Peripheral Cytokine Research Articles

Peripheral blood lymphocyte subsets predict the efficacy of TACE with or without PD-1 inhibitors in patients with hepatocellular carcinoma: a prospective clinical study.

Although peripheral blood lymphocyte subsets, particularly PD-1+ T cells, are promising prognostic indicators for patients with cancer. However, their clinical significance remains unclear. We prospectively enrolled 157 patients with hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization combined with or without PD-1 inhibitors. Twenty peripheral lymphocyte subsets and cytokines were analyzed. We analyzed the differences in PD-1+ T cells between patients treated with and without PD-1 inhibitors and their associations with tumor response, survival prognosis, and clinical features. We found that the baseline CD8+PD-1+ and CD4+PD-1+ T-cell frequencies in patients who had received PD-1 inhibitors were lower than those in patients who had not received PD-1 inhibitors (p < 0.001). In the former patients, there were no differences in PD-1+ T-cell frequencies between the responder and non-responder subgroups (p > 0.05), whereas in the latter patients, the levels of CD8+PD-1+ T cells, CD4+PD-1+ T cells, and CD8+PD-1+/CD4+PD-1+ ratio did not predict tumor response, progression-free survival (PFS), or overall survival (OS) (p>0.05). Furthermore, in multivariate analysis of patients treated with or without PD-1 inhibitors revealed that the levels of CD8+CD38+ T cells (OR = 2.806, p = 0.006) were associated with tumor response, whereas those of CD8+CD28+ T cells (p = 0.038, p = 0.001) and natural killer (NK) cells (p = 0.001, p = 0.027) were associated with PFS and OS. Although, these independent prognostic factors were associated with progressive tumor characteristics (p<0.05), with the exception of CD8+CD28+ T cells, changes in these factors before and after treatment were unassociated with tumor response (p > 0.05). Circulating CD8+CD38+ T cells, CD8+CD28+ T cells, and NK cells were identified as potential prognostic factors for tumor response and survival in patients with HCC. Contrastingly, although PD-1 inhibitors can effectively block the T cell PD-1 receptor, the baseline PD-1+ T-cell frequencies and changes in the frequency of these cells have limited prognostic value.

Phase II study evaluating the efficacy of PDS0301 in combination with hepatic artery infusion pump (HAIP) and systemic therapy for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma.

TPS586 Background: Treatment of advanced liver tumors continues to pose significant challenges. Despite advances in immunotherapies, including immune checkpoint blockade, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. The lack of robust clinical efficacy is likely myriad, including immunosuppression by the tumor microenvironment and poor susceptibility of these tumors to immune infiltration and surveillance. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with extensive anti-tumor properties, but therapeutic development of recombinant human IL-12 (rhIL-12) was halted due to significant systemic toxicities. PDS0301 (formerly M9241) is a novel human monoclonal antibody (NHS76) fused to two IL-12 heterodimers. The NHS76 antibody specifically targets histone/DNA complexes in regions of cellular necrosis resulting in accumulation within tumors. Importantly, recent Phase I trials have shown PDS0301 monotherapy to be well tolerated. We hypothesize that synchronization of PDS0301 administration with tumor cell death induced by locoregional and systemic chemotherapies will demonstrate increased efficacy over standard of care therapy. Methods: This is a single center, non-randomized Phase II study to determine the safety and efficacy of PDS0301 in combination with floxuridine (FUDR) administered by hepatic artery infusion pump (HAIP) and systemic chemotherapies in patients with either unresectable metastatic colorectal cancer (mCRC) or intrahepatic cholangiocarcinoma (ICC). Eligibility criteria include histologically or cytologically confirmed colorectal adenocarcinoma metastatic to the liver (Cohort 1) or unresectable intrahepatic cholangiocarcinoma with no evidence of extrahepatic metastases (Cohort 2). Patients will receive HAIP-administered (FUDR) plus PDS0301 at a starting dose of 12mcg/kg in 28-day cycles. Beginning in cycle 2, systemic chemotherapy with FOLFOX (Leucovorin, 5-Fluorouracil [5-FU], and Oxaliplatin) or FOLFIRI (Leucovorin, 5-FU and Irinotecan) for mCRC or GemOx (Gemcitabine and Oxaliplatin) for ICC will be introduced. Patients will be evaluated for response at eight-week intervals. The primary endpoint is overall response rates to PDS0301 and HAIP/systemic combination therapy. Secondary objectives include hepatic progression-free survival (PFS), extra-hepatic PFS, overall survival, and safety. Scientific objectives include determination of microenvironment alterations through pre-and post-treatment biopsies as well as evaluation of peripheral immune subsets and cytokines. To date, we have enrolled 8 of 23 patients in Cohort 1. Clinical trial information: NCT05286814 .

