Immune Dysregulation Research Articles

Correlation of biochemical markers and inflammatory cytokines in autism spectrum disorder (ASD)

IntroductionAutism Spectrum Disorder (ASD) is a disorder that severely affects neurodevelopment, and its underlying causes are not yet entirely understood. Research suggests that there may be a connection between the occurrence of ASD and changes in immune responses. This study aims to know if some biochemical and inflammatory cytokines are promising biomarkers for ASD and whether they are involved in the pathogenesis of ASD.MethodsThe serum levels of CRP, TNF-α, TGF-β, IL-1β, IL-10, 1 L-8, and IL-6 were measured in all of the patients (n = 22) and in the healthy (n = 12) children using ELISA method.ResultsThe serum concentrations of IL-10 and IL-8 were significantly lower in the ASD patients compared to the control group (p < 0.05) and there were not significant differences between CRP, TNF-α, TGF-β, IL-6 and IL-1β levels in two groups. There were positive correlations between CRP and IL-10, also CRP and IL-8, in ASD group. In contrast to the ASD patients, the correlations of IL-8, IL-10, and CRP were not significant in the control group.ConclusionIn conclusion, this study highlights the potential role of certain biochemical markers and inflammatory cytokines in ASD. Specifically, the lower levels of IL-10 and IL-8 in ASD patients, along with the significant correlations between CRP and these cytokines, suggest an altered immune response in individuals with ASD. These findings support the hypothesis that immune dysregulation may be involved in ASD pathogenesis. Further research is needed to explore these biomarkers and their mechanistic links to ASD, which could lead to improved diagnostics or therapeutic strategies.

Integrating enzyme-nanoparticles bring new prospects for the diagnosis and treatment of immune dysregulation in periodontitis

Integrating enzyme-nanoparticles bring new prospects for the diagnosis and treatment of immune dysregulation in periodontitis

Role of immune dysregulation in peri-implantitis

Role of immune dysregulation in peri-implantitis

Immune regulation: a new strategy for traditional Chinese medicine-based treatment of granulomatous lobular mastitis

Granulomatous lobular mastitis (GLM) presents significant challenges, including high rates of morbidity, recurrence, and disability, ultimately impacting women’s health and quality of life. Local autoimmune imbalance involving dysregulated cytokines and immune cells has been recognized to play a key role in the pathology of GLM. Traditional Chinese medicine (TCM), with its multi-component, multi-pathway and multi-target characteristics, offers unique advantages and broad prospects in the treatment of GLM. Here, we review the relationship between immune dysregulation and GLM, as well as the regulatory mechanisms of TCM-based interventions, with the aim of providing new insights and foundational knowledge for the clinical treatment of GLM, while promoting the further application and development of TCM-based strategies for the treatment of GLM.

Epstein–Barr Virus encephalitis associated hemophagocytic lymphohistiocytosis in childhood-onset systemic lupus erythematosus: a case-based review

BackgroundHemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation that results in an uncontrolled hyperinflammatory state. HLH is classified into two main categories: primary (familial) HLH and secondary (acquired) HLH. Secondary HLH can result from various underlying, including infection-associated hemophagocytic syndrome (IAHS) and macrophage activation syndrome (MAS) associated with rheumatologic disorders, among others. Epstein–Barr virus (EBV) often causes IAHS, but central nervous system (CNS) involvement is rare among systemic lupus erythematosus (SLE) patients. We report a case of EBV encephalitis associated with HLH in a patient with childhood-onset SLE.Case presentationA 12-year-old girl had received a diagnosis of SLE 2 months before presentation. After a period of inactive disease on treatment, fever and seizures, with altered mental status and hallucinations, developed over several weeks. A complete blood cell count (CBC) revealed pancytopenia, accompanied by elevated levels of inflammatory markers: 86 mm/hr erythrocyte sedimentation rate, 8.9 mg/dl c-reactive protein, and 3,966 ng/mL of ferritin. The differential diagnosis included active neuropsychiatric SLE, CNS infection and neurological manifestations in secondary HLH, which could have represented either IAHS or MAS. Meropenem and acyclovir were initially administered for clinical acute encephalitis, followed by pulse methylprednisolone; however, the fever persisted, and another CBC revealed progressive cytopenia. A bone marrow study showed hypocellularity and active hemophagocytic activity, and intravenous immunoglobulin was additionally given due to the diagnosis of HLH. Cerebrospinal fluid (CSF) analysis showed 60/mm3 white blood cells (N 55%, L 45%), 141 mg/dL glucose (0.7 blood-CSF glucose ratio), < 4 mg/dL protein; results of Gram stain and bacterial culture were negative. The viral encephalitis panel from the CSF confirmed EBV infection. Bone marrow immunohistochemistry examination revealed increasing levels of CD8 + T-cell and equivocal positive results for EBV-encoded RNA in situ hybridization; therefore, HLH potentially associated with EBV was diagnosed. After treatment with IVIg, cyclosporin A, and prednisolone, the patient’s symptoms gradually improved and she was eventually able to return to school.ConclusionsOur case highlights the importance of a thorough differential diagnosis, including EBV encephalitis associated with HLH, in patients with childhood SLE, particularly in cases of clinical deterioration occurs after initial treatment.

