Activation Markers Research Articles

Sarcopenia and low prognostic nutritional index as markers of disease activity in patients with inflammatory bowel disease and predictors of poor outcome: a cohort longitudinal study

BackgroundInflammatory Bowel Diseases (IBD) are the gastro-intestinal diseases of the current century. They are described by alternating periods of activity & remission. The assessment of severity is classically done by scoring systems for each disease which depend on patients’ symptoms, inflammatory markers, endoscopic findings, and disease impact on functional activities. The current study focused on some of the potentially modifiable risk factors for activity, not involved in classic scoring systems like sarcopenia & Prognostic Nutritional Index (PNI) in a group of IBD studied cases.ResultsA prospective study on 146 patients with established diagnosis of IBD; divided into two groups; Group1 were studied cases in activity; and Group 2 were patients in remission. Both groups were subjected to clinical assessment, laboratory tests, endoscopies, cross-sectional imaging with specific attention to psoas muscle indices. Both groups were followed up clinically for at least 6 months by clinical activity scores. In this research, the mean patients’ age was 35 years and 45% were females; the prevalence of sarcopenia in studied cases with active IBD had been 49.3% & 6.8% in remission. It was more prevalent in Crohn’s disease. Sarcopenia and low PNI were significantly related to disease activity, & poor clinical outcome in studied cases with IBD with a p- value < 0.05.ConclusionSarcopenia and low PNI can be used as markers of activity of IBD. They are associated with worse outcomes. It is recommended to early detect and manage sarcopenia and malnutrition in IBD patients to improve outcomes.

Inflammation and Ovarian Function in Reproductive-Aged Women.

Inflammation is a marker of immune activation. Inflammation may have an effect on both ovarian function and luteal function, both essential to pregnancy. High inflammation may also signal dysregulated processes within the ovary, which could be in part measured through Anti-Müllerian hormone, follicle-stimulating hormone, and inhibin B levels. To determine the relationship between inflammation, measured by C-reactive protein, and three biomarkers of ovarian function during the early follicular phase: Anti-Müllerian hormone, follicle-stimulating hormone, and inhibin B. Secondary cross-sectional analysis of data and serum obtained in Time to Conceive, a prospective cohort study sample of 843 women attempting pregnancy in central North Carolina from 2008 to 2016. Participants were aged 30 and 44 years, had no history of infertility, endometriosis, or polycystic ovarian syndrome, and were not currently breastfeeding. Serum samples were obtained on days 2, 3, or 4 of the menstrual cycle. C-reactive protein (natural-log transformed), Anti-Müllerian hormone (natural-log transformed), follicle-stimulating hormone (natural-log transformed), and inhibin B (untransformed) were measured in serum. Diminished ovarian reserve was examined dichotomously and defined as an Anti-Müllerian hormone level below 0.7 ng/mL. The analysis included 703 participants with C-reactive protein measured. In an adjusted linear regression model, a 20% increase in C-reactive protein was associated with a 0.57 pg/mL decrease in inhibin B (95% CI: -0.84 to -0.29 pg/mL) and a 0.535% decrease in follicle-stimulating hormone (95% CI: -1.01 to -0.06). Although there was not a significant relationship between Anti-Müllerian hormone and C-reactive protein, a 20% increase in C-reactive protein was associated with a 0.87% increase in Anti-Müllerian hormone (95% CI: -0.27 to 2.01). C-reactive protein was not associated with the odds of diminished ovarian reserve in an adjusted logistic regression model (OR: 0.97, 95% CI: 0.77-1.20). Inflammation, as measured by C-reactive protein, is associated with early follicular phase follicle-stimulating hormone and inhibin B, although this is not true of AMH. Inflammation may exert an effect on ovarian function.

Circulating biomarkers of macrophage activation in different stages of chronic pancreatitis: A pilot study.