Pain and the biochemistry of fibromyalgia: patterns of peripheral cytokines and chemokines contribute to the differentiation between fibromyalgia and controls and are associated with pain, fat infiltration and content.

This explorative study analyses interrelationships between peripheral compounds in saliva, plasma, and muscles together with body composition variables in healthy subjects and in fibromyalgia patients (FM). There is a need to better understand the extent cytokines and chemokines are associated with body composition and which cytokines and chemokines differentiate FM from healthy controls. Here, 32 female FM patients and 30 age-matched female healthy controls underwent a clinical examination that included blood sample, saliva samples, and pain threshold tests. In addition, the subjects completed a health questionnaire. From these blood and saliva samples, a panel of 68 mainly cytokines and chemokines were determined. Microdialysis of trapezius and erector spinae muscles, phosphorus-31 magnetic resonance spectroscopy of erector spinae muscle, and whole-body magnetic resonance imaging for determination of body composition (BC)-i.e., muscle volume, fat content and infiltration-were also performed. After standardizing BC measurements to remove the confounding effect of Body Mass Index, fat infiltration and content are generally increased, and fat-free muscle volume is decreased in FM. Mainly saliva proteins differentiated FM from controls. When including all investigated compounds and BC variables, fat infiltration and content variables were most important, followed by muscle compounds and cytokines and chemokines from saliva and plasma. Various plasma proteins correlated positively with pain intensity in FM and negatively with pain thresholds in all subjects taken together. A mix of increased plasma cytokines and chemokines correlated with an index covering fat infiltration and content in different tissues. When muscle compounds were included in the analysis, several of these were identified as the most important regressors, although many plasma and saliva proteins remained significant. Peripheral factors were important for group differentiation between FM and controls. In saliva (but not plasma), cytokines and chemokines were significantly associated with group membership as saliva compounds were increased in FM. The importance of peripheral factors for group differentiation increased when muscle compounds and body composition variables were also included. Plasma proteins were important for pain intensity and sensitivity. Cytokines and chemokines mainly from plasma were also significantly and positively associated with a fat infiltration and content index. Our findings of associations between cytokines and chemokines and fat infiltration and content in different tissues confirm that inflammation and immune factors are secreted from adipose tissue. FM is clearly characterized by complex interactions between peripheral tissues and the peripheral and central nervous systems, including nociceptive, immune, and neuroendocrine processes.

Association Between Clonal Hematopoiesis Driver Mutations, Immune Cell Function, and the Vasculometabolic Complications of Obesity.

Obesity is accompanied by dysregulated inflammation, which can contribute to vasculometabolic complications including metabolic syndrome and atherosclerosis. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular diseases. We aimed to determine how CHIP is related to immune cell function, systemic inflammation, and vasculometabolic complications in obese individuals. Two hundred ninety-seven individuals with overweight and obesity, between the ages of 54 and 81 years, were recruited in a cross-sectional study. Clonal hematopoiesis driver mutations (CHDMs) were identified with an ultrasensitive targeted assay. Assessment of carotid artery atherosclerosis was performed with ultrasound. Detailed immunological parameters, including cytokine production capacity of peripheral blood mononuclear cells, and targeted plasma proteomics analysis, were studied. Adipose tissue inflammation was determined in subcutaneous fat biopsies. Individuals with CHIP had higher concentrations of circulating IL (interleukin)-6. Total number of leukocytes and neutrophils were higher in individuals with CHIP. In contrast, exvivo cytokine production capacity of peripheral blood mononuclear cells was significantly lower in individuals with CHIP. Sex-stratified analysis showed that men with CHDMs had significantly higher leukocyte and neutrophil counts, and exvivo cytokine production capacity was lower in women with CHDMs. Surprisingly, the presence of atherosclerotic plaques was significantly lower in individuals with CHDMs. There was no relation between CHIP and metabolic syndrome. In individuals with overweight or obesity, CHDMs are not associated with vasculometabolic complications, but rather with a lower presence of carotid plaques. CHDMs associate with increased circulating inflammatory markers and leukocyte numbers, but a lower peripheral blood mononuclear cell cytokine production capacity.

Severe gut mucosal injury induces profound systemic inflammation and spleen-associated lymphoid organ response.

