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BackgroundMicroglia play a critical role in neurodegenerative disorders, such as Alzheimer's disease, where alterations in microglial function may result in pathogenic amyloid-β (Aβ) accumulation, chronic neuroinflammation, and deleterious effects on neuronal function. However, studying these complex factors in vivo, where numerous confounding processes exist, is challenging, and until recently, in vitro models have not allowed sustained culture of critical cell types in the same culture.ObjectiveWe employed a rat primary tri-culture (neurons, astrocytes, and microglia) model and compared it to co-culture (neurons and astrocytes) and mono-culture (microglia) to study microglial function (i.e., motility and Aβ clearance) and proteomic response to exogenous Aβ.MethodsThe cultures were exposed to fluorescently-labeled Aβ (FITC-Aβ) particles for varying durations. Epifluorescence microscopy images were analyzed to quantify the number of FITC-Aβ particles and assess cytomorphological features. Cytokine profiles from conditioned media were obtained. Live-cell imaging was employed to extract microglia motility parameters.ResultsFITC-Aβ particles were more effectively cleared in the tri-culture compared to the co-culture. This was attributed to microglia engulfing FITC-Aβ particles, as confirmed via epifluorescence and confocal microscopy. FITC-Aβ treatment significantly increased microglia size, but had no significant effect on neuronal surface coverage or astrocyte size. Upon FITC-Aβ treatment, there was a significant increase in proinflammatory cytokines in tri-culture, but not in co-culture. Aβ treatment altered microglia motility evident as a swarming-like motion.ConclusionsThe results suggest that neuron-astrocyte-microglia interactions influence microglia function and highlight the utility of the tri-culture model for studies of neuroinflammation, neurodegeneration, and cell-cell communication.

Background: Metabolic syndrome (MS) is a combination of comorbidities that increase pro-inflammatory cytokines (PIC) production, with subsequent body composition (BC) abnormalities and high cardiovascular risk. Treatment with diet and exercise has been suggested as possible non-pharmacological adjuvant treatment. Objective: To determine changes in BC and PIC in patients with MS after a Mediterranean-type diet (MedDiet) and/or isokinetic exercise (IE). Methods: A controlled randomized clinical trial was conducted at a third-level hospital in Mexico City. Intervention groups: G1: MedDiet + IE; G2: IE; G3: MedDiet; G4: control. Anthropometry, BC, and PIC were collected from the baseline and at 12 weeks post-intervention. MedDiet was estimated from a 24-h recall record. IE consisted of a standard high-intensity anaerobic exercise program. Results: Forty-two patients with MS aged 18–65 years old were included. The most frequent comorbidities were obesity, insulin resistance, and dyslipidemia. After 6 months of intervention, a significant reduction of resistin was observed within the IE group and MedDiet + IE, whereas the former group also showed an increase in adiponectin. Interventions of MedDiet and MedDiet + IE showed a decrease in IL-10. Regarding BC, all groups increased the resistance values in relation to the baseline but were lower than the control group. Conclusions: The results suggest that MedDiet and IE have a selective impact on pro-inflammatory mediators, while the combination of MedDiet and IE may induce only minor changes in BC. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitors (PPIs) are one of the most used drugs worldwide. While generally considered safe, the usage of PPIs is associated with several adverse outcomes including acute infectious diseases. PPIs influence macrophage and neutrophil function although a systematic review has never been undertaken. The purpose of this systematic review was to determine the potential mechanisms of how PPI-induced inhibition of macrophage and neutrophil function may increase infection risk in susceptible hosts. Methods: A database search using Scopus and PubMed was performed to identify studies that investigated the effects of PPIs on neutrophils or macrophage function. Results: The final screening yielded 21 English-language research articles that focused on the impacts of PPIs on the function of macrophages and neutrophils. PPI mechanistic effects included cytotoxic effects on polymorphonuclear neutrophils, inhibition of reactive oxygen species (ROS) and reactive nitrogen species, phagocytosis and phagosomal degradation, inhibition of chemotaxis and migration, altering Toll-like receptor signaling and p38 protein phosphorylation in immune cells, and altering neutrophil and macrophage gene expression. Discussion: The impact of PPIs on MΦs and neutrophils regarding their role in the immune response to bacterial pathogens was summarized. PPI effects on macrophages and neutrophils occurred due to the therapeutic mechanism of PPIs, the protonation of sulfhydryl groups and the subsequent formation of a disulfide bond, and other pleiotropic manners. Given the common use of PPIs, these results highlight the necessity to optimize PPI use and stewardship to curtail unnecessary drug use. [ABSTRACT FROM AUTHOR]

