Cytokine Imbalance Research Articles

Eradication of skin microbiota restores cytokine production and release in polymorphic light eruption.

Polymorphic light eruption (PLE) has been mechanistically linked to cytokine abnormalities. Emerging preclinical evidence posits the skin microbiome as a critical modulator of ultraviolet (UV)-induced cytokine expression, thereby influencing subsequent immune responses. This intricate relationship remains underexplored in the context of PLE. Hence, we investigated the differential responses between disinfected and non-disinfected skin following both single and repetitive exposures to solar-simulated UV radiation in patients with PLE. An experimental, half-body pilot study was conducted involving six PLE patients and 15 healthy controls. Participants' skin was exposed to single and multiple doses of solar-simulated UV radiation, both in disinfected and in non-disinfected skin areas. The co-primary outcomes were PLE score and cytokine expression in blister fluid analysed through OLINK proteomic profiling. Secondary outcomes were erythema, pigmentation, induction of apoptotic cells in vacuum-generated suction blisters, and density of infiltrate in skin biopsies of PLE patients. Among the 71 cytokines analysed, baseline expression levels of 20 specific cytokines-integral to processes such as apoptosis, inflammation, immune cell recruitment, cellular growth, and differentiation-were significantly impaired in PLE patients compared with healthy controls. Notably, skin disinfection reversed the observed cytokine imbalances following a single UV exposure at the minimal erythema dose (MED) level and exhibited even more pronounced effects after multiple UV exposures. However, no significant differences were evident in PLE score, erythema, pigmentation, or rates of apoptotic cell induction upon UV radiation. These findings provide evidence for UV-driven cytokine regulation by the skin microbiota and imply microbiome involvement in the PLE immune response.

Abstract TP245: Identifying Ischemic Stroke Etiology Through Cytokine Biomarkers

Background: Ischemic stroke can arise from various etiologies, such as cardioembolism, atherosclerosis, small vessel disease or cryptogenic. Accurate identification of stroke etiology is vital for secondary stroke prevention. Accumulating evidence suggests that an imbalance of neuroprotective and neuroinflammatory cytokines may contribute to stroke outcomes. Interleukin-2 receptor subunit α (IL-2Rα), a cell surface protein that regulates lymphocyte activation, has been shown to have either pro-atherosclerotic or atheroprotective roles through activation of lymphocytes or regulatory T cells, respectively. We hypothesized that distinct cytokine profiles, and in particular IL-2Rα, may correlate with specific stroke etiology. Methods: Plasma samples were collected from patients with ischemic stroke that were admitted to Memorial Hermann Hospital, Houston by UTHealth biobank. ELISA was used to analyze the plasma samples for levels of IL-2Rα. The relationship between stroke etiology (TOAST criteria) and IL-2Rα was assessed using ANOVA and then adjusted for co-morbidities using multilinear regression models. Results: The mean age of patients was 63.4 years, 35.2% were women, 87% had hypertension, 48.1% had diabetes mellitus, and 53.7% had hyperlipidemia. IL-2Rα levels were significantly elevated in patients with ischemic stroke due to large-artery atherosclerosis (53.5±4.7 pg/ml) as compared to cardioembolic (35.6±6.5 pg/ml), small vessel disease (38.2±7.4pg/ml) or cryptogenic etiology 32±7.8; p<0.01). Conclusions: Our study suggests that IL-2Rα is significantly elevated in ischemic strokes caused by atherosclerosis compared to other ischemic etiologies. This suggests the role of lymphocytic activation in strokes from intracranial and extracranial atherosclerotic disease, which may be used as a therapeutic target. It also identifies a novel biomarker for ischemic strokes from atherosclerosis. Future studies identifying the upstream and downstream pathways that lead to IL-2Rα activation and stroke in atherosclerotic lesions, will further add to our understanding of the characteristics of atherosclerotic lesions that lead to ischemic strokes.

Immune Dysregulation, Inflammation in Characterizing Women with Vulvodynia, Depression, and Both.