Clinical evidence indicates a connection between gut injuries, infections, inflammation, and an increased susceptibility to systemic inflammation. Nevertheless, the animal models designed to replicate this progression are inadequate, and the fundamental mechanisms are still largely unknown. This research explores the relationship between gut injuries and systemic inflammation using a Dextran Sulfate Sodium (DSS)-induced colonic mucosal injury mouse model. Continuous treatment of adult mice with 4% DSS drinking water yielded a remarkable mortality rate by day 7, alongside intensified gut injury and detectable peripheral inflammation. Moreover, RNAscope in situ hybridization with 16S rRNA probe noted bacterial penetration into deeper colon compartments of the mice following treatment with DSS for 7 days. Histological analysis revealed inflammation in the liver and lung tissues of DSS-treated mice. In addition, we found that DSS-treated mice exhibited elevation of Alanine transaminase (ALT) and Aspartate transaminase (AST) in peripheral blood and pro-inflammatory cytokine levels in the liver. Notably, the DSS-treated mice displayed a dampened metabolic profile, reduced CD45 marker expression, and an increase in apoptosis within the lymphoid organ such as spleen. These findings suggest that high-dose DSS-induced gut injury gives rise to sepsis-like systemic inflammation characterized by multiple organ injury and profound splenocyte apoptosis and dysfunction of CD45+ cells in the spleen, indicating the role of the spleen in the pathogenesis of gut-derived systemic inflammation. Together, the severe colonic mucosal injury model facilitates research into gut damage and associated peripheral immune responses, providing a vital framework for investigating mechanisms related to clinically relevant, gut-derived systemic inflammation.

Association of Peripheral Pro-inflammatory Cytokines with Depressed Suicidal Patients: A Hospital-based, Cross-sectional Study

Background: Acute-phase reactants, such as C-reactive protein (CRP), along with pro-inflammatory cytokines like interleukin-6 (IL-6) and interleukin-1β (IL-1β), exhibit elevated levels in the peripheral bloodstream during acute mood episodes. In both major depressive disorder and bipolar disorder, instances of suicidal behavior, encompassing suicidal idealization and self-harm attempts, are linked to intensified depressive exacerbation. This study investigates the correlation between pro-inflammatory markers in patients experiencing major depressive episodes (MDE) with or without inclinations toward suicidal tendencies. Methods: The study comprised a sample of 75 outpatients categorized into three equally sized groups. These groups consisted of patients experiencing major depressive episodes with accompanying suicidal behavior, individuals undergoing MDE without any indications of suicidal tendencies, and a control group of mentally healthy individuals. Pertinent demographic information was gathered, and levels of pro-inflammatory markers, namely CRP, IL-6, and IL-1β, were quantified in the serum. The data were analyzed using the Statistical Package for the Social Sciences version 22. Results: Through bi variate analysis, it was observed that all three markers exhibited a noteworthy correlation with the subgroup experiencing MDE alongside suicidality (Pearson correlation coefficient ≤ 0.01). However, this correlation was not evident within the MDE subgroup lacking suicidal tendencies. Utilizing a one-sample t-test, it was established that both MDE groups displayed a substantial association (with a two-tailed significance level of ≤ 0.01) with the inflammatory biomarkers. Notably, the mean difference in biomarker levels was considerably more pronounced in the subgroup characterized by suicidality. Conclusion: Suicidal behavior, encompassing both ideation and attempts, exhibits an independent association with a pro-inflammatory state, irrespective of the severity of the linked depression. This relationship warrants further investigation to identify reliable biomarkers to enhance prediction and facilitate more effective management of suicidal behavior.

Antipyretic effects of Xiangqin Jiere granules on febrile young rats revealed by combining pharmacodynamics, metabolomics, network pharmacology, molecular biology experiments and molecular docking strategies

