Plasma Cytokine Levels Research Articles

CD8+T cells and monocytes were associated with brain alterations in human immunodeficiency virus-infected individuals with cognitive impairment.

Cognitive impairment (CI) continues to be a concern for people living with HIV-1 (PLWH) in the era of antiretroviral therapy (ART), yet the underlying mechanisms remain unclear. We aimed to elucidate the structural and functional brain alterations and peripheral immune profile of PLWH with CI, as well as the correlation between them. PLWH were divided into CI (n= 30) and cognitive normal (CN, n= 59) groups based on the Montreal Cognitive Assessment, and underwent multi-modal magnetic resonance imaging. Mass cytometry was utilized to profile immune cells, while the liquid chip technique was employed to measure plasma levels of cytokines and chemokines. Spearman correlation analyses were conducted for correlation analysis. Here, we found that the gray matter volume in left supramarginal gyrus was reduced, and the ReHo in the right middle frontal gyrus and the functional connectivity between right middle frontal gyrus and left postcentral gyrus were enhanced in CI group compared to CN group. Additionally, the frequencies of naïve CD8+T cells (Tn) and CD31lowCD8+ Tn were significantly correlated with gray matter volume in the left supramarginal gyrus. The amplitude of low frequency fluctuations in a specific brain region of frontal-middle lobe was negatively correlated with the frequencies of non-classical monocytes (nCM) and their subpopulations (CCR2lownCM, CD57lownCM and CD127+nCM), and positively associated with the plasma interleukin 25 and transforming growth factor-α levels. These findings suggest the association between peripheral immunity and the brain abnormalities in PLWH, highlighting a potential role of the immune-brain-cognition axis in the pathogenesis of CI in Chinese PLWH.

P-1853. Peripheral blood monocytes pro-inflammatory and anti-inflammatory cytokine release in elderly patients with heart failure with reduced ejection fraction

Abstract Background Heart failure with reduced ejection fraction (HFrEF) has benn reported to characterize by sub-clinical inflammation status. There are few reports about changes in selected biomarkers of inflammation concomitant with the release of pro-inflammatory and anti-inflammatory cytokines by monocyte in elderly patients with HFrEF. Methods We measured plasma levels of the cytokines in 62 elderly Japanese HFrEF patients (aged 85.8 ± 2.7 years, left ventricular ejection fraction 33.7 ± 3.5%) and 20 healthy controls. Peripheral blood monocytes (PBM) obtained from HFrEF patients were stimulated by LPS (10 μg/ml) in the absence or the presence of adenosine (10 μmol/l). After 6hr incubation, the cytokines levels in the culture supernatants were measured by ELISA. Results Plasma levels of TNF-alpha, IL-6, IL-10, and IL-12p40 were significantly greater in HFrEF patients than in controls. Plasma IL-12p40 levels of HFrEF patients showed significant correlations with IL-6 and IL-10. In vitro study, adenosine inhibited the generation of pro-inflammatory cytokines from LPS-stimulated PBM (TNF-alpha: 764.2±32.3 to 242.5±55.3pg/ml, IL-6: 82.3±13.5 to 21.4±4.2 pg/ml, IL-12p40: 164.8±23.5 to 18.2±5.1, all p< 0.01), while it augmented IL-10 generation (29.2±6.1 to 54.9±7.8pg/ml, p< 0.01) significantly. Conclusion Our data indicated plasma levels of pro-inflammatory and anti-inflammatory cytokine were elevated in eldely patients with HFrEF relating. Adenosine may represent a new pharmacological intervention in such HFrEF patients,the clinical significance of these findings deserves further investigation Disclosures All Authors: No reported disclosures

Abstract B007: CD163+ tumor-associated macrophage evasion contributes radiation resistance and poor prognosis in estrogen receptor-negative breast cancer