Pityriasis rosea (PR) is a self-limited exanthem associated with the endogenous systemic reactivation of human herpesvirus (HHV)-6 and HHV-7. The disease typically begins with a single erythematous patch on the trunk (herald patch), followed by a secondary eruption of smaller papulosquamous lesions. Rarely, the herald patch may be the only cutaneous manifestation of PR. The present work aimed to examine the clinical and laboratory features of the PR cases characterized by the herald patch as the sole cutaneous manifestation and to compare them with the classic form of PR. An observational, retrospective study was conducted on patients presenting with herald patch as the only sign of PR (cases) and on a series of age- and sex-matched patients who presented with a typical PR pattern (controls). The records of the patients were extracted from a PR registry, which collected data on patients with PR diagnosed from 2003 to 2023 by at least two dermatologists from the same study team. Nineteen patients (eleven males, eight females) with a mean age of 27.1 years presented the herald patch as the only cutaneous manifestation of PR. Nineteen age- and sex-matched patients were considered controls. In the cases, the exanthem duration was shorter than in controls, and the mean HHV-6 and HHV-7 DNA plasma load was lower than in controls. This rare variant of PR might be considered an abortive form of the exanthem that occurs when the HHV-6/7 reactivation from latency is contrasted by a more robust immunological response than in classic PR. [ABSTRACT FROM AUTHOR]

Introduction: Glucocorticoids (GCs) are widely used as a treatment for rheumatoid arthritis (RA), leading to high cumulative doses in long-term treated patients. The impact of a high cumulative GC dose on the systemic inflammatory response in RA remains poorly understood. Methods: We investigated long-treated patients with RA (n = 72, median disease duration 14 years) through blood counts and the serum levels of 92 inflammation-related proteins, and disease activity was assessed using the Simple Disease Activity Index (SDAI). Patients were grouped based on the cumulative GC dose, with a cut-off value of 20 g (low/high, n = 49/23). Results and discussion: Patients with a high cumulative GC dose within the active RA group had elevated serum levels in 23 inflammation-related proteins compared with patients with a low dose (cytokines/soluble receptors: CCL3, CCL20, CCL25, IL-8, CXCL9, IL-17A, IL-17C, IL-18, sIL-18R1, IL-10, sIL-10RB, OSM and sOPG; growth factors: sTGFα and sHGF; other inflammatory mediators: caspase 8, STAMBP, sCDCP1, sirtuin 2, 4E-BP1, sCD40, uPA and axin-1; pcorr < 0.05). In non-active RA, the high and low GC groups did not differ in analysed serum protein levels. Moreover, patients with active RA with a high GC dose had an increased white blood cell count, increased neutrophil–lymphocyte and platelet–lymphocyte ratios and a decreased lymphocyte–monocyte ratio compared with the low dose group (p < 0.05). This is the first study to report elevated serum levels in inflammation-related proteins and deregulated blood counts in patients with active RA with a high cumulative GC dose. The elevated systemic inflammation highlights the importance of improving care for patients receiving high cumulative GC doses. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of the brain, manifesting itself with both motor and non-motor symptoms. A critical element of this pathology is neuroinflammation, which triggers a harmful neurotoxic cycle, exacerbating cell death within the central nervous system. AD-16 (also known as GIBH-130) is a recently identified compound capable of reducing the expression of pro-inflammatory cytokines while increasing the expression of anti-inflammatory cytokines in Alzheimer's disease models. Here, for the first time, we sought to comprehend the potential impact of orally administered AD-16 in mitigating neurodegeneration and subsequent disease progression in PD. To accomplish this, 6- hydroxydopamine (6-OHDA) unilateral striatal injections were employed to induce a PD model in male C57BL/6 mice. Cylinder and apomorphine-induced rotation behavior tests were conducted to assess motor behavior and validate the PD model 3 days after the injection. AD-16 was administered via gavage daily between days 3 and 9 after surgery. On the last day of treatment, motor tests were performed again. All animals were euthanized on day 10 and immunohistochemistry techniques were performed to detect tyrosine hydroxylase (TH) and Iba-1 and thus label dopaminergic neurons and microglia in the SNc and striatum (CPu). These same regions were collected for ELISA assays to assess different cytokine concentrations. Our results revealed an enhancement in the motor function of the AD-16-treated animals, as well as reduced nigrostriatal neurodegeneration. In addition, AD-16 reduced the increase in microglia density and prevented the changes in its morphology observed in the PD animal models. Furthermore, AD-16 was able to avoid the increase of pro-inflammatory cytokines levels that were present in 6-OHDA-injected animals who received vehicle. Consequently, AD-16 emerges as a compound with significant potential for negative modulation of neurodegeneration and neuroinflammation suppression in the 6-OHDA animal model of Parkinson's disease. [ABSTRACT FROM AUTHOR]