Xiangqin Jiere granules (XQJRG) is a proprietary Chinese medicine treating children’s colds and fevers, but its mechanism of action is unclear. The aim of this study was to explore the antipyretic mechanisms of XQJRG based on pharmacodynamics, non-targeted metabolomics, network pharmacology, molecular biology experiments, molecular docking, and molecular dynamics (MD) simulation. Firstly, the yeast-induced fever model was constructed in young rats to study antipyretic effect of XQJRG. Metabolomics and network pharmacology studies were performed to identify the key compounds, targets and pathways involved in the antipyretic of XQJRG. Subsequently, MetScape was used to jointly analyze targets from network pharmacology and metabolites from metabolomics. Finally, the key targets were validated by enzyme-linked immunosorbent assay (ELISA), and the affinity and stability of key ingredient and targets were evaluated by molecular docking and MD simulation. The animal experimental results showed that after XQJRG treatment, body temperature of febrile rats was significantly reduced, 13 metabolites were significantly modulated, and pathways of differential metabolite enrichment were mainly related to amino acid and lipid metabolism. Network pharmacology results indicated that quercetin and kaempferol were the key active components of XQJRG, TNF, AKT1, IL6, IL1B and PTGS2 were core targets. ELISA confirmed that XQJRG significantly reduced the plasma concentrations of IL-1β, IL-6, and TNF-α, and the hypothalamic concentrations of COX-2 and PGE2. Molecular docking demonstrated that the binding energies of kaempferol to the core targets were all below −5.0 kcal/mol. MD simulation results showed that the binding free energies of TNF-kaempferol, IL6-kaempferol, IL1B-kaempferol and PTGS2-kaempferol were −87.86 kcal/mol, −70.41 kcal/mol, −69.95 kcal/mol and −106.67 kcal/mol, respectively. In conclusion, XQJRG has antipyretic effects on yeast-induced fever in young rats, and its antipyretic mechanisms may be related to the inhibition of peripheral pyrogenic cytokines release by constituents such as kaempferol, the reduction of hypothalamic fever mediator production, and the amelioration of disturbances in amino acid and lipid metabolism. Communicated by Ramaswamy H. Sarma

Pro Inflammatory Cytokines Profiles of Patients With Long COVID Differ Between Variant Epochs.

Over 30% of patients with COVID-19 have persistent symptoms that last beyond 30 days and referred to as Long COVID. Long COVID has been associated with a persistent elevation in peripheral cytokines including interleukin-6, interleukin-1β, and tumor necrosis factor-α. This study reports cytokine profiles of patients in our clinic across SARS-COV-2 variant epochs. The clinical cytokine panel was analyzed in patients with Long COVID during periods that were stratified according to variant epoch. The 4 variant epochs were defined as: (1) wild-type through alpha, (2) alpha/beta/gamma, (3) delta, and (4) omicron variants. A total of 390 patients had the clinical cytokine panel performed; the median age was 48 years (IQR 38-59) and 62% were female. Distribution by variant was wild-type and alpha, 50% (n = 196); alpha/beta/gamma, 7.9% (n = 31); delta, 18% (n = 72); and omicron, 23% (n = 91). Time to cytokine panel testing was significantly longer for the earlier epochs. Tumor necrosis factor-α (P < .001) and interleukin 1β (P < .001) were significantly more elevated in the earlier epochs (median of 558 days in wild-type through Alpha epoch vs 263 days in omicron epoch, P < .001)). Nucleocapsid antibodies were consistently detected across epochs. When stratified by variant epoch, patients with early epoch Long COVID had persistently elevated peripheral pro-inflammatory cytokine levels when compared to later epoch Long COVID. Patients with Long COVID have similar clusters of symptoms across epochs, suggesting that the underlying pathology is independent of the peripheral cytokine signature.

Elevated levels of peripheral Th17 cells and Th17-related cytokines in patients with periampullary adenocarcinoma

AimPeriampullary adenocarcinoma (PAC) is a malignant tumor originating at the ampulla of Vater, distal common bile duct, head of the pancreas, ampulla and duodenum. The levels of circulating Th17 cells and Th17-related cytokines in patients with PAC remain unreported. Therefore, the aim of this study was to determine the levels of circulating Th17 cells and Th17-related cytokines in patients with PAC. Materials and methodsFlow cytometry was used to measure Th17 cell proportions in PBMCs from 60 PAC patients and 30 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-17A and IL-23 levels in serum samples, while quantitative reverse transcription polymerase chain reaction (qRT-PCR) assessed IL-17A mRNA expression and Th17-related transcription factors (RORγt and STAT3) in tissue samples. ResultsThe findings showed a substantial increase in Th17 cell percentages, elevated concentrations of IL-17A and IL-23, and higher mRNA expression levels of IL-17A, RORγt, and STAT3 in patients with PAC when compared to healthy controls (HCs). ConclusionTh17 cells play an important role in the pathogenesis of PAC and may represent potential therapeutic targets.

Visceral Adiposity and Neutralizing Antibody Expression: An Adult-Based Cross-Sectional Study.