Abstract Patients with estrogen receptor-negative (ER-) breast cancer demonstrate worse clinical outcomes and poor prognosis from post-mastectomy radiation therapy (PM-RT) than those with ER-positive (ER+) breast tumors. RT modulates the tumor microenvironment (TME) dynamic and its impact on immune evasion and resistance remains unclear. In this prospective study, we explore the role of CD163, a scavenger receptor protein primarily expressed in monocytes and M2-like tumor-associated macrophages (TAM), in driving local and systemic immunosuppression and immune evasion after RT, particularly in ER- tumors. For this, ER- and ER+ biopsy breast tumor tissues (n=45) and peripheral blood samples were collected from pre-RT and post-RT exposed patients. A tumor transcriptomic profiling was performed using the NanoString platform, and peripheral blood mononuclear cells and plasma cytokines levels were analyzed through flow cytometry. Patient-derived monocytes were sorted, polarized into M2C macrophages, and co-cultured with healthy T cells to assess the immunosuppressive role of M2C-CD163, with and without the anti-CD163 monoclonal antibody (OR2805). Further, an orthotopic murine breast cancer model (4T1; ER-/TNBC cells) was developed to confirm M2-CD163's role in immunosuppression following RT and its influence on the response to checkpoint immunotherapy. The Cancer Genome Atlas (TCGA) analysis revealed that higher expression of CD163 transcripts associated with poor overall survival in ER- but not in ER+ breast cancer patients, and our data suggest that RT significantly increases CD163, the transcriptomic signature of TAM markers (MRC1, ATF3, DUSP1, PTPRC, DAB2) as well as upregulates several transcription factors (STAT1, STAT2, CEBPB, NFKB1A) that involved in TAM-mediated immunosuppression. Intriguingly, RT-induced immune evasion to ER- breast tumors, elevates CD163 in the plasma and increases monocyte plasticity toward an M2-like phenotype. These monocyte-derived macrophages suppressed T cell activity, highlighting the strong immunosuppressive potential of monocytes from irradiated ER- breast tumors. Inhibition of CD163 by monoclonal antibody reversed the RT-induced immunosuppression, reprogramming monocytes/macrophages to a pro-inflammatory M1 phenotype and restoring T cell activity. In addition, RT promoted myeloid cell differentiation into CD163+M2-like macrophages, leading to immunosuppressive changes within the tumor and systemic circulation in mice in vivo. Pharmacologic depletion of CD163+ macrophages in combination with RT improved overall survival and enhanced tumor responsiveness to checkpoint immunotherapy. In conclusion, our data suggest CD163 is a key mediator of radiation-induced immunosuppression in ER- breast cancer, and pharmacological targeting of CD163 in aggressive and advanced ER- breast tumors may improve radiation response and patient outcomes. Citation Format: Subhajit Ghosh, Suryakant Niture, Jerry Jaboin, Danushka Seneviratne. CD163+ tumor-associated macrophage evasion contributes radiation resistance and poor prognosis in estrogen receptor-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B007.

P0478 Peripheral blood cytokines in patients with paediatric-onset Inflammatory Bowel Disease – a systematic review and meta-analysis

Abstract Background Cytokines play a central role in the aetiology, disease severity and treatment of adult-onset inflammatory bowel disease (IBD)1. However, despite the aggressive phenotype reported in paediatric-onset IBD, little is known about the cytokine levels in paediatric-onset IBD. This systematic review and meta-analysis aimed to summarize findings of cytokine levels in peripheral blood in patients with paediatric-onset IBD compared to healthy controls. Methods This systematic review followed the PRISMA guidelines2 and was registered at Prospero [CRD42024579684]. A literature search was performed on the 1st of August 2024 in PubMed, EMBASE, Web of Science and Scopus. We included studies that reported levels of cytokines in plasma or serum, in patients with paediatric-onset IBD and healthy controls. To ensure a complete overview, we did not exclude studies based on patients’ treatment status. Pooled effect sizes of mean values were calculated using Hedges’ g for any cytokine reported by two or more studies. The Newcastle-Ottawa scale was used for quality assessment. Results The literature search revealed 10,110 papers (4,582 duplicates), and 5,528 articles were independently screened by two authors. Twenty-one articles met the inclusion criteria including a total of 950 patients with paediatric-onset IBD, and 481 healthy controls. Studies reported on 57 different cytokines. Meta-analysis was performed for interleukin-6 (IL-6) (12 studies, of which 7 provided mean values) and tumour necrosis factor-α (TNF-α) (7 studies, of which 2 provided mean values). Mean values of other cytokines were not provided by two or more studies, and meta-analysis could therefore not be performed. Pooled effect sizes showed increased levels of IL-6 (standardized mean difference: 1.99, 95% confidence interval: 1.15-3.26). However, the heterogeneity between studies was high (Figure 1). Levels of TNF-α did not differ between patients and controls (standardized mean difference: 0.36 95% confidence interval: -0.08-0.79). Overall, the included studies had moderate-good quality. Conclusion IL-6 was increased in the peripheral blood of patients with paediatric-onset IBD. Data on other cytokines were scarce. References 1)Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329-342. doi:10.1038/nri3661 2)Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Published 2021 Mar 29. doi:10.1136/bmj.n71