Background: Depression and vulvodynia are often comorbid. The onset of depression and vulvodynia may be immune and/or stress/environmentally induced. We explored whether vulvodynia, depression, or both occur in response to a Th1-mediated versus Th2-mediated immune response. Materials and Methods: We analyzed data from a case-control study of clinically confirmed vulvodynia and history of depression determined through structured clinical interviews. Immune dysregulation and inflammation were categorized based on the following self-reported conditions: rheumatoid arthritis, Sjogren's disease, scleroderma, systemic lupus erythematosus, inflammatory bowel disease, fibromyalgia, osteoarthritis, polycystic ovarian syndrome, diabetes mellitus, uterine fibroids, asthma, atopic dermatitis, and allergic rhinitis. Logistic regression analyses were adjusted for marital status, body mass index, age, and pack years. Results: Women with systemic immune dysregulation had higher odds of depression (adjusted odds ratio [aOR] = 1.61, confidence interval [95% CI]: 0.65-3.98), vulvodynia (aOR = 2.45, 95% CI: 1.00-5.96), and comorbid depression and vulvodynia (aOR = 4.93, 95% CI: 2.19-11.10) versus neither condition. Women reporting local immune dysregulation had similar odds of depression (aOR = 1.89, 95% CI: 0.99-3.59), vulvodynia (aOR = 2.12, 95% CI: 1.08-4.18), and comorbid depression and vulvodynia (aOR = 1.96, 95% CI: 0.98-3.90). Women with Th2 inflammation had similar odds of depression (aOR = 2.23, 95% CI: 1.05-4.77) and vulvodynia (aOR = 2.56, 95% CI: 1.20-5.49). Women with Th1 or Th2 inflammation had similar odds of comorbid depression and vulvodynia (aOR = 3.03, 95% CI: 1.48-6.19; aOR = 3.14, 95% CI: 1.49-6.60, respectively). Conclusions: Our results suggest that an imbalance of cytokines, indicated by the presence of one or more immune-related health conditions, is associated with an increased risk of vulvodynia and/or depression.

Genetically engineered macrophages derived from iPSCs for self-regulating delivery of anti-inflammatory biologic drugs.

In rheumatoid arthritis, dysregulated cytokine signaling has been implicated as a primary factor in chronic inflammation. Many antirheumatic and biological therapies are used to suppress joint inflammation, but despite these advances, effectiveness is not universal, and delivery is often at high doses, which can predispose patients to significant off-target effects. During chronic inflammation, the inappropriate regulation of signaling factors by macrophages accelerates progression of disease by driving an imbalance of inflammatory cytokines, making macrophages an ideal cellular target. To develop a macrophage-based therapy to treat chronic inflammation, we engineered a novel induced pluripotent stem cell (iPSC)-derived macrophage capable of delivering soluble TNF receptor 1 (TNFR1), an anti-inflammatory biologic inhibitor of tumor necrosis factor alpha (TNF-α), in an auto-regulated manner in response to TNF-α. Murine iPSCs were differentiated into macrophages (iMACs) over a 17-day optimized protocol with continued successful differentiation confirmed at key timepoints. Varying inflammatory and immunomodulatory stimuli demonstrated traditional macrophage function and phenotypes. In response to TNF-α, therapeutic iMACs produced high levels of sTNFR1 in an autoregulated manner, which inhibited inflammatory signaling. This self-regulating iMAC system demonstrated the potential for macrophage-based drug delivery as a novel therapeutic approach for a variety of chronic inflammatory diseases.

Temporal cytokine storm dynamics in dengue infection predicts severity

The immunopathogenesis of dengue severity is convoluted. The primary objective of the research was to examine the dynamics of cytokine storm and its correlation with disease development in individuals affected by DENV infection. Additionally, the study aimed to discover potential biomarkers that could indicate severe dengue infection and determine the most suitable timeframe for predicting the severity of these biomarkers during the acute stage of dengue infections. We conducted a temporal analysis of the daily viral load and cytokine levels in 60 hospitalized dengue patients until discharge. Our findings reveal a distinct cytokine profile (elevated IL-8, IL-10, IL-6, GM-CSF, MCP-1, IL-13, and IL-4 and decreased IL-12, MIP-1β) on the third day after symptom onset is predictive of severe dengue in secondary dengue infection. The imbalanced cytokine signature may inform clinical decision-making in treating severe dengue infections.