Activation of type M2 macrophages has been implicated in the pathogenesis of chronic pancreatitis (CP). In a clinical pilot study, we investigated blood-based markers of macrophage activation at different stages of CP. We performed a cross-sectional analysis of prospectively collected plasma samples from healthy controls and patients with suspected or definitive CP according to the M-ANNHEIM criteria. Plasma concentrations of soluble CD163 (sCD163), soluble CD206 (sCD206), and monocyte chemoattractant protein-1 (MCP-1) were analyzed using enzyme-linked immunosorbent assays. Group and pairwise comparisons of analytes were performed using regression models and area under the receiver operating curves (AUC-ROC). In total, 73 subjects with CP (28 suspected CP and 45 definitive CP) and 40 controls were included. Compared to controls, the median plasma concentrations of sCD163 (p = 0.019) and sCD206 (p = 0.033) were elevated in patients with definitive CP. sCD206 was also elevated in patients with definitive CP (p = 0.042). ROC analysis revealed that the optimal sCD163 cutpoint to distinguish definitive CP from controls was 1.84 mg/ml (AUC-ROC 0.65; 95 % confidence interval [CI], 0.54-0.77). The optimal sCD206 cutpoint to distinguish definitive CP from controls was 0.24 mg/ml (AUC-ROC 0.66; 95 % CI 0.54-0.78). The analytes did not significantly discriminate patients with suspected CP from controls. MCP-1 concentrations showed no differences across subgroups. Our study demonstrates that subjects with definitive CP, sampled during a clinically quiescent phase, exhibited increased levels of sCD163 and sCD206. This indicates the presence of activated M2 macrophages in patients with CP at advanced, but not early, clinical stages.

Systemic Administration of a Site-Targeted Complement Inhibitor Attenuates Chronic Stress-Induced Social Behavior Deficits and Neuroinflammation in Mice

Chronic stress, a risk factor for many neuropsychiatric conditions, causes dysregulation in the immune system in both humans and animal models. Additionally, inflammation and synapse loss have been associated with deficits in social behavior. The complement system, a key player of innate immunity, has been linked to social behavior impairments caused by chronic stress. However, it is not known whether complement inhibition can help prevent neuroinflammation and behavioral deficits caused by chronic stress. In this study, we investigated the potential of a site-targeted complement inhibitor to ameliorate chronic stress-induced changes in social behavior and inflammatory markers in the prefrontal cortex (PFC) and hippocampus. Specifically, we investigated the use of C2-Crry, which comprises a natural antibody-derived single-chain antibody (ScFv) targeting domain-designated C2, linked to Crry, a C3 activation inhibitor. The C2 targeting domain recognizes danger-associated molecular patterns consisting of a subset of phospholipids that become exposed following cell stress or injury. We found that systemic administration of C2-Crry attenuated chronic stress-induced social behavioral impairments in mice. Furthermore, C2-Crry administration significantly decreased microglia/macrophage and astrocyte activation markers in the PFC and hippocampus. These findings suggest that site-targeted complement inhibition could offer a promising, safe, and effective strategy for treating chronic stress induced behavioral and immune function disorders.

Obesity is associated with higher levels of circulating cytokines involved in the development of cardiovascular disease in people living with HIV.

Obesity is increasingly described in people living with HIV (PLWH), but its impact on immune activation and inflammation in HIV is still poorly characterised. We aimed to analyse the difference in circulating cytokines involved in pathways associated with co-morbidities in PLWH according to the presence or absence of obesity. Age and sex matched PLWH with and without obesity (BMI ≥30 kg/m2) from a multicentre, prospective cohort were recruited with a 1:2 ratio. Twenty-three biomarkers covering pathways associated with systemic inflammation (hsCRP, IL-2, IL-6, TNFR1, TNFR2, TNF-α, IFN-γ, IL-18), coagulation (vWF, D-dimer, sCD40L), endothelial function (E-selectin, P-selectin, sICAM-1, sVCAM-1), atherosclerosis (MPO, Lp-PLA2), immune regulation (IL-1RA), innate immune activation (MIP-1, MCP-1, sCD163, sCD14) and microbial translocation (LBP) were measured in the two groups. Between-group difference in biomarkers were assessed using Mann-Whitney test. Associations between obesity and biomarkers were assessed using logistic regression adjusted for age, gender, ethnicity, smoking status, and antiretroviral therapy (ART). Ninety-nine ART-treated PLWH were included in the analysis (33 with obesity, 66 without obesity). PLWH with obesity had higher levels of hsCRP, IL-6, vWF, D-dimer, E-selectin, MPO, IL-1RA, and LBP. Six markers (hsCRP, IL-6, vWF, E-selectin, MPO, IL-1RA), reflecting systemic inflammation, coagulation and atherosclerosis pathways were associated with increased odds of obesity in the adjusted logistic regression model: hsCRP (aOR 2.7, 95% CI [1.7, 4.29]), IL-6 (3.77 [1.43, 9.93]), vWF (5.33 [1.51, 18.75]), E-selectin (6.28 [1.36, 29.04]), MPO (6.85 [1.87, 25.04]), IL-1RA (6.45 [2.28, 18.2]). No association was observed between obesity and markers of innate immune activation and gut microbial translocation. Obesity in PLWH was associated with activation of systemic inflammatory, endothelial, atherosclerosis and coagulation pathways, rather than those associated with innate immune activation and gut microbial translocation. These pathways point towards an unfavourable cardiovascular profile in PLWH with obesity, which will have to be further explored in future studies on long-term outcomes.