Massively Parallel Screening of Toll/Interleukin-1 Receptor (TIR)-Derived Peptides Reveals Multiple Toll-Like Receptors (TLRs)-Targeting Immunomodulatory Peptides.

Toll-like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety of inflammatory diseases. Interference of intracellular TLR signaling, which is mediated by multiple Toll/interleukin-1 receptor (TIR) domains on all TLRs and TLR adapters, is an effective therapeutic strategy against immune dysregulation. Peptides that inhibit TIR-TIR interactions by fragmenting interface residues have potential as therapeutic decoys. However, a systematic method for discovering TIR-targeting moieties has been elusive, limiting exploration of the vast, unsequenced space of the TIR domain family. A comprehensive parallel screening method is developed to uncover novel TIR-binding peptides derived from previously unexplored surfaces on a wide range of TIR domains. A large peptide library is constructed, named TIR surfacesome, by tiling surface sequences of the large TIR domain family and screening against MALTIR and MyD88TIR, TIRs of two major TLR adaptor proteins, resulting in the discovery of hundreds of TIR-binding peptides. The selected peptides inhibited TLR signaling and demonstrated anti-inflammatory effects in macrophages, and therapeutic potential in mouse inflammatory models. This approach may facilitate the development of TLR-targeted therapeutics.

GPR55 antagonist CID16020046 suppresses DNCB-induced atopic dermatitis-like symptoms by suppressing Th1/Th2/Th17 populations in mice.

G protein-coupled receptor 55 (GPR55) is a lipid-sensing receptor that plays a role as an immune mediator and is primarily upregulated during immune cell activation. There is a lack of knowledge about the role of GPR55 in allergic inflammatory diseases such as atopic dermatitis. The purpose of this study was to investigate the role of GPR55 through the use of its antagonist, CID16020046, in an atopic dermatitis mouse model. It was found that BALB/c mice develop lesions similar to those associated with atopic dermatitis following sensitization and repeated exposure to 1-chloro-2,4-dinitrobenzene (DNCB). It was found that CID16020046 (1 mg/kg, i.p.) alleviated the atopic dermatitis-like symptoms as well as immune dysregulation caused by DNCB. Based on histopathological analysis, CID16020046 reduced ear thickening and mast cell counts in the dermis. CID16020046 decreased DNCB-induced increases in serum IgE levels, as measured using enzyme-linked immunosorbent assays. A significant reduction in lymph node hypertrophy was also observed with CID16020046 as well as significant reductions in CD4+ T helper 1 (Th1), Th2, and Th17 cells in the lymph nodes. As a result of the administration of CID16020046, cytokines of Th1 (IFN-γ), Th2 (IL-4 and IL-13), and Th17 (IL-17A) types were also reduced in the skin and lymph nodes. In conclusion, blocking GPR55 alleviates DNCB-induced atopic dermatitis-like symptoms, suggesting that GPR55 is a potential therapeutic target for allergic inflammatory diseases via immunoregulation.