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Simple Summary: Environmental pollution by low doses of xenobiotic is an important problem, including for aquaculture. To reduce the effects of constant stress, probiotics are often used as functional feed additives in aquaculture. This study investigates the possibility of using the strain Levilactobacillus brevis 47f as an adaptogen in aquaculture using the model organism zebrafish (Danio rerio). The cytokine profile in intestinal tissues of Danio rerio against the background of their exposure to xenobiotic solution and the fact of receiving the L. brevis 47f was examined. The transcriptome profile of the L. brevis 47f was also studied and the proteins that change their quantity against stress were revealed, which makes it possible to suggest that bisphenol A does not affect the adaptogenic properties of the L. brevis 47f. Agricultural and industrial activities are increasing pollution of water bodies with low doses of xenobiotics that have detrimental effects on aquaculture. The aim of this work was to determine the possibility of using Levilactobacillus brevis 47f culture in fish aquaculture under the influence of low doses of xenobiotics as an adaptogen. An increase in the survival of Danio rerio individuals exposed to the xenobiotic bisphenol A solution and fed with the L. brevis 47f was shown compared to control groups and, at the same time, the cytokine profile in the intestinal tissues of Danio rerio was also investigated. Analysis of differential gene expression of the L. brevis 47f grown under the action of high concentrations of bisphenol A showed changes in mRNA levels of a number of genes, including genes of various transport proteins, genes involved in fatty acid synthesis, genes of transcriptional regulators, genes of the arabinose operon, and the oppA gene. The identification of L. brevis 47f proteins from polyacrylamide gel by mass spectrometry revealed L-arabinose isomerase, Clp chaperone subunit, ATP synthase subunits, pentose phosphate pathway and glycolysis enzyme proteins, which are likely part of the L. brevis 47f strain's anti-stress response, but probably do not affect its adaptogenic activity toward Danio rerio. [ABSTRACT FROM AUTHOR]