SP1-mediated transcriptional repression of SFRP5 is correlated with cardiac fibroblast activation and atrial myocyte apoptosis in the development of atrial fibrillation

Secreted frizzled related protein 5 (SFRP5) is a recognized cardioprotective protein with diminished expression in atrial fibrillation (AF). This study investigates SFRP5's function in AF-related cardiac fibrosis and cardiomyocyte apoptosis, exploring the underlying dysregulation causes. Utilizing C57BL/6 mice, mouse cardiac fibroblasts (CFs), and HC-1 mouse atrial myocyte cell line, AF models were induced by angiotensin Ⅱ (Ang Ⅱ). SFRP5 levels were consistently decreased in plasma samples from clinical patients, modeled mice, and CF culture supernatants. Treatment with recombinant SFRP5 restored its levels, mitigating Ang Ⅱ-induced AF in mice and ameliorating atrial tissue fibrosis and oxidative stress. In vitro, SFRP5 recombinant protein suppressed CF activation and fibrosis-related markers. The study identified Sp1 transcription factor (SP1) binding to the SFRP5 promoter, causing transcriptional repression. SP1 knockdown reinstated SFRP5 levels in mice and CFs, thus suppressing fibrosis. Additionally, SP1 knockdown attenuated Ang Ⅱ-induced apoptosis in HC-1 cells, but this effect was counteracted by concurrent SFRP5 knockdown. In conclusion, this investigation underscores that SP1 mediates SFRP5 loss during AF by transcriptional repression, contributing to fibrosis and myocyte apoptosis. These findings illuminate potential therapeutic interventions targeting the SFRP5-SP1 axis in AF-related cardiac complications.

Autoreactive B cells remain active despite clinical disease control in rheumatoid arthritis

BackgroundAutoimmune diseases (AIDs) are frequently hallmarked by the presence of autoreactive B cell responses which are involved in disease pathogenesis. However, the dynamics of such responses and their relation to clinical disease activity in humans is poorly understood. Rheumatoid arthritis (RA), a prototypic chronic AID, is hallmarked by B cell responses directed against citrullinated proteins. ObjectiveTo determine the relation between the activity of the anti-citrullinated protein antibody (ACPA) B cell response and clinical disease activity in ACPA+ patients with RA. MethodsExpression of B cell activation markers by ACPA+, tetanus toxoid (TT)+ and ACPA− memory B cells (MBCs) from peripheral blood of ACPA+ RA patients receiving different treatments was analyzed by flow cytometry. Results were correlated to clinical disease activity. ResultsCompared to TT+ and ACPA− MBCs, ACPA+ MBCs displayed a highly activated phenotype as evidenced by increased expression of Ki-67, CD86, CD80, CD19 and CD20 and reduced expression of CD32. The activated phenotype of ACPA+ MBCs did not associate with clinical disease activity in a cross-sectional analysis of RA patients treated with various therapeutic agents. Also, in a longitudinal analysis of patients treated with Janus kinase (JAK) inhibitors, ACPA+ MBCs retained their activated phenotype despite effective control of inflammation and clinical disease. ConclusionACPA+ MBCs remain active despite clinical disease control in patients with RA across a range of interventions. This persistent activity indicates the absence of immunological remission and might explain why ACPA+ patients rarely reach sustained drug-free remission and frequently flare upon drug tapering.