Visceral adiposity is a significant risk factor for severe COVID-19. However, the impact of the Chinese visceral adiposity index (CVAI) on the efficacy of SARS-CoV-2 vaccines remains poorly understood. This study aims to explore the impact of CVAI on the production of neutralizing antibodies (NAb) in inactivated SARS-CoV-2 vaccines and the potential mechanism, thereby optimizing vaccination guidance. In this cross-sectional study, 206 health workers (completed two SARS-CoV-2 vaccination on February 8th and March 10th, 2021, respectively) were recruited. All baseline anthropometric parameters of the participants were collected, and venous blood samples were obtained 6 weeks later to measure peripheral innate immune cells, inflammatory cytokines, and NAb titers against SARS-CoV-2. CVAI were calculated according to the formula and divided participants into two groups depending on CVAI median. The median NAb titer among healthcare workers was 12.94 AU/mL, with an efficacy of 87.86% for the SARS-CoV-2 vaccine. NAb titers were lower in the CVAI dysfunction group than in the CVAI reference group (median: 11.40 AU/mL vs 15.57 AU/mL), the hsCRP levels (median: 0.50 mg/L vs 0.30 mg/L) and peripheral monocyte count (mean: 0.47 × 109/L vs 0.42 × 109/L) in the CVAI dysfunction group were higher than in the CVAI reference group. Additionally, CVAI showed positive correlations with hsCRP, monocytes, lymphocytes, and B-lymphocytes, and a negative correlation with NAb titers. CVAI may inhibit SARS-CoV-2 neutralizing antibody expression through inducing immune dysfunction and chronic inflammation. Thus, more attention should be paid to the vaccination for high CVAI population to improve the effectiveness of vaccination, which could provide more robust support for COVID-19 epidemic prevention and control.

Relationship between serum inflammatory cytokines and suicide risk in patients with major depressive disorder.

Studies have shown that increased inflammatory cytokines are associated with suicide risk, but the relationship between suicide risk and inflammatory cytokines is not clear. This study aimed to investigate the relationship between specific inflammatory markers and suicide risk in patients with MDD. This is a cross-sectional study. Firstly, we measured and compared psychological characteristics and 10 peripheral inflammatory cytokines in 130 MDD patients and 130 healthy controls(HC). Secondly, MDD patients were divided into 4 groups according to the severity of suicide risk for comparison between groups. Finally, multiple linear regression analysis was used to explore the predictors of suicide risk. We found that the group with higher suicide risk had higher levels of IL-6, CRP, TNF-α, CXCL-2, and IFN-γ, and lower levels of IL-2 and IL-8 (all p<0.01). However, we found no difference in CRP between MIS and LS groups (p=0.337). Regression models were well-fitted. IL-2,IL-8 negatively predicted suicide risk (all p<0.05),IL-6,CRP,TNF-α,CXCL-2, and IFN-γ can positively predict the risk of suicide (all p<0.05). This study employed a self-assessment scale. The higher the levels of IL-6, CRP, TNF-α, CXCL-2, and IFN-γ and the lower the levels of IL-2 and IL-8 of MDD patients, the higher the risk of suicide.

Ремиссия и иммунологический профиль пациентов на начальных стадиях шизофрении

Aim. To study the types of remission and levels of peripheral inflammatory cytokines as potential biomarkers of remission in patients at the early stages of schizophrenia. Design. A naturalistic study. Materials and methods. Forty-eight patients (25 women and 23 men) were examined at the initial stages of schizophrenia during the period of remission (age — 28.3 ± 5.8 years). The duration of the disease was 2.7 ± 1.3 years, the average age of disease onset — 25.8 ± 5.5 years. The average number of relapses reached 1.8 ± 0.7. 19 (40%) of patients had one psychotic episode in their anamnesis, 24 (50%) — two, 5 (10%) — three. The control group included 86 people, 38 men and 48 women, aged 18 to 30 years without mental, autoimmune disorders, exacerbation of chronic somatic diseases (standard relatively healthy group, the level of proinflammatory cytokines in participants tended to zero). The study used a clinical and psychopathological method and a standardized assessment using the Positive and Negative Syndrome Scale (PANSS). Results. The average duration of remission was 11.4 months. In the early stages of schizophrenia, the paranoid type of remission was predominant (48%). The thymopathic type of remission occurred in 18% of cases, apathetic and hypochondriacal — 10% each, pseudopsychopathic — in 8%, asthenic — in 6%. General psychopathological symptoms were most pronounced in hypochondriacal, residual negative symptoms — in the apathetic type of remission. In the hypochondriacal type, the severity of positive and negative symptoms did not differ, and in the paranoid type, residual positive symptoms prevailed over negative ones. The thymopathic type of remission was distinguished by the least severity of residual symptoms. In 70% of patients in the early stages of schizophrenia, a significant increase in blood cytokine levels was found compared to those in the control group. The levels of interleukins (IL) 6, IL-9, IL-10, IL-13, IL-22, tumor necrosis factor α, CCL20/MIP3-α increased to the greatest extent (p = 0.001). The level of IL-22 correlated with the total PANSS score (r = –0.52; p = 0.008), and the level of IL-6 — with the composite PANSS index (the difference between the sum of the scores of positive and negative symptoms) (r = 0.46; p = 0.022). The strongest cytokine reaction was observed in the paranoid and pseudopsychopathic variants due to an increase in the content of IL-6, IL-33 and IL-13. The longer the duration of the present remission, the lower were the levels of IL-33 (r = –0.45; p = 0.023), IL-17A (r = –0.40; p = 0.049), IL-17F (r = –0.59; p = 0.002). Conclusion. The available data indicate an important role of cytokines in the development of schizophrenia. The presented results may have prognostic value for assessing the stability of remission, the studied cytokines — serve as potential biomarkers of schizophrenia remission and therapeutic targets for pathogenetic therapy. Keywords: schizophrenia, first psychotic episode, remission, cytokines.