Imbalance of Th1 and Th2 Cytokines and Stem Cell Therapy in Pathological Pain.

The pathophysiological importance of T helper 1 (Th1) and Th2 cell cytokines in pathological pain has been highly debated in recent decades. However, the analgesic strategy targeting individual cytokines still has a long way to go for clinical application. In this review, we focus on the contributions of Th1 cytokines (TNF-α, IFN-γ, and IL-2) and Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) in rodent pain models and human pain-related diseases. A large number of studies have shown that Th1 and Th2 cytokines have opposing effects on pain modulation. The imbalance of Th1 and Th2 cytokines might determine the final effect of pain generation or inhibition. However, increasing evidence indicates that targeting the individual cytokine is not sufficient for the treatment of pathological pain. It is practical to suggest a promising therapeutic strategy against the combined effects of Th1 and Th2 cytokines. We summarize the current advances in stem cell therapy for pain-related diseases. Preclinical and clinical studies show that stem cells inhibit proinflammatory cytokines and release enormous Th2 cytokines that exhibit a strong analgesic effect. Therefore, a shift of the imbalance of Th1 and Th2 cytokines induced by stem cells will provide a novel therapeutic strategy against intractable pain. It is extremely important to reveal the cellular and molecular mechanisms of stem cell-mediated analgesia. The efficiency and safety of stem cell therapy should be carefully evaluated in animal models and patients with pathological pain.

Interleukins in the pathogenesis of influenza and other acute respiratory viral infections.

Influenza and other acute respiratory viral infections (ARVIs) are among the most common human diseases. In recent decades, the discovery of cytokines and their significance in the pathogenesis of diseases has led to extensive research on these compounds in various pathologies including ARVIs. The aim of the research was to study the cytokine profile in patients with ARVIs. The cases of 30 patients were investigated. Etiological diagnosis was performed by polymerase chain reaction. Different classes of cytokines in the serum were defined by the enzyme-linked immunosorbent assay (ELISA). The level of cytokines depended on the number of pathogens. The highest levels of pro-inflammatory interleukins and the lowest levels of anti-inflammatory IL-4 were observed in patients with a combination of five or more viruses compared to those with a monoinfection. Analysis of the data showed that in the acute phase, the levels of all studied pro-inflammatory cytokines - IL-2, IL-6, and TNF-α - increased by 8, 39, and 9 times, respectively, compared to those in healthy individuals. In the acute phase of ARVI, the levels of pro-inflammatory cytokines were significantly higher and depended on the severity of the disease. The imbalance of cytokines in the serum has been established in cases of ARVIs, depending on the severity of the disease.

Smoking increases risk of complication after musculoskeletal surgery: analysis of single immune parameter to predict complication risk.

Smoking is the most significant and modifiable risk factor for a range of conditions, including cancer, cardiovascular and respiratory diseases. Furthermore, it significantly reduces bone mass and increases the risk of fragility fractures due to its detrimental effects on bone metabolism and regeneration. Moreover, smoking is a known cause of chronic systemic inflammation, leading to an imbalance of cytokines. Comprehending the pathological mechanisms that underlie cytokine production and its impact on post-surgical healing is essential to prevent post-surgical complications. The present study recruited a total of 1144 patients, including 897 patients, among them non-smokers (N = 413), current smokers (N = 201) and ex-smokers (N = 283). Human proteome profiler arrays were used to screen for smoking-dependent differences in the serum cytokine and protein profiles, after matching samples for age, gender, body mass index (BMI), alcohol use, and diabetes risk. Cytokines and immune checkpoint proteins such as CD28, B7-1, MIG, TGFβ2 and IL-1α/β were quantified by ELISA. Our study demonstrates a comprehensive understanding of the relationship between smoking, the development of complications, the systemic immune inflammation index (SII) and cytokine/protein levels. We found that a comparison of non-smokers, former smokers, and active smokers in our study cohort did not exhibit significantly altered cytokine and protein serum levels although other studies reported differences between smokers and non-smokers. We were unable to identify single blood circulating markers that could predict complications in smokers after trauma. However, we found the ratio of women to men to be inverted between non-smokers and active smokers resulting in a ratio of 0.62 in smokers. Furthermore, we demonstrate a higher complication rate, longer hospitalizations and elevated SII values among smokers, indicating an involvement of the immune system. See also the graphical abstract(Fig. 1).