Effect of Distress, Anxiety, and Depressive Symptoms on SARS-CoV-2 mRNA BNT162b2 Vaccine Efficacy in Cancer Patients

Background/Objectives: Our previous study of 291 cancer patients, we showed that 20% did not respond to two doses of COVID-19 vaccine administered six weeks apart. Methods: Here, we investigated if psychological factors (distress, anxiety, and depressive symptoms) affected antibody response and markers of vaccine activation (D-dimer) after 6 months from initial vaccination. Results: Overall, 31 subjects (14.2%) had no antibody response at 6 months. Our analysis revealed significant predictors of vaccine failure, including the stage of metastatic disease and high-stress levels (OR = 2.46, 95% CI, 1.05–5.77, p = 0.04). Notably, nonresponders showed twice the prevalence of distress than responders (21% vs. 10%, p = 0.04). Longitudinal measurements of IgG levels indicated that participants with high depressive symptoms at baseline maintained lower antibody levels over six months (p = 0.003). In addition, women with high anxiety showed reduced levels of D-dimer at 6 months (p = 0.03). These data also showed that smokers and former smokers had significantly lower antibody levels than their nonsmoking counterparts (p = 0.0004). At baseline, the high discomfort rate (≥5) was 34.4% in women and 23.8% in men; only men experienced an increase in median discomfort during the observation period. Moreover, a higher educational level was related to increased distress among women (p = 0.046). Conclusions: These findings underscore a critical association between elevated psychological distress and reduced immune responses to the COVID-19 vaccine, emphasizing the urgent need for targeted psychological and behavioral support within this vulnerable population.

SGLT2 inhibition improves endothelium-independent vasodilatory function in type 2 diabetes: A double-blind, randomized, placebo-controlled crossover trial.

The objective of this study was to examine the effects of empagliflozin on endothelium-dependent and endothelium-independent vasodilatation and systemic hemodynamic parameters and to assess the role of the nitric oxide (NO) system in patients with type 2 diabetes (T2DM). In this double-blind, placebo-controlled cross over trial, patients with T2DM were treated with either empagliflozin 10 mg or matching placebo for 4 weeks. Following a 2-week washout, participants were crossed over to 4 weeks of the opposite treatment. Forearm blood flow (FBF) was measured after each treatment period using venous occlusion plethysmography. Acetylcholine and sodium nitroprusside (SNP) were infused into the brachial artery to assess endothelium-dependent and endothelium-independent vasodilatory function, respectively. Total peripheral resistance, 24-h blood pressure (BP) and biochemical markers of NO activity were measured as well. Sixteen participants completed the trial. The mean age was 68 ± 8 years, and 69% were male. The SNP response increased by 21% (geometric mean ratio 1.21, 95% CI: 1.09; 1.33) during treatment with empagliflozin compared to placebo (p ≤ 0.001), but not during acetylcholine infusion (p = 0.290). Empagliflozin decreased 24-h systolic BP by 5 mmHg (95% CI: -9; -1 mmHg) (p = 0.015), diastolic BP by 2 mmHg (95% CI: -5; 0 mmHg) (p = 0.029) and systemic vascular resistance by 48 dyn×s/m5 (95% CI: -94; -1 dyn×s/m5) (p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx. Empagliflozin improves endothelium-independent vasodilation, reduces vascular resistance and lowers 24-h BP in patients with T2DM, whereas no change in endothelial-dependent vasodilation was observed. EU Clinical Trials Register number: 2019-004303-12 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK).

Association of endotheliopathy with coagulofibrinolytic reactions and disseminated intravascular coagulation after trauma: a retrospective observational study