In 2019, the COVID-19 pandemic began and changed the world. Coronavirus SARS-CoV-2 has caused widespread illness and death around the world. In this regard, vaccination become the most important tool for creating herd immunity. Our study analyzed the dynamics of pro- and anti-inflammatory cytokines and antibodies to SARS-CoV-2 in the blood serum of young patients before and after vaccination against COVID-19. The study group included 76 young men. Determination of IL-1β, IL-4, IL-6, IL-8, IL-10, IL-17, IFNγ, TNFα and IgM and IgG antibodies to COVID-19 in venous blood sera was carried out twice, by ELISA using the test systems of Vector-Best Company, Novosibirsk. The first blood samples were carried out before vaccination, the second — 1 month after vaccination against COVID-19. The results were processed using STATISTICA 8.0. The vaccinated people were monitored for 6 months after vaccination. Levels of indices before vaccination: IL-1β (5.6 pg/ml (Q₂₅–Q₇₅ = 3.1–14.2); IL-4 (1.02 pg/ml (Q₂₅–Q₇₅ = 0.75–1.28); IL-6 (27.8 pg/ml (Q₂₅–Q₇₅ = 7.1–59.9); IL-8 (29.9 pg/ml (Q₂₅–Q₇₅ = 19.51–32.14); IL-10 (4.47 pg/ ml (Q₂₅–Q₇₅ = 1.84–14.75); IL-17 (7.33 pg/ml (Q₂₅–Q₇₅ = 6.82–8.58); IFNγ (0.7 pg/ml (Q₂₅–Q₇₅ = 0.4–0.9); TNFα (3.9 pg/ml (Q₂₅–Q₇₅ = 2.2–6.4). Levels of indices after vaccination: IL-1β (1.6 pg/ml (Q₂₅–Q₇₅ = 1.4- 2.2); IL-4 (0.84 pg/ml (Q₂₅–Q₇₅ = 0.59–1.12); IL-6 (1.2 pg/ml (Q₂₅–Q₇₅ = 0.6–1.7); IL-8 (10.1 pg/ml (Q₂₅–Q₇₅ = 3.8–28.9); IL-10 (5.84 pg/ml (Q₂₅–Q₇₅ = 1–9.99); IFNγ (0.6 pg /ml (Q₂₅–Q₇₅ = 0.3–0.8); TNFα (0.6 pg/ml (Q₂₅–Q₇₅ = 0.3–1.9). Both before and after vaccination against SARS-CoV-2, different distributions of cytokine levels were identified with a downward trend, but despite this, strong correlations were observed between many of them, which indicates an increase in the tension of the immune system in response to vaccination. When calculating the ratio of pro- and anti-inflammatory cytokines, its two-fold decrease was revealed, which reflects a decrease in the levels of pro-inflammatory cytokines after vaccination. The level of IgG antibodies to COVID-19 exceeded the protective level: more than 14 times in 98% of subjects. Further research into the impact of SARS-CoV-2 vaccination on innate immunity will allow us to reconsider the current vaccination strategy and determine the best approach to preventing COVID-19.

Introduction. Retained products of conception (RPOC) are detected in 15 % of women after spontaneous or medical abortion. RPOC blind removal from the uterine cavity remains the "gold standard" of surgical treatment, which, however, may be associated with a high risk of certain complications that pose a serious threat to female reproductive function and quality of life. An alternative method for eliminating RPOC proposed by operative hysteroscopy demonstrating the visual control advantages.Aim: to evaluate clinical effectiveness and safety of RPOC removal in incomplete spontaneous abortion using hysteroscopic morcellation.Materials and Methods. The prospective comparative study included 135 women with incomplete spontaneous abortion aged 18 to 40 years, divided into 3 groups: group 1 – 42 patients after RPOC electromechanical vacuum aspiration (EVA); group 2 – 44 patients after RPOC manual vacuum aspiration (MVA); group 3 – 49 patients after RPOC hysteroscopic morcellation (HM). In all patients, the level of total endotoxin was measured, metroaspirate cytokine profile was analyzed, the indicator of endometrial microcirculation was assessed before surgical treatment and on day 1 afterwards, and genital ultrasound examination was performed on day 3–5 post-surgery.Results. In the post-surgical vs. pre-treatment period, the EVA and MVA groups revealed significantly increased levels of total endotoxin and interleukin (IL) IL-1β (p < 0.05). In contrast, these parameters in the HM group changed insignificantly (p > 0.05). In all groups, IL-8 and tumor necrosis factor alpha (TNF-α) levels after surgery were significantly elevated (p = 0.001). In the EVA and MVA groups, levels of anti-inflammatory cytokines IL-4 and IL-10 were markedly decreased (p = 0.001), which did not change in the HM group (p > 0.05). A significantly accelerated microcirculation rate was noted in the EVA and MVA groups while comparing it at pre-surgery level (p = 0.001), but not in the HM group (p = 0.415). Incomplete RPOC removal was reported for 4.5 % MVA patients, all EVA and HM patients had total RPOC elimination. Intraoperative bleeding, uterine perforation were not reported in any examined patient.Conclusion. The early-stage treatment results showed that RPOC removal by the HM is an effective and safe approach. Limited inflammatory response and stable endometrial microcirculation upon using the HM evidence about a minimal impact on the endometrium that lowers probability of postoperative adhesion.