Polymorphisms Influence the Expression of the Fas and FasL Genes in COVID-19.

The apoptotic molecule Fas and its ligand FasL are involved in the process of T-lymphocyte death, which may lead to lymphopenia, a characteristic of severe coronavirus disease 2019 (COVID-19). In this study, we investigated the influence of polymorphisms in the FAS and FASL genes, FAS and FASL gene expression, and plasma cytokine levels on COVID-19 severity and long COVID occurrence. A total of 116 individuals with severe COVID-19 and 254 with the non-severe form of the disease were evaluated. In the post-COVID-19 period, samples from 196 individuals with long COVID and 67 from people who did not have long COVID were included. Genotyping and quantification of gene expression were performed via real-time PCR, and cytokine measurement was performed via flow cytometry. The AA genotype for FAS rs1800682 (A/G) and the TT genotype for FASL rs763110 (C/T) were associated with increased FAS and FASL gene expression, respectively (p < 0.005). Higher plasma IFN-γ levels were associated with higher FAS and FASL gene expression (p < 0.05). Among individuals with non-severe COVID-19, carriers of the AA genotype for FAS rs1800682 (A/G) had higher levels of FAS expression, more symptoms, and higher IFN-γ levels (p < 0.05). No association of the evaluated markers with long COVID were observed. The AA genotype of FAS rs1800682 (A/G) and the TT genotype of FASL rs763110 (C/T) influence the levels of FAS and FASL gene expression. Higher gene expression of FAS and FASL may lead to greater inflammation in COVID-19 patients, with higher levels of IFN-γ and T lymphocyte death.

Exploration of Cytokines and Microbiome Among Males and Females with Diarrhea-Predominant Irritable Bowel Syndrome.

Whether pathophysiological factors differ between males and females with irritable bowel syndrome-diarrhea (IBS-D) remains to be tested. To better understand potential sex differences, males with IBS-D were compared to naturally cycling females and to females with IBS-D taking hormonal contraception on plasma levels of cytokines and gut microbiome characteristics. Males and females with Rome III IBS-D completed questionnaires and kept a daily symptom diary for 28days. Blood and stool samples were collected between days 3 and 8 of the daily diary (estrogen-dominant days in naturally cycling females). Blood samples were analyzed for lipopolysaccharide (LPS)-stimulated and unstimulated cytokine levels. Stool samples were analyzed for microbiota signatures using 16S rRNA sequencing. Forty-seven participants with IBS-D (13 males, 22 naturally cycling females, 12 females with hormonal contraception use) ages 18 to 50years were studied. Males had similar unstimulated IL10, IL12P40, IL12P70, IL1β, IL8, and TNFα plasma cytokine levels compared to naturally cycling females, but higher levels compared with females using hormonal contraception. LPS-stimulated IL12P70 levels were lower in both groups of females vs. males. Alpha- and beta-diversity did not differ although differences in genus-level bacteria were found. Cytokine levels differed between males and females using hormonal contraceptives but not between males and normally cycling females. It is important to consider that naturally cycling females may have a different cytokine and microbiome profile than females using hormonal contraceptives. Whether this portends a sex difference in potential etiologic factors remains to be determined.

Plasmatic Levels of Cytokines and Quality of Life among Elderly Individuals with Dizziness.