We carried out a retrospective observational investigation to explore the association of endotheliopathy with coagulofibrinolytic reactions and the progression of disseminated intravascular coagulation (DIC) in adult trauma patients. We measured syndecan-1 (SDC-1), an indicator of endotheliopathy, and biomarkers of coagulofibrinolysis in 100 trauma patients immediately transferred to Ehime University Hospital. We evaluated the correlations between the coagulofibrinolytic parameters and SDC-1. We also investigated the association between SDC-1 elevations and the development of DIC, and determined the discriminators of DIC development. The median SDC-1 concentration was 82.7 (43.5–178.1) ng/mL. DIC developed in 16 patients (16.0%), and SDC-1 concentrations were significantly higher in DIC patients than in non-DIC patients (218.8 [134.5–798.2] ng/mL vs. 67.2 [39.6–114.5] ng/mL, p < 0.001). Receiver operating characteristic curve analysis revealed that the circulating SDC-1 level effectively predicted the progression of DIC, with an area under the curve of 0.862 (95% confidence interval [CI], 0.789–0.936). The optimal cut-off value was determined to be 92.5 ng/mL, yielding a sensitivity of 100.0% and a specificity of 67.8% (p < 0.001). A simple logistic regression analysis showed that a circulating SDC-1 concentration of > 92.5 ng/mL was significantly correlated with DIC progression (odds ratio [OR], 31.67; 95%CI: 3.97–252.31, p = 0.001). Many coagulofibrinolytic parameters were significantly correlated with SDC-1. Estimating the discriminators of DIC development by the least absolute shrinkage and selection operator (LASSO) and elastic-net regression analysis identified markers of coagulofibrinolytic activation, such as thrombin-antithrombin complex (TAT) and tissue plasminogen activator (tPA). A multivariate logistic regression model using TAT, tPA, and SDC-1 demonstrated that TAT and tPA, but not SDC-1, were independent factors predicting the development of DIC (TAT per 10 µg/L: OR, 1.14, 95%CI: 1.05–1.24, p = 0.003; tPA per 100pg/mL: OR, 1.03, 95%CI: 1.01–1.05, p = 0.003; SDC-1 per 10ng/mL: OR, 1.00, 95%CI: 0.99–1.01, p = 0.973). Mediation analysis showed that SDC-1 elevation was predominantly associated with the development of DIC indirectly through the increase in TAT (proportion mediated = 96.1%, p < 0.001), while there was no significant indirect effect of SDC-1 elevation on the role of TAT elevation in DIC development was observed (p = 0.340). The primary pathogenesis of DIC in the acute phase of trauma is likely driven by coagulofibrinolytic activation. Endotheliopathy, as reflected by elevated circulating levels of SDC-1, is strongly associated with coagulofibrinolytic responses. Although endotheliopathy may contribute to the early development of DIC through coagulation activation, its role appears to be limited.

A novel multiple marker microarray analyzer and methodology to predict major obstetric syndromes using surface markers of circulating extracellular vesicles from maternal plasma.

Placental-derived extracellular vesicles (EVs) are nano-organelles that facilitate intercellular communication between the feto-placental unit and the mother. We evaluated a novel Multiple Microarray analyzer for identifying surface markers on plasma EVs that predict preterm delivery and preeclampsia compared to term delivery controls. In this prospective exploratory cohort study pregnant women between 24 and 40 gestational weeks with preterm delivery (n = 16), preeclampsia (n = 19), and matched term delivery controls (n = 15) were recruited from Bnai Zion Medical Center, Haifa, Israel. Plasma samples were tested using a multiple microarray analyzer. Glass slides with 17 antibodies against EV surface receptors - were incubated with raw plasma samples, detected by biotinylated secondary antibodies specific to EVs or placental EVs (PEVs), and labeled with cyanine 5-streptavidin. PBS and whole human IgG served as controls. The fluorescent signal ratio to negative controls was log 2 transformed and analyzed for sensitivity and specificity using the area under the receiver operating characteristics curves (AUROC). Best pair ratios of general EVs/PEVs were used for univariate analysis, and top pairs were combined for multivariate analysis. Results were validated by comparison with EVs purified using standard procedures. Heatmaps differentiated surface profiles of preeclampsia, preterm delivery, and term delivery receptors on total EVs and PEVs. Similar results were obtained with enriched EVs and EVs from raw plasma. Univariate analyses identified markers predicting preterm delivery and preeclampsia over term delivery controls with AUC >0.6 and sensitivity >50% at 80% specificity. Combining the best markers in a multivariate model, preeclampsia prediction over term delivery had an AUC of 0.89 (95% CI: 0.72-1.0) with 90% sensitivity and 90% specificity, marked by inflammation (TNF RII), relaxation (placenta protein 13 (PP13)), and immune-modulation (LFA1) receptors. Preterm delivery prediction over term delivery had an AUC of 0.97 (0.94-1.0), 84% sensitivity, and 90% specificity, marked by cell adhesion (ICAM), immune suppression, and general EV markers (CD81, CD82, and Alix). Preeclampsia prediction over preterm delivery had an AUC of 0.91 (0.79-0.99) with 80% sensitivity and 90% specificity with markers for complement activation (C1q) and autoimmunity markers. The new, robust EV Multi-Array analyzer and methodology offer a simple, fast diagnostic tool that reveals novel surface markers for major obstetric syndromes.