Drug- or Vaccine-Induced/Aggravated Psoriatic Arthritis: A Systematic Review.

Drugs and vaccines have been less studied as inducing or aggravating factors for psoriatic arthritis (PsA) compared with psoriasis. Thus, the present study collected and summarized the publications to date about this issue. We conducted a systematic literature search through the PubMed, Embase, and Cochrane databases to identify all reports on potential drug- and vaccine-related PsA events until 28 February 2023. In total, 179 cases from 79 studies were eligible for study. Drugs commonly reported include coronavirus disease 2019 (COVID-19) mRNA vaccines (6 cases), bacillus Calmette-Guerin (BCG) vaccine (3 cases), interferon (18 cases), immune-checkpoint inhibitors (ICI) (19 cases), and biologic disease-modifying antirheumatic drugs (bDMARDs) (127 cases). Drugs causing psoriasis may also induce or aggravate PsA (6 cases). BDMARD-related PsA mostly occurred in a "paradoxical" setting, in which the bDMARDs approved for the treatment of psoriasis induce or aggravate PsA. The reported latency may be delayed up to 2years. Peripheral arthritis (82.3%) was the most common manifestation of drug- and vaccine-related PsA, followed by dactylitis (29.1%), enthesitis (23.4%), and spondyloarthritis (17.7%). Drugs and vaccines may be implicated in the aggravation of PsA. Possible mechanisms include cytokine imbalance, immune dysregulation, or inadequate PsA treatment response compared with psoriasis. Most reports are case based without controls, so more studies are needed to further prove the causality. However, early recognition of factors causing or aggravating PsA is important to prevent the irreversible joint damage.

Serum Levels of IL-21, IL-23 and 8-hydroxy-2′-deoxyguanosine in Pediatric Severe Pneumonia Cases

Background: Pneumonia causes the majority of acute respiratory distress syndrome (ARDS) cases. The microbes that cause pneumonia are very diverse. In addition to DNA, RNA viruses, Gram-negative and Gram-positive bacteria cause two types of cytokine imbalances, anti-inflammatory and pro-inflammatory. It can also influence the progno-sis of sepsis and other infectious diseases. This study aims to search for 8-hydroxy-2'-deoxyguanosine (8-OHdG), IL-21, IL-23, and c-reactive protein (CRP) and compare cytokine levels. It is also to determine if Pediatric pneumonia patients CRP and cytokine levels correlate with results. Materials and Methods: In the study, blood was drawn from approximately 43 pediatric pneumonia patients and 43 healthy controls who came to the pediatric clinic to investigate serum IL-21, IL-23, 8-OHdG, and CRP levels. The levels of biomarkers were determined by ELISA method. Serum CRP levels were measured using the ATELLICA IM Analyzer. Results: Serum CRP, 8-OHdG, IL-21 and IL-23 levels were significantly higher in the pediatric pneumonia patient group than in the control group. Conclusions: Increased serum IL-21, IL-23, 8-OHdG and CRP expression in pediatric pneumonia patients is a poten-tial determinant suggesting that IL-21, IL-23-related cytokines may play a role in endothelial cell activation reported in patients. Increased 8-OHdG oxidative stress is more pronounced in patients without pediatric pneumonia while pro inflammatory cytokines are higher in pediatric pneumonia patients. However, it is used as a possible therapeu-tic target to reduce inflammation. Further study on the impact of these findings on comorbidities with larger num-ber test size is needed

Targeting Key Inflammatory Mechanisms Underlying Heart Failure: A Comprehensive Review.