Higher IL-6 and IL-4 plasma levels in depressed elderly women are influenced by diabetes mellitus.

This study aimed at investigating a set of peripheral cytokines in elderly female patients with MDD, comparing them to controls, and assessing the potential influence of clinical comorbidities on inflammatory markers. Twenty-five elderly female patients diagnosed with MDD and 19 age-matched female controls were enrolled on this study. Plasma levels of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were evaluated with commercially-available assays. Elderly female patients with MDD exhibited higher plasma IL-6 and IL-4 levels when compared to controls. In a logistic regression model taking cytokine levels, comorbidities, and age into account, only type 2 diabetes mellitus (DM2) remained associated with MDD. Diabetes influences the association between MDD and higher levels of cytokines in elderly female patients. Future studies should take this evidence into account in order to mitigate confounding factors.

Levels of cytokines in the cerebrospinal fluid of patients with psychotic disorders compared to individually matched healthy controls

BackgroundIncreased peripheral cytokine levels have been observed in patients with psychotic disorders; however, large high-quality studies with individually matched healthy controls have been lacking regarding cytokines in cerebrospinal fluid (CSF) of individuals with psychotic disorders. MethodsPatients diagnosed with a non-organic, non-affective psychotic disorder (ICD-10: F20/22–29) within a year prior to inclusion and individually age- and sex-matched healthy controls were included by identical in- and exclusion criteria’s except for the psychiatric diagnoses. All participants were aged 18–50 years and individuals with neurological or immunological disorders were excluded. CSF cytokines were analyzed with MesoScale V-PLEX neuroinflammation panel. Co-primary outcomes were CSF interleukin-6 (IL-6) and IL-8. ResultsWe included 104 patients and 104 healthy controls, matching on age, sex and BMI. No significant differences were found for the primary outcomes IL-6 (relative mean difference (MD): 0.97, 95 %CI: 0.84–1.11, p = 0.637) or IL-8 (MD: 1.01, 95 %CI: 0.93–1.09, p = 0.895). Secondary analyses found patients to have higher IL-4 (MD: 1.30, 95 %CI: 1.04–1.61, p = 0.018), a trend towards higher IFN-γ (MD: 1.26, 95 %CI: 0.99–1.59, p = 0.056), and lower IL-16 (MD: 0.83, 95 %CI: 0.74–0.94, p = 0.004) than healthy controls, though not significant after correction for multiple testing. IL-8 and IL-16 were found positively associated with CSF white blood cells and CSF/serum albumin ratio. The study was limited by 77.9 % of the patients being on antipsychotic treatment at time of intervention, and that levels of nine of the 26 cytokines were below lower limit of detection (LLOD) in >50 % of samples; however, for the primary outcomes IL-6 and IL-8 more than 99.5 % of the samples were above LLOD and for IL-8 all samples exceeded the lower limit of quantification (LLOQ). ConclusionsWe found no evidence of increased IL-6 and IL-8 in patients with recent-onset psychotic disorders in contrary to previous findings in meta-analyses of CSF cytokines. Secondary analyses found indication of higher IL-4, decreased IL-16, and borderline increased IFN-γ in patients, neither of which have previously been reported on in CSF analyses of individuals with psychotic disorders.