The objective of this article is to evaluate the salivary levels of tumor necrosis factor‐alpha (TNF‐α), interferon‐gamma (IFN‐γ), interleukin‐2 (IL‐2), and IL‐10 in patients with active psoriasis and compare them with those in healthy control subjects. This study included 60 subjects who were clinically diagnosed cases with active psoriasis (categorized further into 33 mild to moderate and 27 severe cases based on the Psoriasis Area Severity Index score) and 60 age‐ and gender‐matched healthy control subjects. Levels of TNF‐α, IFN‐γ, IL‐2, and IL‐10 in the unstimulated saliva of subjects were determined via enzyme‐linked immunosorbent assay (BT Lab). The salivary levels of TNF‐α, IFN‐γ, and IL‐2 were significantly higher, whereas IL‐10 concentration was significantly reduced in psoriatic patients in comparison to controls, and the difference increased with the progressing severity of the disease. Assessment of cytokine profiles in psoriasis patients is significant for diagnostic validation and monitoring the disease severity. Saliva offers an alternate, noninvasive, and readily available biological sample for evaluating cytokine levels. Extensive research in this field has been recommended for better scientifically proven conclusions. [ABSTRACT FROM AUTHOR]

The enduring impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease manifestation, COVID-19, on public health remains significant. Postacute sequelae of SARS-CoV-2 infection (PASC) affect a considerable number of patients, impairing their quality of life. While the role of the cytokine storm in acute COVID-19 is well established, its contribution to the pathophysiology of PASC is not fully understood. This study aimed to analyze the cytokine profile of patients with PASC following in vitro stimulation of Toll-like receptor (TLR) pathways, comparing them with a healthy control group. From October 2020 till March 2021, Brugmann University Hospital's clinical research unit included patients with PASC in the study. Whole blood samples were collected from 50 patients and 25 healthy volunteers. After in vitro stimulation under five different conditions, cytokine levels were measured using a multiplex method. Significantly decreased cytokine levels were observed in patients with PASC compared with healthy volunteers, particularly after TLR4 (interleukin [IL]-1α, IL-1β, IL-2, IL-10, interferon (IFN)α, IFNγ, IFNω, and tumor necrosis factor (TNF)α) and TLR7/8 (IL-1α, IL-1β, IFNα, IFNω, IFNγ, and TNFα) pathway stimulation. Principal component analysis identified two distinct clusters, suggesting a likely dysregulation of immunity involving TLR4 and TLR7/8 pathways in patients with PASC. Our study suggests that TLR4 and TLR7/8 pathways play a role in the pathophysiology of PASC. Continuous basal activation of immunity could explain the high basal concentrations of cytokines described in these patients and the decreased amplitude of response of these signaling pathways following specific stimulation. [ABSTRACT FROM AUTHOR]

IntroductionGlucocorticoids (GCs) are widely used as a treatment for rheumatoid arthritis (RA), leading to high cumulative doses in long-term treated patients. The impact of a high cumulative GC dose on the systemic inflammatory response in RA remains poorly understood.MethodsWe investigated long-treated patients with RA (n = 72, median disease duration 14 years) through blood counts and the serum levels of 92 inflammation-related proteins, and disease activity was assessed using the Simple Disease Activity Index (SDAI). Patients were grouped based on the cumulative GC dose, with a cut-off value of 20 g (low/high, n = 49/23).Results and discussionPatients with a high cumulative GC dose within the active RA group had elevated serum levels in 23 inflammation-related proteins compared with patients with a low dose (cytokines/soluble receptors: CCL3, CCL20, CCL25, IL-8, CXCL9, IL-17A, IL-17C, IL-18, sIL-18R1, IL-10, sIL-10RB, OSM and sOPG; growth factors: sTGFα and sHGF; other inflammatory mediators: caspase 8, STAMBP, sCDCP1, sirtuin 2, 4E-BP1, sCD40, uPA and axin-1; pcorr < 0.05). In non-active RA, the high and low GC groups did not differ in analysed serum protein levels. Moreover, patients with active RA with a high GC dose had an increased white blood cell count, increased neutrophil–lymphocyte and platelet–lymphocyte ratios and a decreased lymphocyte–monocyte ratio compared with the low dose group (p < 0.05). This is the first study to report elevated serum levels in inflammation-related proteins and deregulated blood counts in patients with active RA with a high cumulative GC dose. The elevated systemic inflammation highlights the importance of improving care for patients receiving high cumulative GC doses.