Inflammation is a major component of heart failure (HF), causing peripheral vasculopathy and cardiac remodeling. High levels of circulating inflammatory cytokines in HF patients have been well recognized. The hallmark of the inflammatory imbalance is the insufficient production of anti-inflammatory mediators, a condition that leads to dysregulated cytokine activity. The condition progresses because of the pathogenic consequences of the cytokine imbalance, including the impact of endothelial dysfunction and adrenergic responsiveness deterioration, and unfavorable inotropic effects on the myocardium. Hence, to develop possible anti-inflammatory treatment options that will enhance the outcomes of HF patients, it is essential to identify the potential pathophysiological mechanisms of inflammation in HF. Inflammatory mediators, such as cytokines, adhesion molecules, and acute-phase proteins, are elevated during this process, highlighting the complex association between inflammation and HF. Therefore, these inflammatory markers can be used in predicting prognosis of the syndrome. Various immune cells impact on myocardial remodeling and recovery. They lead to stimulation, release of alarmins and risk-related molecule patterns. Targeting key inflammatory mechanisms seems a quite promising therapy strategy in HF. Cytokine modulation is only one of several possible targets in the fight against inflammation, as the potential molecular targets for therapy in HF include immune activation, inflammation, oxidative stress, alterations in mitochondrial bioenergetics, and autophagy.

Зміни рівнів про- і протизапальних цитокінів у жінок із хронічним ендометритом та можливість медикаментозної корекції цих рівнів на преконцепційному етапі

The incidence of chronic endometritis is more than twice higher the prevalence of other clinical forms of intrauterine pathology, leading to infertility, unsuccessful attempts of in vitro fertilization and spontaneous abortion. There is a lack of data on the alteration of pro- and anti-inflammatory cytokine production in chronic endometritis and their role in the subsequent development of miscarriage. Purpose - to investigate the levels of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ), as well as the anti-inflammatory cytokine interleukin 10 (IL-10) in cervical mucus of women with chronic endometritis and to assess the impact of the developed comprehensive preconception treatment on normalizing cytokine disorders in these women. Materials and methods. The levels of pro-inflammatory cytokines TNF-α and INF-γ, as well as the anti-inflammatory cytokine IL-10, were determined using the enzyme-linked immunosorbent assay method in the cervical mucus of 426 women with chronic endometritis who were planning pregnancy. Among them, 168 patients (the Group I) received preconception comprehensive treatment, which included broad-spectrum antibacterial agents (azithromycin), hormonal estrogen-progestin therapy (Femoston 2/10) and L-arginine. The remaining 258 women (the Group II) did not receive treatment for chronic endometritis at the preconception stage. The control group consisted of 30 healthy individuals. Data analysis was performed using mathematical statistical methods, calculating the mean sample values (M), variance (σ) and standard errors of the mean (m). The Student’s t-test was applied, and probabilities were determined using the statistical program «STATISTICA» (StatSoft Inc., USA). Results. In the cervical mucus of women with chronic endometritis, an increase in the levels of pro-inflammatory cytokines INF-γ by 2.8 times (p<0.001) and TNF-α by 2 times (p<0.001) was detected, along with a 2-fold decrease in the concentration of the anti-inflammatory cytokine IL-10 (p<0.001). The shift in the cytokine balance towards pro-inflammatory cytokines is associated with a high frequency of miscarriage in these women. After the treatment of chronic endometritis, women had a 2.6 times lower level of INF-γ (p<0.05), a 2 times lower level of TNF-α (p<0.01), and a 1.7 times higher level of IL-10 (p<0.05) compared to untreated patients. Conclusions. Women with chronic endometritis experience a cytokine imbalance, characterized by an excessive increase in pro-inflammatory cytokines and a decrease in anti-inflammatory cytokines. Women with chronic endometritis who are planning pregnancy require comprehensive preconception treatment, which includes the administration of azithromycin, femoston 2/10 and L-arginine in addition to traditional preconception folate prophylaxis. This treatment, by promoting improved conditions for implantation, leads to a 15% increase in the pregnancy rate and a 1.9-fold reduction in the frequency of spontaneous abortion. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

DYNAMICS IN MAIN CLINICAL AND IMMUNOLOGICAL INDICATORS IN PATIENTS WITH COMORBIDITY OF CHRONIC HEPATITIS C AND CHRONIC PANCREATITIS FOLLOWING INTEGRATED THERAPY INCLUDING VITAMIN D