Alteration of white matter microstructure in patients with sleep disorders after COVID-19 infection

BackgroundThe pathophysiology of coronasomnia remains unclear. This study aimed to investigate changes in white matter (WM) microstructure and inflammatory factors in patients with sleep disorders (SD) characterized by poor sleep quantity, quality, or timing following coronavirus disease 2019 (COVID-19) infection in the acute phase (within one month) and whether these changes could be recovered at 3-month follow-up. Methods29 acute COVID-19 patients with SD (COVID_SD) and 27 acute COVID-19 patients without SD (COVID_NonSD) underwent diffusion tensor imaging (DTI), tested peripheral blood inflammatory cytokines level, and measured Pittsburgh Sleep Quality Index (PSQI), and matched 30 uninfected healthy controls. Analyzed WM abnormalities between groups in acute phase and explored its changes in COVID_SD at 3-month follow-up by using tract-based spatial statistics (TBSS). Correlations between DTI and clinical data were examined using Spearman partial correlation analysis. ResultsBoth COVID_SD and COVID_NonSD exhibited widespread WM microstructure abnormalities. The COVID_SD group showed specific WM microstructure changes in right inferior fronto-occipital fasciculus (IFOF) (lower fractional anisotropy [FA]/axial diffusivity [AD] and higher radial diffusivity [RD]) and left corticospinal tract (CST) (higher FA and lower RD) and higher interleukin-1β (IL-1β) compared with COVID_NonSD group. These WM abnormalities and IL-1β levels were correlated PSQI score. After 3 months, the IFOF integrity and IL-1β levels tended to return to normal accompanied by symptom improvement in the COVID_SD relative to baseline. ConclusionAbnormalities in right IFOF and left CST and elevated IL-1β levels were important neurophenotypes correlated with COVID_SD, which might provide new insights into the pathogenesis of neuroinflammation in SD patients induced by COVID-19.

Safety and Immunogenicity of an In Vivo Muscle Electroporation Delivery System for DNA-hsp65 Tuberculosis Vaccine in Cynomolgus Monkeys.

A Bacille Calmette-Guérin (BCG) is still the only licensed vaccine for the prevention of tuberculosis, providing limited protection against Mycobacterium tuberculosis infection in adulthood. New advances in the delivery of DNA vaccines by electroporation have been made in the past decade. We evaluated the safety and immunogenicity of the DNA-hsp65 vaccine administered by intramuscular electroporation (EP) in cynomolgus macaques. Animals received three doses of DNA-hsp65 at 30-day intervals. We demonstrated that intramuscular electroporated DNA-hsp65 vaccine immunization of cynomolgus macaques was safe, and there were no vaccine-related effects on hematological, renal, or hepatic profiles, compared to the pre-vaccination parameters. No tuberculin skin test conversion nor lung X-ray alteration was identified. Further, low and transient peripheral cellular immune response and cytokine expression were observed, primarily after the third dose of the DNA-hsp65 vaccine. Electroporated DNA-hsp65 vaccination is safe but provides limited enhancement of peripheral cellular immune responses. Preclinical vaccine trials with DNA-hsp65 delivered via EP may include a combination of plasmid cytokine adjuvant and/or protein prime-boost regimen, to help the induction of a stronger cellular immune response.

Classification of Peripheral Blood Leukocyte Phenotypes and Serum Cytokines in Vogt-Koyanagi-Harada Disease before and after Glucocorticoid Therapy.

Vogt-Koyanagi-Harada disease (VKH) is an autoimmune disease, and glucocorticoid therapy (GC) is widely used for VKH. We provided a profile of leukocyte populations and serum cytokines in VKH patients under GC. A prospective observational study was conducted on three treatment-naïve VKH patients. Peripheral blood samples were collected from the patients before GC (VKH-acute) and after 6 months (VKH-remission), and healthy individuals were used as controls. Proportions of 37-type leukocytes and levels of 27-kind cytokines were measured by mass cytometry and multiplex bead analysis. Property similarity was analyzed using hierarchical cluster analysis. The leukocytes and cytokines were broadly classified into four and three clusters: (1) a cluster with high intensity in VKH-acute consisting of B cells, Th2-like, Th17-like, basophils, and IL-7 and IP-10; (2) a cluster with high intensity in VKH-remission composed of monocytes, neutrophils, IL-4, and TNFα; in leukocytes, (3) a cluster with low intensity in VKH-acute and -remission consisting of CD8+ T cells, Th1-like, and NKT cells; (4) a cluster with low intensity in VKH-remission composed of NK cells, Tregs, and DCs; and in cytokines, (5) a cluster with high intensities in VKH-acute and -remission comprising G-CSF, MCP-1, eotaxin, and IL-17A. These findings suggest that inflammatory composition in blood during the acute phase of VKH represents complex hyperimmune responses dominantly driven by Th and B cells.

The clinical trajectory of peripheral blood immune cell subsets, T-cell activation, and cytokines in septic patients.