Screening of pathologically significant diagnostic biomarkers in tears of thyroid eye disease based on bioinformatic analysis and machine learning

BackgroundLacrimal gland enlargement is a common pathological change in patients with thyroid eye disease (TED). Tear fluid has emerged as a new source of diagnostic biomarkers, but tear-based diagnostic biomarkers for TED with high efficacy are still lacking.ObjectiveWe aim to investigate genes associated with TED-associated lacrimal gland lesions. Additionally, we seek to identify potential biomarkers for diagnosing TED in tear fluid.MethodsWe obtained two expression profiling datasets related to TED lacrimal gland samples from the Gene Expression Omnibus (GEO). Subsequently, we combined the two separate datasets and conducted differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) on the obtained integrated dataset. The genes were employed for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The genes were intersected with the secretory proteins profile to get the potential proteins in the tear fluid. Machine learning techniques were then employed to identify optimal biomarkers and develop a diagnostic nomogram for predicting TED. Finally, gene set enrichment analysis (GSEA) and immune infiltration analysis were conducted on screened hub genes to further elucidate their potential mechanisms in TED.ResultsIn our analysis of the integrated TED dataset, we identified 2,918 key module genes and 157 differentially expressed genes and finally obtained 84 lacrimal-associated key genes. Enrichment analysis disclosed that these 84 genes primarily pertain to endoplasmic reticulum organization. After intersecting with the secretory proteins, 13 lacrimal gland-associated secretory protein genes (LaSGs) were identified. The results from machine learning indicated the substantial diagnostic value of dyslexia associated gene (KIAA0319) and peroxiredoxin4 (PRDX4) in TED-associated lacrimal gland lesions. The two hub genes were chosen as candidate biomarkers in tear fluid and employed to establish a diagnostic nomogram. Furthermore, single-gene GSEA results and immune cell infiltration analysis unveiled immune dysregulation in the lacrimal gland of TED, with KIAA0319 and PRDX4 showing significant associations with infiltrating immune cells.ConclusionsWe uncovered the distinct pathophysiology of TED-associated lacrimal gland enlargement compared to TED-associated orbital adipose tissue enlargement. We have demonstrated the endoplasmic reticulum-related pathways involved in TED-associated lacrimal gland lesions and established a diagnostic nomogram for TED utilizing KIAA0319 and PRDX4 through integrated bioinformatics analysis. This contribution offers novel insights for non-invasive, prospective diagnostic approaches in the context of TED.

Elevated levels of peripheral and central nervous system immune markers reflect innate immune dysregulation in autism spectrum disorder.

Evidence suggests dysregulated immune functions in the pathophysiology of Autism spectrum disorder (ASD), although specific immune mechanisms are yet to be identified. We assessed circulating levels of 25 immune/neuroinflammatory markers in a large ASD sample (n = 151) and matched controls (n = 72) using linear models. In addition, we performed global brain transcriptomics analyses of relevant immune-related genes. We also assessed the expression and function of factors and pathway elements of the inflammasome system in peripheral blood mononuclear cells (PBMC) isolated from ASD and controls using in vitro methods. We found higher circulating levels of IL-18 and adhesion factors (ICAM-1, MADCAM1) in individuals with ASD relative to controls. Consistent with this, brain levels of ICAM1 mRNA were also higher in ASD compared to controls. Furthermore, we found higher expression/activity of Caspase-1 and the inflammasome sensor NLRP3 in PBMCs in ASD, both at baseline and following inflammatory challenge. This corresponded with higher levels of secreted IL-18, IL-1β, and IL-8, as well as increased expression of adhesion factors following inflammasome activation in ASD PBMC cultures. Inhibition of the NLRP3-inflammasome rescued the observed immune phenotype in ASD in vitro. Our results suggest a role for inflammasome dysregulation in ASD pathophysiology.

Polysaccharide, Conjugate, and mRNA-based Vaccines are Immunogenic in Patients with Netherton Syndrome