The aim of this study is to evaluate the impact of integrated therapy including vitamin D on the clinical and immunological parameters of patients with chronic hepatitis C combined with chronic pancreatitis.
 Materials and methods. 52 patients with chronic hepatitis C and chronic pancreatitis with exocrine pancreatic insufficiency who had an insufficient level of vitamin D were under observation. They were divided into 2 groups depending on the treatment prescribed. All patients received antiviral therapy and sofosbuvir 400 mg + daclatasvir 60 mg once a day for 12 weeks and rabeprazole 20 mg once a day for a month. Depending on the scheme of taking enzyme preparations and vitamin D, all patients were divided into 2 groups. Group 1 (n=24) received Creon 25,000 according to the scheme and vitamin D 4,000 IU/day for 12 weeks of antiviral therapy and 12 weeks after the completion of antiviral therapy. Group 2 (n=28) took only Creon 10,000 according to the scheme. Analysis of findings obtained and their processing were carried out in Jamovi 2.3.2.1, Microsoft Office Excel for Windows 2016 programs using the Mann-Whitney, Wilcoxon U-test. The difference was considered statistically significant at p<0.05.
 Results: The administration of complex therapy, supplemented with vitamin D, resulted in a 100% achievement of sustained virological response (SVR) in patients belonging to group 1, while group 2 exhibited an SVR rate of 82.1%. It has been found out the treatment in group 1 demonstrated a significantly more pronounced reduction in ALT, AST, and total bilirubin levels compared to group 2. Furthermore, patients in group 1 exhibited more substantial changes in the cytokine profile, including a decrease in the levels of IL-6, TNF-б, neopterin, IL-4, IL-10, and TGF-в. Three months after the completion of antiviral therapy, the average FE-1 level in group 1 normalized, whereas in group 2, it only displayed a tendency toward normalization.
 Conclusion: The integration of a polyenzyme drug with minimal lipase activity (25,000 units) and vitamin D (4,000 IU/day) into the therapy for patients with comorbidity of chronic hepatitis C and chronic pancreatitis enhances the efficacy of antiviral therapy. This combination facilitates the rapid normalization of ALT, AST, and total bilirubin, mitigates cytokine imbalances, and improves exocrine pancreas function.

Gastric acid-responsive deformable sodium alginate/Bletilla striata polysaccharide in situ gel for the protection and treatment of alcohol-induced peptic ulcers

First-line drugs for peptic ulcer (PU) treatment are typically limited by poor targeting and adverse effects associated with long-term use. Despite recent advancements in novel therapeutic approaches for PU, the development of sustained-release delivery systems tailored to specific pathological characteristics remains challenging. Persistent inflammation, particularly gastric inflammatory microenvironment imbalance, characterizes the PU. In this study, we prepared an in situ gel composed of sodium alginate, deacetylated gellan gum, calcium citrate, and Bletilla striata polysaccharide (BSP) to achieve sustained release of BSP. The BSP in situ gel demonstrated favorable fluidity in vitro and completed self-assembly in vivo in response to the acidic milieu at a pH of 1.5. Furthermore, the shear, extrusion, and deformation properties increased by 26.4 %, 103.7 %, and 46.3 %, respectively, with long-term gastric retention (4 h) and mucosal adaptation. Animal experiments confirmed that the BSP in situ gel could attenuate necrotic injury and inflammatory cell infiltration, maintain mucosal barrier integrity, regulate cytokine imbalance and inflammation-associated hyperapoptosis, thus effectively alleviate the inflammatory microenvironmental imbalance in PU without significant side effects. Overall, our findings demonstrated that the BSP in situ gel is a promising therapeutic strategy for PU and opens avenues for developing self-assembled formulations targeting the pathological features of PUs.

The dual role of interleukin-6 in Crohn's disease pathophysiology.