Introduction Few studies have investigated the relationship between cytokines and dizziness in elderly individuals. Objective To assess the levels of inflammatory biomarkers and their relationship with quality of life (QoL) among elderly individuals with dizziness. Methods We conducted a cross-sectional study with 103 participants (90 women and 13 men) who were assessed through the Visual Analogue Scale (VAS) and the Dizziness Handicap Inventory (DHI). The plasma levels of cytokines were measured through the cytometric bead array (CBA) method. Cross-tabulations with the Chi-squared test were used to verify sample homogeneity, and parametric tests were used to analyze the data. Results Out of the total sample of 103 individuals, dizziness was reported by 40 women and 5 men. A difference between the groups with and without dizziness was observed regarding the levels of interleukin 4 (IL-4; p = 0.011): the group without dizziness presented a higher mean level (2.1 ± 2.8 pg/mL) when compared to the group that presented dizziness (1.0 ± 1.7 pg/mL). Another difference was found between the DHI classifications and the plasma levels of tumor necrosis factor alpha (TNF-α;) p = 0.015): the groups without any losses in QoL presented lower TNF-α levels (1.4 pg/mL) compared to the group that presented moderate QoL loss (6.3 pg/mL). Conclusion Dizziness affects the functional, physical and emotional dimensions of QoL and plays a role in the decrease in the levels of IL-4 and in the presence of fullness and tinnitus. Higher VAS scores are related to dizziness in the elderly. Moreover, the increased levels of TNF-α were associated to light-to-moderate losses in QoL among elderly patients with dizziness.

Overfeeding and overweight rapidly reprogram inflammatory signaling.

Epidemiologic studies have shown a continuous increase in mortality risk associated with overweight, thus highlighting the health risks beginning before the onset of obesity. However, early changes in inflammatory signaling induced by an obesogenic diet remain largely unknown since studies of obesity typically utilize models induced by months of continuous exposure to a high-fat diet. Here, we investigated how short-term overfeeding remodels inflammatory signaling. We developed and characterized a mouse model of overweight induced by seven days of the Western diet enriched in saturated fats and sucrose, compared to the standard, low-fat laboratory diet or a long-term Western diet for 22 weeks. The short-term Western diet caused a median weight gain of 6 %, while the long-term Western diet increased weight by 92 %. Circulating levels of cholesterol, triglycerides, insulin, and leptin were increased by both diets, but only the long-term Western diet caused transaminitis and significant hepatic steatosis. Both models reduced the alpha and beta diversity of the microbiome. Tryptophan metabolism was perturbed by both models; the long-term Western diet also affected histidine and vitamin B6 metabolism. The short-term and long-term Western diets increased expression of TLR4 on peritoneal immune cells and TLR4-driven plasma levels of proinflammatory cytokines comparably, showing one week of the Western diet was sufficient for inducing inflammation typical of chronic obesity. These findings highlight the importance of diet not only in preclinical studies, but also in the clinical care of individuals with inflammatory disorders.

Blood levels of cytokines highlight the role of inflammation in Alzheimer's disease.

Inflammation and angiogenesis have been defined as potential mechanisms associated with clinical progression from a cognitively normal state to Alzheimer's disease (AD). In this observational case-control study, we aimed to determine plasma levels of cytokines as indicators of inflammation involved in cognitive decline. We measured 30 plasma proteins in 49 controls (CTL), 36 individuals with mild cognitive impairment (MCI) and 52 patients diagnosed with probable AD. After applying strict filters for quantification limits, only 13 analytes were included in the analysis. Kruskal-Wallis tests showed significant differences between diagnostic groups for nine cytokines (IL-16, IL-7, VEGF, IL-8, eotaxin, MCP-1, MCP-4, MDC and TARC). Non-parametric MANCOVA showed that sex and diagnosis affected cytokine levels in the blood. To determine the sensitivity and specificity of the markers, we performed receiver operating characteristic (ROC) curve analysis. Only those analytes that showed an area under the curve (AUC)≥0.70 were included in the multivariate logistic regression models to better understand the contribution of cytokines to clinical status. Three models: 1) CTL vs. AD; 2) CTL vs. MCI, and 3) MCI vs. AD were developed, with sex and age as covariates. In each model, two cytokines remained significantly different (model 1: IL-16 and MDC; model 2: eotaxin and MDC and model 3: IL-7 and VEGF). Taken together, this report identifies a set of plasma markers of inflammation and strengthens the role of glial biology in different clinical stages of AD.