BackgroundNetherton syndrome (NS) is a rare, severe genetic skin disorder, currently classified as an inborn error of immunity (IEI) due to previously reported immune dysregulation. We recently reported the results of an immunological evaluation showing no evidence for a relevant B- and/or T-cell mediated immunodeficiency, but immune responses after vaccination were not evaluated in that study. Therefore, we evaluated immune responses to three vaccine platforms in adult NS patients to further investigate the presence of a clinically relevant B- and/or T-cell immunodeficiency.MethodsVaccination responses in eight adult NS patients were assessed in a cross-sectional study performed between January and August 2022. Clinical patient data were retrospectively retrieved from electronic patient files. Immune responses to a polysaccharide Streptococcus pneumoniae vaccine (PPV23) and conjugate Haemophilus influenzae type b vaccine (ActHiB) were measured. SARS-CoV-2-specific (functional) antibody and T-cell responses following booster vaccination with an mRNA-based COVID-19 vaccine were compared to controls.ResultsNone of the included patients suffered from recurrent and/or severe infections that could be attributed to a B- and/or T-cell immunodeficiency. ActHiB induced immune responses were normal in 7/7 NS patients. PPV23 induced responses were absent in 1/7, diminished in 2/7, and normal in 4/7 patients. Levels of SARS-CoV-2-specific binding and neutralizing antibodies after mRNA-based COVID-19 booster vaccination in NS patients were comparable to controls. SARS-CoV-2-specific CD4 + T-cell responses were detectable in all NS patients. In contrast, SARS-CoV-2-specific CD8 + T-cell responses were detectable in only 2/6 NS patients. T-cell responses to a positive control antigen pool were comparable to controls.ConclusionsVaccine-induced immune responses were detectable after polysaccharide, conjugate and mRNA-based vaccination in our cohort of NS patients. A spectrum of responsiveness to vaccine challenges was found, with the ranges of vaccine responses overlapping those demonstrated in healthy control populations.

Oxygen-Bonded Amorphous Transition Metal Dichalcogenides with pH-Responsive Reactive Oxygen Biocatalysis for Combined Antibacterial and Anti-inflammatory Therapies in Diabetic Wound Healing.

Diabetic wound healing is a formidable challenge, often complicated by biofilms, immune dysregulation, and hindered vascularization within the wound environments. The intricate interplay of these microenvironmental factors has been a significant oversight in the evolution of therapeutic strategies. Herein, the design of an efficient and versatile oxygen-bonded amorphous transition metal dichalcogenide biocatalyst (aRuS-Or) with pH-responsive reactive oxygen biocatalysis for combined antibacterial and anti-inflammatory therapies in promoting diabetic wound healing is reported. Leveraging the incorporation of Ru─O bonds, aRuS-Or exhibits optimized adsorption/desorption behavior of oxygen intermediates, thereby enhancing both the reactive oxygen species (ROS) generation activity in acidic conditions and ROS scavenging performance in neutral environments. Remarkably, aRuS-Or demonstrates exceptional bactericidal potency within infected milieus through biocatalytic ROS generation. Beyond its antimicrobial capability, post-eradication, aRuS-Or serves a dual role in mitigating oxidative stress in inflammatory wounds, providing robust cellular protection and fostering an M2-phenotype polarization of macrophages, which is pivotal for accelerating the wound repair process. The findings underscore the multifaceted efficacy of aRuS-Or, which harmoniously integrates high antibacterial action with anti-inflammatory and pro-angiogenic properties. This triad of functionalities positions aRuS-Or as a promising candidate for the comprehensive management of complex diabetic ulcers, addressing the unmet needs in the current therapeutics.

Emerging Role of the p53 Pathway in Modulating Natural Killer Cell Mediated Immunity.

The p53 pathway plays an important role in role in cancer immunity. Mutation or downregulation of the proteins in the p53 pathway are prevalent in many cancers, contributing to tumor progression and immune dysregulation. Recent findings suggest that the activity of p53 within tumor cells, immune cells, and the tumor microenvironment can play an important role modulating natural killer (NK) cell-mediated immunity. Consequently, efforts to restore p53 pathway activity are being actively pursued to modulate this form of immunity. This review focuses on p53 activity regulating the infiltration and the activation of NK cells in the tumor immune microenvironment, which are illustrated in the Graphical Abstract for this review. Furthermore, impact of p53 and its regulation of NK cells on immunogenic cell death within solid tumors and the abscopal effect is reviewed. Finally, future avenues for therapeutically restoring p53 activity to improve NK cell-mediated anti-tumor immunity and optimize the effectiveness of cancer therapies are discussed.

Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA) Related to Breast Implants: A Comprehensive Review

Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA) is a complex clinical entity characterized by the onset of autoimmune or inflammatory responses following exposure to adjuvants, substances that enhance immune responses. One of the most studied triggers of ASIA is breast implants, which are commonly composed of silicone. While breast implants are generally considered safe, a subset of patients may develop systemic symptoms collectively termed as "Breast Implant Illness" (BII), now recognized within the broader spectrum of ASIA. This review provides a thorough analysis of the pathophysiology, clinical presentation, diagnostic challenges, and management options for ASIA associated with breast implants. We aim to elucidate the underlying mechanisms of immune dysregulation and inflammatory responses induced by silicone and explore the latest evidence-based therapeutic approaches, including explantation surgery and immunosuppressive therapies. Our review underscores the need for heightened clinical awareness and further research into ASIA, as early recognition and intervention can significantly improve patient outcomes.

A Comprehensive Review of Thyroid Eye Disease Pathogenesis: From Immune Dysregulations to Novel Diagnostic and Therapeutic Approaches

Thyroid eye disease is a complex inflammatory disorder of the orbit that has gained tremendous interest over the past years, and numerous scientific efforts have been deployed to elucidate its pathophysiology for novel drug development. Our manuscript will delve into the molecular dysregulations involved in the pathogenesis of thyroid eye disease that led to its clinical manifestations. Abnormalities within the apoptotic pathway, inflammatory cascade, and autoimmune regulatory systems will be covered. We will further discuss the challenges involved in its diagnosis and management and provide a summary of the current diagnostic tools (i.e., molecular biomarkers, diagnostic scores) from the perspective of clinicians. Finally, our comprehensive literature review will provide a thorough summary of most recent preclinical and clinical studies around the topic of thyroid eye disease, with an emphasis on the manuscripts published within the last five years. We believe our manuscript will bring novelty within the field by bridging the fundamental sciences with the clinical aspect of this disease. This review will be a great tool for clinicians in better understanding the pathogenesis of thyroid eye disease while providing an outlook on future perspectives (i.e., liquid biopsies, artificial intelligence).

High serum levels of CXCL13 predict lower response to csDMARDs in both ACPA-positive and ACPA-negative early rheumatoid arthritis.

Increased circulating levels of CXCL13 reflect synovial production and indicate immune dysregulation in patients with rheumatoid arthritis (RA). Here we tested whether CXCL13 predicts response to first-line treatment with methotrexate (MTX) in patients with early RA, independently and in association with anti-citrullinated protein antibodies (ACPA) and IgM-rheumatoid factor (RF). A prospective cohort of 243 early RA patients undergoing treat-to-target with MTX was evaluated. CXCL13, ACPA and IgM-RF were determined on baseline sera. Short-term variations of CXCL13 were measured after 2 months. The association of high CXCL13 (≥100 pg/ml) with disease remission after 6 months and escalation to second-line therapies within year 2 was evaluated in the total population and in ACPA-subgroups separately. High levels of CXCL13 were found in 53.6% of ACPA-positive and 31.5% of ACPA-negative patients, with minimal association with disease activity and RF. Serum CXCL13 remained stable after 2 months. High baseline CXCL13 independently predicted failure to achieve remission and more frequent requirement of second-line treatment in ACPA-positive patients, with adjusted ORs in the range of 0.17-0.49 for remission and 6.75 for second-line treatment. In ACPA-negative patients with high CXCL13, remission occurred at the expense of higher doses of MTX, and levels of CXCL13 predicted MTX escalations with an adjusted OR (95% CI) of 2.69 (1.35-5.34). High serum levels of CXCL13 identify a subgroup of RA patients who are more refractory to first-line treatment with MTX. CXCL13 appears a promising biomarker of response to MTX in both ACPA-positive and -negative early RA.

Mechanisms of ozone-induced neurotoxicity in the development and progression of dementia: a brief review

Dementia encompasses a spectrum of neurodegenerative disorders significantly impacting global health, with environmental factors increasingly recognized as crucial in their etiology. Among these, ozone, has been identified as a potential exacerbator of neurodegenerative processes, particularly in Alzheimer’s disease (AD). Ozone exposure induces the production of reactive oxygen species (ROS), which penetrate the BBB, leading to oxidative damage in neuronal cells. This oxidative stress is closely linked with mitochondrial dysfunction and lipid peroxidation, processes that are foundational to the pathology observed in dementia, such as neuronal death and protein aggregation. Furthermore, ozone triggers chronic neuroinflammation, exacerbating these neurodegenerative processes and perpetuating a cycle of CNS damage. Recent studies highlight the role of peripheral biomarkers like High Mobility Group Box 1 (HMGB1) and Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in mediating ozone’s effects. Disruption of these and other identified proteins by ozone exposure impairs microglial function and response to amyloid plaques, suggesting a novel pathway through which ozone may influence AD pathology via immune dysregulation. This review discusses the concept of a bidirectional lung-brain axis, illustrating that systemic responses to air pollutants like ozone may reflect and contribute to neurodegenerative processes in the CNS. By delineating these mechanisms, we emphasize the critical need for integrating environmental health management into strategies for the prevention and treatment of dementia.