Gut microbiota, physical activity and/or metabolic markers in healthy individuals - towards new biomarkers of health

Gut microbiota, physical activity and/or metabolic markers in healthy individuals - towards new biomarkers of health

Exploring the mechanism of Taohong Siwu Decoction in treating ischemic stroke injury via the circDnajc1/miR-27a-5p/C1qc signaling axis

BackgroundIschemic stroke (IS) is the most prevalent type of cerebrovascular disease. Taohong Siwu Decoction (THSWD) has been demonstrated to have neuroprotective benefits during Cerebral Ischemia-Reperfusion Injury (CIRI). Whether THSWD mitigates CIRI by modulating the circDnajc1/miR-27a-5p/C1qc signaling axis is not known. ObjectiveExamine how THSWD provides neuroprotective benefits in reducing the damage wrought by IS. MethodsWe employed middle cerebral artery occlusion/reperfusion (MCAO/R) rat model and oxygen glucose deprivation/re-oxygenation (OGD/R) in vitro model. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot (WB), and immunofluorescence analyses (IF) were utilized to detect microglial activation markers TMEM119, CD11b, and Iba1, inflammatory mediators CCL2, CCL6, IL1, IL6, IL10, and TNF-α, as well as circDnajc1, miR-27a-5p, C1qc, C3, and C5aR. ConclusionOur data suggest that THSWD can mitigate inflammatory response, inhibit microglial activation and neuron apoptosis, and exert neuroprotective effects by regulating the circDnajc1/miR-27a-5p/C1qc signaling axis.

Effects of Cognitive Behavior Therapy on Heart Rate Variability among Medical Students at a Teaching Institution in Jaipur, India

Abstract Introduction: Heart rate variability (HRV) is the variation in the time interval between heartbeats. It is controlled by the autonomic nervous system, which also regulates many other vital body functions. HRV has been used as a noninvasive marker of cardiac autonomic activity and cardiovascular risk stratification. The present study aimed to investigate the effect of cognitive behavior therapy (CBT) on different domains of HRV and their correlation at baseline and after 3 months of intervention. Methods: After obtaining institutional ethical clearance, the study was conducted from July to October 2022 among 140 1st-year Bachelor of Medicine and Bachelor of Surgery students at a medical college in Jaipur, Rajasthan, India. Linear component, i.e., time and frequency domain, and nonlinear components, i.e., Poincare plot of HRV assessed at baseline and after the 3 months of CBT. Results: Findings show that there was a significant decrease in linear components, i.e., time domain and frequency domain parameters (P &lt; 0.001) and nonlinear components Poincare plot standard deviation (SD) 1/SD2 (P &lt; .0.001) after 3 months of CBT. Linear and nonlinear components of HRV were positively correlated (P &lt; 0.01). Conclusion: The study indicates that after 3 months of CBT, the autonomic nervous system shifted toward parasympathetic dominance, which was assessed by linear components, time domain and frequency domain parameters, and nonlinear components, i.e., Poincare plot (SD1/SD2) of HRV.

Elevated serum interferon-α2 associates with activity and flare risk in Juvenile-onset Systemic Lupus Erythematosus.

This study investigated serum IFN-α2 as a putative marker of disease activity and predictor of disease flares in juvenile systemic lupus erythematosus (jSLE). 222 serum samples were analysed, including 28 healthy controls (HCs), 88 JSLE (159 samples), and 35 juvenile idiopathic arthritis (JIA) patients. IFN-α2 levels were determined using Single-molecule array (Simoa). Cross-sectionally, median IFN-α2 levels were compared between patient groups and disease activity state sub-groups. Time to flare was analysed by linear regression. Longitudinally, the ability of the IFN-α2 and other traditional biomarkers (erythrocyte sedimentation rate/ESR, low C3 and anti-dsDNA antibodies) to detect and predict flares was assessed via a generalised linear mixed model. Cross-sectional analysis showed higher median IFN-α2 levels in the active/intermediate group (median 3,185 fg/mL, IQR 48-13,703) compared to the LDAS (571 fg/mL, IQR 57-1,310 fg/mL, p = 0.04) and remission sub-groups (271 fg/mL, IQR 3-56, p < 0.001). IFN-α2 was higher in all JSLE patients (median 587 fg/mL, IQR 11-2,774) as compared to JIA patients (median 7 fg/mL, IQR 3-236, p = 0.0017) and HCs (p = 0.017). JSLE patients in remission or LDAS with abnormal IFN-α2 levels had a shorter time to flare over the subsequent six months compared to those with normal IFN-α2 levels (p = 0.022). Longitudinally, multivariable analysis demonstrated high IFN-α2 to be the only predictor of an ongoing flare (p = 0.028). Serum IFN-α2 levels associate with disease activity and can predict ongoing and future flares in jSLE. These findings suggest that quantification of IFN-α2 may support risk stratification and disease monitoring in these patients.