Interleukin-6 (IL-6) is a key mediator cytokine of the immune response as well as a regulator of many physiological and pathological processes. In Crohn's disease (CD), cytokine imbalance rules the intestinal microenvironment and leads to chronic inflammation of the gut. Pro-inflammatory cytokines are generally upregulated in inflammatory bowel disease (IBD) including TNFα and IL-6. Consequently, drugs that target these cytokines have been long sought and approved. Despite the short-term success in treating CD patients with anti-TNFα, many patients stopped responding to treatment, which made IL-6 an alternative target to alleviate inflammation in these patients. IL-6 has long been approached as part of the therapeutic strategies to treat CD and other inflammatory disorders. Clinical trials of CD patients have targeted IL-6 signaling in different mechanisms: blocking IL-6, neutralizing IL-6 receptor (IL-6R), or trapping the soluble IL-6/IL-6R complex. These trials have faced challenges and side effects in patients with gastrointestinal perforations and ulcers, for example, all of which highlight the dual role of IL-6 during intestinal inflammation and the need for this cytokine for intestinal tissue integrity. IL-6 is involved in a complex of upstream regulators and downstream signaling cascades and maintaining a physiological level of IL-6 in the blood and in the intestine is key for achieving health and homeostasis. In this review, we describe IL-6 biology and signaling and its involvement in intestinal health and inflammation. We also discuss the current strategies for targeting IL-6 pathways in CD patients, as well as molecular regulators representing potential therapeutic targets for IL-6 attenuation.

New approaches to the correction of immune disorders in adenomyosis

ABSTRACT. A large number of studies have been devoted to the study of the problem of genital endometriosis, however, the etiology and mechanisms of the disease remain unresolved. Adenomyosis affects about 10% of women of reproductive age, occurs in 30% of women with pelvic pain syndrome and up to 50% of patients with female infertility. Numerous theories of the origin of endometriosis cannot explain the key points in the development of the disease, namely the penetration of the basal layer of the endometrium into the adjacent myometrium. This makes it difficult to choose an adequate treatment strategy for patients with adenomyosis. Treatment of adenomyosis is one of the most difficult issues in modern gynecology, one of the promising approaches in increasing the effectiveness of treatment of patients with adenomyosis is immunocorrective therapy. The aim of the work was to increase the effectiveness of treatment of adenomyosis patients by improving the diagnostic and prognostic tactics of patient management based on the study of pathogenetic aspects. Materials and methods. 115 patients of reproductive age were included in the study. The effectiveness of complex compared to traditional treatment was evaluated. Clinical and laboratory, instrumental and immunological indicators were evaluated in dynamics. Research results and their discussion. Taking into account the peculiarities of pathogenetic mechanisms, which indicate a violation of the cellular and macrophage links of immunity, cytokine imbalance, which contribute to the development of the disease and its persistence, we have developed a comprehensive approach to increasing the effectiveness of the treatment of patients with adenomyosis, which aims to reduce the pro-inflammatory immunological potential. Against the background of the comprehensive treatment, the activity of autoimmune reactions is reduced, the indicators of phagocytic and oxygen activity of neutrophils and monocytes are normalized, cytokine imbalance is reduced - the level of production of pro-inflammatory cytokines and VEGF is normalized. Conclusions. Based on the results of the work, the approaches to the treatment of adenomyosis patients were optimized, the feasibility of using corrective drugs in complex therapy was substantiated.

Features of innate and adaptive immunity in patients with moderate course of COVID-19 with various degrees of lung tissue damage

Objective: to study changes in innate and adaptive immunity in patients with a moderate course of COVID-19 with varying degrees of lung tissue damage. 40 patients with a moderate form of COVID-19 and varying degrees of damage to the lung tissue (up to 25% and up to 50%) and 30 patients from the control group (healthy donors) were examined using methods: computed tomography of the lungs, evaluation of a complete blood count, biochemical parameters, immunological studies, statistical. Differences in all patients with the control group consisted in a decrease in the absolute content of lymphocytes, in a significant increase in the relative content of natural killers and cytokine imbalance. The most significant differences were registered in the content of IL-6, depending on the degree of damage to the lung tissue. A smaller area of lung damage reflects a milder course of the disease, which does not exclude the need for dispensary observation and rehabilitation after discharge.