Exploring the associations of tobacco smoking and serum cotinine levels with selected inflammatory markers in adults with HIV in South Africa

This study examined the associations between tobacco smoking and serum cotinine levels, an objective biochemical measure of tobacco smoke exposure, with markers of inflammation, i.e., interferon-gamma (IFN-γ), interleukin 10 (IL-10), interleukin 2 (IL-2) and tumour necrosis factor-alpha (TNF-α) in people living with HIV (PLWH).These specific markers were selected because of their hypothesised associations with smoking, PLWH and their outcomes. In a random sample of ≥ 18-year-old PLWH receiving care at 17 public healthcare facilities across the Western Cape Province in South Africa, data collection included self-reported smoking history, and serum levels of cotinine and selected inflammatory markers. The inflammatory marker data were log transformed because of the skewedness of their distribution. Linear regression models (1) adjusted for age and gender, and (2) fully adjusted for age, gender, current alcohol use, body mass index and CD4 counts were used to examine the associations between smoking tobacco or serum cotinine and inflammatory markers. Level of significance was p < 0.05. Among 749 PLWH who were mainly women (79%), the mean age was 38.5 (8.9) years and similar when stratified by smoking status. Serum cotinine levels exhibited a striking discrepancy, with a median of 154 ng/mL among current smokers, in stark contrast to the consistent median values of 10 ng/mL observed among past and never smokers. In regression models adjusted for age and gender, current smoking and frequent smoking were associated with lower IL-2 but higher TNF-α. Log-cotinine exhibited associations with IFN-γ, IL-10, and TNF-α, while cotinine levels ≥ 10 ng/mL compared to < 10 ng/mL were associated with higher IFN-γ and TNF-α. In fully adjusted models, log-cotinine and cotinine levels ≥ 10 ng/mL displayed significant associations with higher IFN-γ and lower IL-2. This study underscores the importance of investigating the interplay between smoking tobacco or serum cotinine levels with pro-inflammatory cytokines in PLWH. It signals the need for comprehensive research to unravel the potential synergistic impacts of smoking tobacco and HIV infection on chronic inflammation and immune dysregulation, shedding light on critical avenues for intervention and management strategies.

A Review on the Effects of Aerobic Exercise on Immune Dysregulation in Polycystic Ovarian Syndrome

A Review on the Effects of Aerobic Exercise on Immune Dysregulation in Polycystic Ovarian Syndrome