Multiomics approaches disclose very-early molecular and cellular switches during insect-venom allergen-specific immunotherapy: an observational study

Allergen-specific immunotherapy (AIT) induces immune tolerance, showing the highest success rate (>95%) for insect venom while a much lower chance for pollen allergy. However, the molecular switches leading to successful durable tolerance restoration remain elusive. The primary outcome of this observational study is the comprehensive immunological cellular characterization during the AIT initiation phase, whereas the secondary outcomes are the serological and Th2-cell-type-specific transcriptomic analyses. Here we apply a multilayer-omics approach to reveal dynamic peripheral immune landscapes during the AIT-initiation phase in venom allergy patients (VAP) versus pollen-allergic and healthy controls. Already at baseline, VAP exhibit altered abundances of several cell types, including classical monocytes (cMono), CD4+ hybrid type 1-type 17 cells (Th1-Th17 or Th1/17) and CD8+ counterparts (Tc1-Tc17 or Tc1/17). At 8-24 h following AIT launch in VAP, we identify a uniform AIT-elicited pulse of late-transitional/IL-10-producing B cells, IL-6 signaling within Th2 cells and non-inflammatory serum-IL-6 levels. Sequential induction of activation and survival protein markers also immediately occur. A disequilibrium between serum IL-6 and cMono in VAP baseline is restored at day seven following AIT launch. Our longitudinal analysis discovers molecular switches during initiation-phase insect-venom AIT that secure long-term outcomes. Trial number: NCT02931955.

Unveiling a novel signalling pathway involving NRF2 and PGAM5 in regulating the mitochondrial unfolded protein response in stressed cardiomyocytes

The mitochondrial unfolded protein response (UPRmt) is a conserved signalling pathway that initiates a specific transcriptional programme to maintain mitochondrial and cellular homeostasis under stress. Previous studies have demonstrated that UPRmt activation has protective effects in the pressure-overloaded human heart, suggesting that robust UPRmt stimulation could serve as an intervention strategy for cardiovascular diseases. However, the precise mechanisms of UPRmt regulation remain unclear. In this study, we present evidence that the NRF2 transcription factor is involved in UPRmt activation in cardiomyocytes during conditions of mitochondrial stress. Silencing NRF2 partially reduces UPRmt activation, highlighting its essential role in this pathway. However, constitutive activation of NRF2 via inhibition of its cytosolic regulator KEAP1 does not increase levels of UPRmt activation markers, suggesting an alternative regulatory mechanism independent of the canonical KEAP1-NRF2 axis. Further analysis revealed that NRF2 likely affects UPRmt activation through its interaction with PGAM5 at the mitochondrial membrane. Disruption of PGAM5 in cardiomyocytes subjected to mitochondrial stress reduces the interaction between PGAM5 and NRF2, enhancing nuclear translocation of NRF2 and significantly upregulating the UPRmt in an NRF2-dependent manner. This NRF2-regulated UPRmt amplification improves mitochondrial respiration, reflecting an enhanced capacity for cardiomyocytes to meet elevated energetic demands during mitochondrial stress. Our findings highlight the therapeutic potential of targeting the NRF2-PGAM5-KEAP1 signalling complex to amplify the UPRmt in cardiomyocytes for cardiovascular and other diseases associated with mitochondrial dysfunction. Future studies should aim to elucidate the mechanisms via which NRF2 enhances the protective effects of UPRmt, thereby contributing to more targeted therapeutic approaches.

Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity

Introduction and AimsVitamin D has an immunomodulatory property influencing the activity of NKT cells. We aimed to study the impact of osteopontin (OPN), a key driver of fibrosis, on NKT cells’ vitamin D receptor (VDR) and activity alterations.MethodsLiver fibrosis was induced in BALB/C mice with carbon-tetrachloride (CCl4) for 8 weeks with either vitamin D [100 ng/kg] or InVivoMAb anti-mouse OPN [100 μg/kg] 2X/week started at week-4 of CCl4. The liver injury profile of serum ALT, AST, and inflammatory cytokines were evaluated. Histopathological findings were assessed via H&amp;amp;E staining and Sirius-Red staining. Fibrotic genes of αSMA, CREBP, and collagen III were assessed using RT-PCR. Fast blood sugar, insulin, liver cholesterol, and triglyceride were evaluated. Liver tissue-resident (tr)-NKT cells were obtained for VDR expressions, molecular pathways of p-STAT1 and P-STAT-5, and activation markers of CD107a and NKp46 using flow cytometry.ResultsFollowing vitamin D treatment, H&amp;amp;E staining revealed reduced microvascular and macrovascular steatosis, while Sirius-Red staining showed less fibrosis accumulation in liver fibrosis mice than in untreated counterparts. Results were associated with a significant decrease in serum cytokines of IL-β/IL-6/IL-4/OPN/TNF-α and serum AST and ALT by 2-fold and 3-fold, respectively. Fibrotic markers showed an average 1.3-fold decrease in αSMA, CREB, and Col-III in liver fibrosis mice following vitamin D treatment. Quantitated liver cholesterol and triglycerides, serum insulin, and fasting blood sugar ameliorated their levels following vitamin D treatment in liver fibrosis mice. OPN-neutralizing antibody over-expressed VDR on trNKT cells and increased CD107a and NKp46 activities of 3.1 and 3.5 folds, respectively, associated with increasing in p-STAT1 and p-STAT5 phosphorylation. These results were accompanied with a decrease in hepatic-stellate-cell activation markers of αSMA, Col-III, and desmin.ConclusionVDR expressions affect trNKT cells activity and could modulate progressions of liver fibrosis. Using an OPN-neutralizing antibody exhibited an antifibrotic effect by alleviating the liver injury profile through NKT cells. It is also suggested as an immunomodulatory target of liver fibrosis.

Immune Signatures of Solid Tumor Patients Treated With Immune Checkpoint Inhibitors: An Observational Study.

Our study aimed to comprehensively describe the features of peripheral blood multiple immune cell phenotypes in solid tumor patients during pretreatment and after immunotherapy, providing a more convenient approach for studying the prognosis of immunotherapy in different solid tumor patients. We prospectively recruited patients with advanced solid tumors from Peking Union Medical College Hospital (PUMCH) between February 2023 and April 2024. Using multicolor flow cytometry, our study comprehensively observed and described the signatures of peripheral blood lymphocyte subsets including activation, proliferation, function, naïve memory, and T cell exhaustion immune cell subsets in this population of pretreatment and after immunotherapy. Our study enrolled 59 advanced solid tumor patients with immunotherapy and 59 healthy controls were matched by age and gender. The results demonstrated a marked upregulation in the expression of lymphocyte activation markers CD38 and HLA-DR, as well as exhaustion and proliferation markers PD-1 and Ki67, in solid tumor patients compared to healthy controls. After immune checkpoint blockade (ICB) treatment, mainly the expression of Ki67CD4+T and HLA-DRCD38CD4+T, was significantly upregulated compared to pretreatment levels (p = 0.017, p = 0.019, respectively). We further found that gynecological tumors with better prognoses had higher baseline activation levels of CD4+ T cells compared to other solid tumors with poorer prognoses. Our study elucidated the characteristics of different lymphocyte subsets in the peripheral blood of solid tumor patients. Further research revealed changes in the phenotypes of different lymphocyte subsets after ICIs treatment, with the activated phenotype of CD4+ T cells playing a crucial role in the antitumor effect. This lays the groundwork for further exploration of prognostic biomarkers and predictive models for cancer patients with immunotherapy.

Dendritic cells under the control of the preimplantation embryo secretome: an in vitro study

ObjectiveTo study the crosstalk between maternal immune cells and the developing embryo by investigating the immunogenic properties of human blastocyst spent media (SM) on dendritic cells.MethodsIn this prospective multicenter experimental study, human preimplantation embryo spent media were collected after blastocyst formation, grouped based on successful or unsuccessful implantation, and analyzed by protein array or used to stimulate monocyte derived dendritic cells (moDC). The immunomodulatory properties of SM on moDC were investigated by analyzing changes in phenotype, cytokine secretion, indoleamine 2,3-dioxygenase (IDO) activity, and ability to activate T cells.ResultsA plethora of cytokines and growth factors secreted from preimplantation embryos was detected. Exposure to embryo SM altered the phenotype of moDC in a manner dependent on the implantation outcome. Specifically, SM from non-implanted embryos increased the expression of co-stimulatory molecules and activation markers on moDC. Furthermore, SM treated dendritic cells secreted low levels of cytokines and growth factors and were able to stimulate naïve T cells. Activation of IDO was decreased in moDC after stimulation with SM.ConclusionsOur findings show that human preimplantation embryos secrete an abundance of molecules with the ability to significantly affect and even regulate immune cells in their environment.