SARS-CoV-2 Viral Load and Cytokine Dynamics Profile as Early Signatures of Long COVID Condition in Hospitalized Individuals.

The global pandemic caused by SARS-CoV-2 has resulted in millions of people experiencing long COVID condition, a range of persistent symptoms following the acute phase, with an estimated prevalence of 27%-64%. To understand its pathophysiology, we conducted a longitudinal study on viral load and cytokine dynamics in individuals with confirmed SARS-CoV-2 infection. We used reverse transcriptase droplet digital PCR to quantify viral RNA from nasopharyngeal swabs and employed multiplex technology to measure plasma cytokine levels in a cohort of people with SARS-CoV-2 infection. Our study included individuals with long COVID condition and those without, all of whom had at least three nasopharyngeal and plasma samples collected within 55 days after diagnosis of SARS-CoV-2 infection. Individuals affected with long COVID symptoms had delayed viral clearance and lower viral loads at diagnosis compared to those without symptoms. Additionally, cytokine analysis revealed variations in IL-18, MIG, and IP-10 levels, with delayed normalization in individuals affected by long COVID syndrome. Correlation analysis indicated associations between viral load and IP-10 and interrelations among cytokines IL-1β, IL-18, MIG, and IP-10. Our study provides insights into the association between nasopharyngeal viral load, cytokine dynamics, and the development of long COVID syndrome, providing an early signature of this condition.

Effects of Supplementing Yeast Fermentation Products on Growth Performance, Colonic Metabolism, and Microbiota of Pigs Challenged with Salmonella Typhimurium.

Yeast fermentation products (YFPs) are known to contain bioactive compounds, such as nutritional metabolites and cell wall polysaccharides (specifically glucan and mannan), which have been demonstrated to exert positive effects on the growth performance and immunity of livestock and poultry. However, the impact of YFPs on intestinal inflammation and microflora composition in pigs infected with Salmonella typhimurium remains unclear. To investigate this, a total of 18 weaned pigs were divided into three treatment groups: a non-challenged control group (Con), a group challenged with Salmonella typhimurium (ST), and a group challenged with Salmonella typhimurium and supplemented with 0.4% YFP (YFP). The experiment spanned five weeks, encompassing a period of 21 days prior to and 14 days subsequent to the initial Salmonella typhimurium challenge. The findings indicated that the YFP group exhibited an increase in average daily gain (ADG) and a decrease in the feed-gain ratio (F/G) in comparison to the ST group following the Salmonella challenge. Additionally, the YFP group demonstrated a reduction in the levels of inflammatory cytokines in plasma and a decrease in the expression of inflammatory genes in the colon. Treatment with YFP also resulted in improved colon histomorphology, heightened alpha diversity of the gut microbiota, augmented the abundance of butyrate-producing bacteria, and elevated concentrations of short-chain fatty acids (SCFAs). In addition, YFP reprogrammed energy metabolism in colon epithelial cells by blunting glycolysis. Together, dietary YFP supplementation alleviated colon inflammation in weaned pigs challenged with Salmonella typhimurium, and shaped the beneficial microbiota, thereby maintaining gut homeostasis. The results provided evidence supporting the application of yeast fermentation products in livestock production.

The role of a hemoadsorption filter on cytokine levels during 1 hour of thoraco-abdominal normothermic regional perfusion for donation after circulatory death heart donation in a porcine model.