Sex-biased proteomic regulation in obesity

Abstract Background Obesity is a major risk factor for heart failure with preserved ejection fraction, particularly in women. Obesity-associated inflammation is thought to contribute to this relationship. However, the role of biological sex in the regulation of circulating inflammatory proteins in obesity is not well understood. Purpose We aimed to explore sex differences in the plasma inflammatory protein profile in obese subjects. Methods Clinical data and samples were collected from 450 women and men with a body mass index (BMI) &amp;gt;27 kg/m² without known cardiovascular disease participating in the FAT associated CardiOvasculaR dysfunction study. Obesity was defined as BMI≥30 kg/m². Olink’s Target 96 inflammation panel, which profiles 92 proteins using proximity extension assay technology, was analysed in biobank samples. A comprehensive correlation analysis was performed to describe relationships between protein biomarkers and clinical variables. Gene enrichment analysis was performed to shed light on biological pathways associated with differentially expressed proteins (DEPs). To determine the functional significance of the DEPs, we used the repositories Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Pearson correlation coefficients were calculated to assess linear associations between the DEPs and relevant clinical variables. Results Women and men did not differ by age (49±9 vs 48±9 years), BMI (32.3±4.6 vs 31.6±3.7 kg/m²) or in prevalences of diabetes (both 11%) or obesity (65% vs 62%) (all p&amp;gt;0.05). However, hypertension was more common in men than women (74% vs 52%, p&amp;lt;0.001). In men (n=188), obesity was associated with downregulation of monocyte chemotactic protein 3, tumor necrosis factor (ligand) superfamily member 12, interleukin 10 and protein S100-A12 and with upregulation of neurotrophin-3 (all p&amp;lt;0.05), thereby suggesting a mechanism for the observed impaired inflammatory response and insulin resistance. In women (n=262), obesity was associated with the downregulation of interleukin 7, interleukin 12 subunit beta, interleukin 6, and C-X-C motif chemokine 11, suggesting a state of persistent low-grade inflammation. In addition, the upregulated sulfotransferase 1A1 and SIR2-like protein 2 proteins indicate a physiologic adaptation to oxidative stress and the metabolic excess endemic to obesity. Conclusion We found that the abundance of several circulating inflammatory proteins was altered in presence of obesity, and that the plasma proteomic profile differed by sex. Interestingly, there was no overlap in the DEPs between women and men in the presence of obesity. These findings support the hypothesis that the pathophysiological mechanisms driving obesity-associated inflammation and immune dysregulation differ by sex. In turn, this may aid in the pursuit of discovering sex-specific biomarkers to identify obese individuals at particular risk of heart failure.

Postoperative Innate Immune Dysregulation, Proteomic, and Monocyte Epigenomic Changes After Colorectal Surgery: A Substudy of a Randomized Controlled Trial.

Colorectal surgery is associated with moderate-to-severe postoperative complications in over 25% of patients, predominantly infections. Monocyte epigenetic alterations leading to immune tolerance could explain postoperative increased susceptibility to infections. This research explores whether changes in monocyte DNA accessibility contribute to postoperative innate immune dysregulation. Damage-associated molecular patterns (DAMPs) and ex vivo cytokine production capacity were measured in a randomized controlled trial (n = 100) in colorectal surgery patients, with additional exploratory subgroup proteomic (proximity extension assay; Olink) and epigenomic analyses (Assay for Transposase-Accessible Chromatin [ATAC sequencing]). Monocytes of healthy volunteers were used to study the effect of high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70) on cytokine production capacity in vitro. Plasma DAMPs were increased after surgery. HMGB1 showed a mean 235% increase from before- (preop) to the end of surgery (95% confidence interval [CI] [166 - 305], P < .0001) and 90% increase (95% CI [63-118], P = .0004) preop to postoperative day 1 (POD1). HSP70 increased by a mean 12% from preop to the end of surgery (95% CI [3-21], not significant) and 30% to POD1 (95% CI [18-41], P < .0001). Nuclear deoxyribonucleic acid (nDNA) increases by 66% (95% CI [40-92], P < .0001) at the end of surgery and 94% on POD1 (95% CI [60-127], P < .0001). Mitochondrial DNA (mtDNA) increases by 370% at the end of surgery (95% CI [225-515], P < .0001) and by 503% on POD1 (95% CI [332-673], P < .0001). In vitro incubation of monocytes with HSP70 decreased cytokine production capacity of tumor necrosis factor (TNF) by 46% (95% CI [29-64], P < .0001), IL-6 by 22% (95% CI [12-32], P = .0004) and IL-10 by 19% (95% CI [12-26], P = .0015). In vitro incubation with HMGB1 decreased cytokine production capacity of TNF by 34% (95% CI [3-65], P = .0003), interleukin 1β (IL-1β) by 24% (95% CI [16-32], P < .0001), and IL-10 by 40% (95% CI [21-58], P = .0009). Analysis of the inflammatory proteome alongside epigenetic shifts in monocytes indicated significant changes in gene accessibility, particularly in inflammatory markers such as CXCL8 (IL-8), IL-6, and interferon-gamma (IFN-γ). A significant enrichment of interferon regulatory factors (IRFs) was found in loci exhibiting decreased accessibility, whereas enrichment of activating protein-1 (AP-1) family motifs was found in loci with increased accessibility. These findings illuminate the complex epigenetic modulation influencing monocytes' response to surgical stress, shedding light on potential biomarkers for immune dysregulation. Our results advocate for further research into the role of anesthesia in these molecular pathways and the development of personalized interventions to mitigate immune dysfunction after surgery.