Changes in the immune status of patients with sepsis may have a major impact on their prognosis. Our research focused on changes in various immune cell subsets and T-cell activation during the progression of sepsis. We collected data from 188 sepsis patients at the First Affiliated Hospital of Zhejiang University School of Medicine. The main focus was on the patient's immunocyte subset typing, T-cell activation/Treg cell analysis, and cytokine assay, which can indicate the immune status of the patient. The study found that the number of CD4+ T cells, CD8+ T cells, NK cells, and B cells decreased early in the disease, and the decrease in CD4+ and CD8+ T cells was more pronounced in the death group. T lymphocyte activation was inhibited, and the number of Treg cells increased as the disease progressed. T lymphocyte inhibition was more significant in the death group, and the increase in IL-10 was more significant in the death group. Finally, we used patients' baseline conditions and immunological detection indicators for modeling and found that IL-10, CD4+ Treg cells, CD3+HLA-DR+ T cells, and CD3+CD69+ T cells could predict patients' prognosis well. Our study found that immunosuppression occurs in patients early in sepsis. Early monitoring of the patient's immune status may provide a timely warning of the disease.

Plasma IL‐6 levels are Negatively Associated with MRI‐Based Water Exchange Rate Across the Blood‐Brain Barrier

AbstractBackgroundChanges in blood‐brain barrier (BBB) integrity are associated with cognitive decline in aging. Inflammatory processes are thought to contribute to BBB dysfunction but this link has been difficult to measure in humans using non‐invasive, in‐vivo methods. Recently, a novel magnetic resonance imaging (MRI) technique, diffusion‐prepared arterial spin labeling (DP‐ASL), has been shown to provide a means to test the water exchange rate across the BBB (kw) as well as arterial transit time (ATT) and cerebral blood flow (CBF). Here, we tested the association between these DP‐ASL measures and a specific plasma marker of inflammation, IL‐6, in older adults without dementia.MethodWe tested the association between kw, ATT, and CBF and a marker of peripheral inflammation in a sample of 58 older adults without dementia. Regions of interest (ROIs) included the putamen, caudate, and pallidum. Plasma IL‐6 levels were assessed using Simoa assays. IL‐6 was natural log transformed and data collected ≤ 1 year from the MRI visit were used for subsequent analyses. Multiple linear regression models, controlling for age, sex, and ROI size, tested the impact of plasma IL‐6 on kw, ATT, and CBF metrics. Both linear and quadratic effects of IL‐6 on the outcomes of interest were examined.ResultThere was a negative linear association between IL‐6 and kw in the putamen. As plasma IL‐6 levels increased, kw values decreased. In contrast, no relationships were observed between plasma IL‐6 and ATT or CBF in any of the ROIs tested.ConclusionOur results suggest that the water exchange rate across the BBB in the putamen was most uniquely associated with the peripheral proinflammatory cytokine, IL‐6. These findings could be indicative of the involvement of peripheral inflammation in reducing glymphatic clearance which would manifest as reduced water exchange rate across the BBB. The lack of association with ATT and CBF suggest that peripheral cytokines could act on a mechanism more closely related to water channel function rather than overall brain perfusion.

Objectively‐measured physical behaviors, peripheral cytokines, and plasma neurofilament light chain in older adults: a population‐based study

AbstractBackgroundEvidence has linked self‐reported sedentary behavior (SB) and physical activity (PA) with cognitive impairment; however, the underlying neuropathological mechanisms are poorly understood. We examined the dose‐response associations of the accelerometer‐measured daily SB and PA time with plasma neurofilament light chain (NfL) among older adults and the role of systemic low‐grade inflammation in the associations.MethodThis population‐based study included 1,029 dementia‐free older adults (age ≥60 years, 59.48% women) who undertook the ActiGraph substudy (March 2018‐December 2020) in MIND‐China. Plasma NfL and serum cytokines were measured on SIMOA and MSD platforms, respectively. Movement parameters were assessed with an accelerometer. Data were analyzed using the restricted cubic splines, general linear, and mediation models.ResultThere were J‐shaped associations of daily SB and PA time with plasma NfL concentration, such that more daily SB time or less daily light‐intensity physical activity (LPA) and moderate‐to‐vigorous‐intensity physical activity (MVPA) time were significantly associated with increased plasma NfL only when SB time ≥8.00 hours/day or LPA time &lt;5.00 hours/day or MVPA time &lt;2.00 hours/day. Furthermore, more daily SB time or less daily LPA and MVPA time was significantly associated with higher serum inflammation scores (P&lt;0.05). Finally, serum biomarkers of low‐grade inflammation could account for 15% to 19% of the associations between movement behaviors and plasma NfL level.ConclusionMore daily SB and less PA time are associated with peripheral biomarker for neurodegeneration and systemic low‐grade inflammation in older adults. The association of movement behaviors with neurodegeneration is partially mediated by systemic low‐grade inflammation.