Both global ischemia caused by circulatory arrest and extracorporeal circulation circuits have been shown to trigger cytokine release. We hypothesized that inserting a hemoadsorption device during thoraco-abdominal normothermic regional perfusion (TA-NRP) in the donation after circulatory death setting would mitigate the inflammatory response, potentially resulting in improved cardiac allograft function. In 15 pigs, circulatory arrest was induced by hypoxia. After a 15-min no-touch-period, TA-NRP was performed for 60 min. Eight pigs had a hemoadsorption device incorporated in the ECC, while seven did not. Plasma concentrations of IFN-α, IFN-γ, TNF-α, IL-1β, IL-4, IL-6, IL-8, IL-10, and IL-12p40 were assessed by ELISA at baseline, immediately at start of TA-NRP, 60 min after start of TA-NRP (just before weaning from ECC), and at 30 and 60 min after weaning from ECC. Cardiac function was assessed with pressure-volume loop analysis. Hemoadsorption had no relevant effects on systemic cytokine levels post TA-NRP. IL-6 plasma levels gradually rose throughout the procedure for both groups. Hemoadsorption did not affect systolic or diastolic left ventricular function, nor were global hemodynamics improved by hemoadsorption. The insertion of a hemoadsorption device did not significantly affect plasma cytokine levels or cardiac function. Further research is necessary to assess the role of the inflammatory response in DCD heart transplantation and its modulation by TA-NRP.

Complex Thrombo-Inflammatory Responses versus Outcomes of Non-COVID-19 Community-Acquired Pneumonia and COVID-19

Introduction: The thrombo-inflammatory response and outcomes of community-acquired pneumonia (CAP) due to various organisms (non-COVID-19 CAP) versus CAP due to a single virus, SARS-CoV-2 (i.e., COVID-19) may differ. Methods: Adults hospitalized with non-COVID-19 CAP (December 1, 2021–June 15, 2023) or COVID-19 (March 2, 2020–June 15, 2023) in Canada. We compared non-COVID-19 CAP and COVID-19 baseline, thrombo-inflammatory response, and mortality. We measured plasma cytokine and coagulation factor levels in a sample of patients, did hierarchical clustering, and compared cytokine and coagulation factor levels. Results: In 2,485 patients (non-COVID-19 CAP, n = 719; COVID-19 patients, n = 2,157), non-COVID-19 CAP patients had significantly lower 28-day mortality (CAP vs. COVID-19 waves 1 and 2; 10% vs. 18% and 16%, respectively), intensive care unit admission (CAP vs. all waves; 15% vs. 39%, 37%, 33%, and 24%, respectively), invasive ventilation (CAP vs. waves 1, 2, and 3 patients; 11% vs. 25%, 20%, and 16%), vasopressor use (CAP 12% vs. 23%, 21%, and 18%), and renal replacement therapy use (CAP 3% vs. Omicron 7%). Complexity of hierarchical clustering aligned directly with mortality: COVID-19 wave 1 and 2 patients had six clusters at admission and higher mortality than non-COVID-19 CAP and Omicron that had three clusters at admission. Pooling all COVID-19 waves increased complexity with seven clusters on admission. Conclusion: Complex thrombo-inflammatory responses aligned with mortality of CAP. At a fundamental level, the human thrombo-inflammatory response to a brand new virus was “confused” whereas humans had eons of time to develop a more concise efficient thrombo-inflammatory host response to CAP.

Association of systemic inflammation and long-term dysfunction in COVID-19 patients: A prospective cohort.

COVID-19 has significant long-term impacts, including a chronic syndrome known as long-COVID, characterized by persistent symptoms post-recovery. The inflammatory response during acute infection is hypothesized to influence long-term outcomes. This study aimed to identify inflammatory biomarkers predictive of functional outcomes one year after hospital discharge. A prospective cohort study was conducted with 213 COVID-19 patients admitted to ICUs in Southern Brazil between June and November 2020. After exclusions and follow-ups, 109 patients were evaluated for one-year post-discharge. Plasma levels of Th1 (TNF-α, INF-γ, IL-12), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), and Th17 (IL-17, IL-22) cytokines were measured. Functional outcomes in psychiatric, cognitive, general health, and health perception domains were assessed. Statistical analyses included multivariate regression, regularized partial correlation network analysis, and K-means clustering. We demonstrate that plasma levels of various cytokines, along with demographic and clinical characteristics, can predict four distinct domains of functional outcomes one year following hospital discharge due to COVID-19 and that an hyperinflammatory phenotype was associated with the occurrence of a worse in psychiatric, general health, and health perception domains. The network analysis highlighted complex interconnections among immune markers and clinical variables, elucidating their roles in long-term health. These findings support using biomarkers for patient stratification and indicate potential targets for therapeutic interventions.

