatory cytokines were measured by ELISA. Retinal function and RGC survival were assessed in animals treated with P2X7R and TNFR1 antagonists alone or in combination. In LPS-treated animals of both sexes, there was transient retinal dysfunction, loss of vision-forming but not non-vision forming RGCs, retinal swelling, microglial activation, cell infiltration, and increases in TNF and IL-1β. Compared to females, males showed higher vision-forming RGC death, slower functional recovery, and overexpression of lymphotoxin alpha in their retinas. P2X7R and TNFR1 antagonism, alone or in combination, rescued vision-forming RGCs. P2X7R antagonism also rescued retinal function. Response to treatment was better in females than in males. Systemic LPS has neuronal and sex-specific adverse effects in the mouse retina, which are counteracted by targeting the NLRP3 inflammasome and the extrinsic pathway of apoptosis. Our results highlight the need to analyse males and females in preclinical studies of inflammatory diseases affecting the central nervous system.

Integration of genomics database and bioinformatics to identify genome-wide variants for myasthenia gravis across multiple continents

Autoimmune disease is an immune response that damages the body’s tissues, thereby disrupting the body’s physiological functions. Myasthenia gravis represents one such condition characterized by muscle weakness due to impaired neuromuscular transmission. While it can affect anyone, it tends to be more prevalent among women aged 20–30 and men over 50. This disease, deemed a genetic disorder, typically emerges in old age when antibodies target receptors in the muscles. In this study, we sought to identify the genes that can affect myasthenia gravis by leveraging several databases, including the GWAS Catalog, HaploReg, GTEx portal, and Ensembl. Specifically, our focus was on exploring genomic variants and the expression of the LTA and CTLA4 genes. Our findings reveal that two variants (rs2071591 and rs231770) impact LTA expression in both muscle and brain tissue, while affecting CTLA4 expression in testicular cell tissue. Subsequently, we assessed the allele frequency of these variants across regional populations, namely African, American, East Asian, European, and Southeast Asian. This study demonstrates that the LTA and CTLA4 genes have a higher frequency in African, East Asian, and European populations compared to American and Southeast Asian populations. Consequently, our finding suggests that the latter two populations might have relatively higher susceptibility to the autoimmune disease myasthenia gravis. Therefore, variations in these genes not only offer insights into disease susceptibility, diagnostic or prognostic biomarkers, but also open up avenues for identifying candidate drug targets through genomic-driven drug repurposing.

Adalimumab Effectively Decreases Inflammation Downstream of TNFα Signaling in Synoviocytes from Extended Oligoarticular Juvenile Idiopathic Arthritis.

Fibroblast-like synoviocytes (FLS) play a critical role in inflammation that contributes to disease progression in juvenile idiopathic arthritis (JIA). In rheumatoid arthritis (RA), FLS express tumor necrosis factor alpha (TNFα). TNFα signaling has been shown to be upstream of transforming growth factor beta (TGFβ) signaling. Overexpression of TNFα and TGFβ, as well as related proteins, can cause increased inflammation in RA. In this study, we examine the effects of inhibiting TNFα signaling with adalimumab on FLS isolated from synovial fluid of patients with JIA. Synovial fluid samples were selected from 41 patients in our repository. Of these samples, 23 were diagnosed with persistent oligoarticular JIA and 18 were diagnosed with extended oligoarticular JIA. All samples were taken prior to patients extending to a polyarticular course, or what we termed extended-to-be (ETB), and were on no medications or nonsteroidal anti-inflammatory drugs (NSAIDs) only at the time of arthrocentesis. For cell studies, FLS were isolated from synovial fluid and treated with adalimumab for 24h. Protein antibody arrays were performed by RayBiotech, Inc. according to their protocols. In persistent FLS, TNFα (fold change [FC] = 1.2 p = 0.001), TGFβ (FC = 1.5 p = 0.001), lymphotoxin alpha (LTα) (FC = 4.3 p = 0.015), soluble tumor necrosis factor receptor1 (sTNFRI) (FC = 5.1 p = 0.008), and soluble tumor necrosis factor receptor2 (sTNFRII) (FC = 3.8 p = 0.025) were significantly elevated in adalimumab treated cells compared to untreated cells. In ETB FLS, TNFα was significantly elevated (FC = 1.04 p = 0.023) while TGFβ (FC = 1.03 p = 0.037) was significantly decreased in adalimumab-treated cells compared to untreated cells. This data suggests that, after only 24h, adalimumab is effective at decreasing inflammation that occurs downstream of initial TNFα signaling in extended-to-be fibroblast-like synoviocytes.

Gene Polymorphism of Human Lymphotoxin Alpha in Iraqi Breast Cancer Women

The lymphotoxin alpha is a highly polymorphic gene and any genetic variation in it may lead to an increased production of cytokine LTA thus helping tumor development and progression. The aim of this work was to investigate the association of LTA polymorphism with the risk of breast cancer among Iraqi women. The findings of this study demonstrated that the age group &gt; 50 years old formed 52% of the breast cancer patients (P &lt;0.001). Hardy–Weinberg equilibrium analysis revealed that genotype frequencies of most SNPs in BC patients and HC were consistent with HWE. No association was found between LTA polymorphisms and BC. Moreover, seven haplotypes were detected in BC group. However, only one of them developed significant increase; T -A -C -C -G -C –G (0.20 vs. 0.04, OR: 5.931, P = 0.015). Markedly, some SNPs were in a strong LD, while others showed weak or no LD. We can conclude that an insignificant association was found between LTA polymorphisms and breast cancer in Iraqi women.

Role of lymphotoxin alpha as a new molecular biomarker in revolutionizing tear diagnostic testing for dry eye disease.

Dry eye disease (DED), primarily classified as multifactorial ocular surface disorder, afflicts tens of millions of individuals worldwide, adversely impacting their quality of life. Extensive research has been conducted on tear film analysis over the past decades, offering a range of tests to evaluate its volume, health, and integrity. Yet, early diagnosis and effective treatment for DED continue to pose significant challenges in clinical settings. Nevertheless, by recognizing key phenomena in DED such as ocular surface inflammation, hyperosmolarity, and tear film instability, this article provides a comprehensive overview of both traditional and recently developed methods for diagnosing and monitoring DED. The information serves as a valuable resource not only for clinical diagnosis but also for further research into DED.