Abstract 11949: Novel First-Trimester Serum Biomarkers for Early Prediction of Preeclampsia

Background: Preeclampsia (PE) is a leading cause of maternal and perinatal mortality and morbidity worldwide, but effective early prediction remains a challenge due to the lack of reliable biomarkers. Research questions: Could potential imbalances in cytokines and autoimmune antibodies be detectable in the first trimester of pregnancy in women who later develop PE? Goals: Our study aims to discover novel biomarkers within the first trimester and construct an efficient predictive model to enhance early PE screening strategies. Methods: Based on the extensive human biobank of our large-scale assisted reproductive cohort platform, we measured the first-trimester serum levels of 48 cytokines, total immunoglobulins (Igs), anti-phosphatidylserine (aPS) antibodies, and several previously identified PE biomarkers—including placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and activin A—in 34 women diagnosed with PE and 34 matched normotensive controls. Results: Our analysis revealed that the PE group exhibited significantly elevated first-trimester serum levels of hepatocyte growth factor (HGF), interleukin (IL)-2Rα, IL-9, RANTES, tumor necrosis factor-β (TNF-β), total IgM, and total IgG, and aPS IgG optical density (OD) value, in addition to decreased first-trimester serum levels of PlGF and total IgA and aPS-IgG immune complexes (IC) OD value compared to the control group. The combination of the top five first-trimester serum biomarkers (total IgM, total IgG, PlGF, aPS IgG, and total IgA) achieved superior predictive value [area under the curve (AUC) and 95% confidence interval (CI): 0.983 (0.952-1.000)] for PE development compared to PlGF and PlGF/sFlt-1 independently [AUC and 95% CI: 0.825 (0.726-0.924) and 0.670 (0.539-0.800), respectively]. Conclusion: We identified novel first-trimester serum biomarkers and developed an effective prediction model integrating immune-related factors and PlGF for early PE detection, which could facilitate the development of early diagnostic strategies and provide immunological insight into the further mechanistic exploration of PE.

The PPARα agonist fenofibrate reduces the cytokine imbalance in a maternal immune activation model of schizophrenia

Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor-α (PPARα), with the clinically available agonist fenofibrate (FEN), attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)]. By using the Bio-Plex Multiplex-Immunoassay-System, we measured cytokine/chemokine/growth factor levels in maternal serum and in the fetal brain of rats treated with fenofibrate, at 6 and 24 h after poly (I:C). We found that MIA induced time-dependent changes in the levels of several cytokines/chemokines/colony-stimulating factors (CSFs). Specifically, the maternal serum of the poly (I:C)/control (CTRL) group showed increased levels of (i) proinflammatory chemokine macrophage inflammatory protein 1-alpha (MIP-1α), (ii) tumor necrosis factor-alpha (TNF-α), the monocyte chemoattractant protein-1 (MCP-1), the macrophage (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, in the fetal brain of the poly (I:C)/CTRL group, interleukin 12p70 and MIP-1α levels were lower than in vehicle (veh)/CTRL group. Notably, MIP-1α, TNF-α, keratinocyte derived chemokine (GRO/KC), GM-CSF, and M-CSF levels were lower in the poly (I:C)/FEN than in poly (I:C)/CTRL rats, suggesting the protective role of the PPARα agonist. PPARα might represent a therapeutic target to attenuate MIA-induced inflammation.

Disruption of Intranasal GnRH Neuronal Migration Route into the Brain Induced by Proinflammatory Cytokine IL-6: Ex Vivo and In Vivo Rodent Models

Maternal immune activation results in altered levels of cytokines in the maternal–fetal system, which has a negative impact on fetal development, including the gonadotropin-releasing hormone (GnRH) system, which is crucial for the reproduction. Suppression of GnRH–neuron migration may be associated with cytokine imbalances, and primarily with proinflammatory cytokine interleukin (IL)-6. This study aimed to determine the effects of IL-6 and monoclonal antibody to IL-6 or IL-6R or polyclonal IgG on the formation of migration route of GnRH–neurons in ex vivo and in vivo rodent models on day 11.5 of embryonic development. The increased level of IL-6 in mouse nasal explants suppressed peripherin-positive fiber outgrowth, while this led to an increase in the number of GnRH–neurons in the nose and olfactory bulbs and a decrease in their number in the fetal brain. This effect is likely to be realized via IL-6 receptors along the olfactory nerves. The suppressive effect of IL-6 was diminished by monoclonal antibodies to IL-6 or its receptors and by IgG.