Enzymatic Modulation of the Pulmonary Glycocalyx Enhances Susceptibility to Streptococcus pneumoniae.

The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the importance of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice with Streptococcus pneumoniae in the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan in combination with S. pneumoniae infection further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma concentrations of proinflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage, and pulmonary inflammation in mice infected with S. pneumoniae. Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier during S. pneumoniae infection. Notably, enzymatic pretreatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococci-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in limiting pneumococci-induced damage, pulmonary inflammation, and epithelial barrier function and integrity.

Common variable immunodeficiency clinical manifestations are shaped by presence and type of heterozygous NFKB1 variants.

NFKB1 encodes p105, which is processed to p50 to mediate canonical NF-κB signaling. Though NF-κB is a central driver of inflammation and heterozygous NFKB1 variants are considered the most common monogenic etiologies of common variable immunodeficiency (CVID), few studies have explored how NFKB1 variants shape clinical course or inflammation in CVID. We leveraged a regional cohort of CVID patients with and without heterozygous NFKB1 variants to assess how clinical and inflammatory features of CVID are shaped by the presence of these variants. We compared clinical complications, immunological features, and plasma cytokine levels of 15 CVID patients with heterozygous NFKB1 variants with 77 genetically undefined CVID patients from the same referral base. We also assessed differences between CVID patients with frameshift or nonsense NFKB1 variants compared to those with missense NFKB1 variants. We found CVID patients with heterozygous NFKB1 variants to have increased autoimmune disease, bronchiectasis, gastrointestinal infections, inflammatory bowel disease (IBD), and plasma cytokines. These findings were more pronounced, and included elevation of monocytes, in CVID patients with frameshift or nonsense NFKB1 variants relative to those with missense NFKB1 variants. In a regional cohort, heterozygous NFKB1 variants were associated with worsened CVID clinical course and increased evidence of inflammation in the blood. CVID patients with frameshift or nonsense NFKB1 variants had more significant increases in non-infectious complications and peripheral monocytes than those with missense NFKB1 variants. Presence of pathogenic NFKB1 variants in CVID patients may worsen disease course and warrant closer monitoring.

IL-37 Isoform A Prevents Collagen-Induced Arthritis in Mice by Modulating the Th17/Treg Balance via IL1R8 Receptors.

Cytokines play a complex and pivotal role in modulating synovitis in rheumatoid arthritis. Interleukin (IL)-37 is known for its extensive anti-inflammatory properties that set it apart from the majority of other IL-1 family members. However, IL-37a, a member of the IL-37 family, lacks research into rheumatoid arthritis. This research aims to explore the role of IL-37a in regulating T-cell homeostasis in rheumatoid arthritis using the Collagen-Induced Arthritis(CIA) model. IL-37atg mice, a genetically altered strain carrying the human IL-37a gene, were used to test the influence of this cytokine on the progression of arthritis. The results show that IL-37atg mice demonstrated a notable reduction in both the incidence and severity of arthritis relative to WT mice. The protective effect was accompanied by lower levels of cytokines in plasma and synovial tissues (such as IL-17A and IL1β) that drive the inflammatory response. The ratio of Th17/Treg decreased in the lymph nodes of IL-37atg mice. However, the knockout of IL1R8 in IL37atg mice eliminated the effects of IL-37a. Additionally, transcriptomic analysis revealed that Th17 cell differentiation is a key pathway through which IL-37a exerts its protective effects, and experiments confirmed that IL-37a suppresses Th17-polarizing in vitro.

Role of neutrophils in the pathogenesis of Post Kala-azar Dermal Leishmaniasis (PKDL).

Post Kala-azar Dermal Leishmaniasis (PKDL) is a dermal sequel of visceral leishmaniasis (VL), poses a significant threat to the success of ongoing kala-azar elimination program, due to its potential role in sustaining transmission cycles and complicating disease management strategies. In VL, neutrophils have been identified as the 'first line of defence', having multiple roles in disease pathogenesis, but their role in PKDL, if any, still remains elusive; presenting a critical gap in knowledge, and was the aim of this study. In a cohort of PKDL patients, CD66b+ neutrophils were quantified in skin biopsies, followed by immunostaining of FFPE sections to identify activated neutrophils (CD66b+/CD64+) and degranulated (CD66b+/MPO+), along with expression of neutrophil elastase (NE), matrix metalloprotease 9 (MMP9) and collagen I. Plasma levels of neutrophil chemo-attractants CXCL8/1/2/5, CCL2 and 20 and cytokines, (IL-6, IFN-γ, IL-4, IL-10, TNF-α, IL-17 and IL-22, 23) were evaluated by a multiplex assay, while lesional expression of IL-8, IL-10 and IL-17 was evaluated by immunohistochemistry. As compared to healthy individuals (control skin samples), PKDL cases at the lesional sites had an increased number of activated CD66b+ neutrophils (positive for CD64+, MPO+ and NE+). The plasma levels of neutrophil chemo-attractants, pro-inflammatory and regulatory cytokines were raised as was circulating and lesional IL-8, along with an enhanced lesional expression of IL-10 and IL-17A. An increase in circulatory and lesional MMP9 was accompanied by decreased collagen I, suggesting disintegration of matrix integrity. Taken together, in PKDL, activated neutrophils possibly contribute towards modulating the lesional landscape. Understanding this involvement of neutrophils in patients with PKDL, particularly in the absence of an animal model, could offer better understanding of the disease pathogenesis and provide insights into novel therapeutic strategies for the ongoing elimination program.

Profile of Inflammatory Cytokines in Gingival Crevicular Fluid and Plasma in Patients With Grade C Periodontitis During Orthodontic Treatment: A Longitudinal Case Series Report.

To examine the immune responses in patients diagnosed as grade C periodontitis during orthodontic treatment. Our study included seven orthodontic patients with grade C periodontitis and measured their levels of inflammatory cytokines in gingival crevicular fluid and plasma before orthodontic treatment, during the alignment and levelling phase, and during the detailing and finishing phase. The key signal pathways in the orthodontic process of patients with periodontitis were detected by KEGG analysis. Studies have shown that orthodontic treatment brings great improvement to patients with grade C periodontitis, and most of the local/systemic inflammatory cytokines can be reduced after orthodontic treatment. Simultaneously, orthodontic treatment can reduce the percentage of IFN-γ+ Th1 cells in patients with grade C periodontitis. Through KEGG analysis, the IL-17 signalling pathway and TNF signalling pathway are closely interrelated in the orthodontic treatment of patients diagnosed with grade C periodontitis (p-value < 0.001). Orthodontic treatment can effectively control the local and system levels of inflammation in patients with grade C periodontitis, with IL-17A and TNF-α as potential distinctive inflammatory markers for orthodontic-periodontal combined treatment in individuals with periodontitis.

Chronic inflammation degrades CD4 T cell immunity to prior vaccines in treated HIV infection

To date, our understanding of how HIV infection impacts vaccine-induced cellular immunity is limited. Here, we investigate inflammation, immune activation and antigen-specific T cell responses in HIV-uninfected and antiretroviral-treated HIV-infected people. Our findings highlight lower recall responses of antigen-specific CD4 T cells that correlate with high plasma cytokines levels, T cell hyperactivation and an altered composition of the T subsets enriched with more differentiated cells in the HIV-infected group. Transcriptomic analysis reveals that antigen-specific CD4 T cells of the HIV-infected group have a reduced expression of gene sets previously reported to correlate with vaccine-induced pathogen-specific protective immunity and further identifies a consistent impairment of the IFNα and IFNγ response pathways as mechanism for the functional loss of recall CD4 T cell responses in antiretroviral-treated people. Lastly, in vitro treatment with drugs that reduce inflammation results in higher memory CD4 T cell IFNγ responses. Together, our findings suggest that vaccine-induced cellular immunity may benefit from strategies to counteract inflammation in HIV infection.