Paediatric Mycoplasma pneumoniae pneumonia (MPP) is a heterogeneous disease with a diverse spectrum of clinical phenotypes. No studies have demonstrated the relationship between underlying endotypes and clinical phenotypes as well as prognosis about this disease. Thus, we conducted a multicentre prospective longitudinal study on children hospitalized for MPP between June 2021 and March 2023, with the end of follow-up in August 2023. Blood samples were collected and processed at multiple time points. Multiplex cytokine assay was performed to characterize serum cytokine profiles and their dynamic changes after admission. Cluster analysis based on different clinical phenotypes was conducted. Among the included 196 patients, the levels of serum IL-17A and IL-6 showed remarkable variabilities. Four cytokine clusters based on the two cytokines and four clinical groups were identified. Significant elevation of IL-17A mainly correlated with diffuse bronchiolitis and lobar lesion by airway mucus hypersecretions, while that of IL-6 was largely associated with lobar lesion which later developed into lung necrosis. Besides, glucocorticoid therapy failed to inhibit IL-17A, and markedly elevated IL-17A and IL-6 levels may correlate with lower airway obliterans. Our study provides critical relationship between molecular signatures (endotypes) and clustered clinical phenotypes in paediatric patients with MPP.

Disease-modifying therapies (DMTs) impact the cellular immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (pwMS). In this study, we aim to elucidate the characteristics of the involved antigen-specific T cells via the measurement of broad cytokine profiles in pwMS on various DMTs. We examined SARS-CoV-2-specific T cell responses in whole blood cultures characterized by the release of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, IL-17A, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), as well as antibodies (AB) targeting the SARS-CoV-2 spike protein in pwMS following either two or three doses of mRNA or viral vector vaccines (VVV). For mRNA vaccination non-responders, the NVX-CoV2373 protein-based vaccine was administered, and immune responses were evaluated. Our findings indicate that immune responses to SARS-CoV-2 vaccines in pwMS are skewed towards a Th1 phenotype, characterized by IL-2 and IFN-γ. Additionally, a Th2 response characterized by IL-5, and to a lesser extent IL-4, IL-10, and IL-13, is observed. Therefore, the measurement of IL-2 and IL-5 levels could complement traditional IFN-γ assays to more comprehensively characterize the cellular responses to SARS-CoV-2 vaccines. Our results provide a comprehensive cytokine profile for pwMS receiving different DMTs and offer valuable insights for designing vaccination strategies in this patient population. [ABSTRACT FROM AUTHOR]

Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, abnormalities of the cytokine profiles are deeply involved in its pathophysiology. Therefore, an approach focused on the cytokine profile of individual patients with UC is ideal. Recent studies have demonstrated that molecular analysis of cytokine profiles in UC can predict response to each advanced therapy. This narrative review summarizes the molecules involved in the efficacy of various advanced therapies for UC. Understanding these associations may be helpful in selecting optimal therapeutic agents. [ABSTRACT FROM AUTHOR]

Aim: The current study aimed to describe various types of myelitis associated with a novel coronavirus infection [coronavirus disease 2019 (COVID-19)] as well as to analyze cytokine profiles and cerebrospinal fluid (CSF) parameters in affected patients and to compare them to patients with other immune-mediated disorders—multiple sclerosis (MS), in order to identify possible common pathogenetic pathways and consequently treatment targets. Methods: Clinical, radiological, and laboratory characteristics were studied based on patients’ history. CSF from patients with myelitis associated with COVID-19 (11 patients) was compared with CSF of healthy controls (HC) (7 patients) and patients with MS (37 patients) from the non-COVID era. CSF cytological examination, protein levels and oligoclonal bands (OCBs) evaluation, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus detection and cytokine profiling using Bio-Plex Pro Human Inflammation Panel 1, 37-Plex were performed. Results: In total 11 patients with different types of myelitis developed up to 3 months after COVID-19 were enrolled in the study. Radiological findings were diverse: short transverse myelitis (lesion of fewer than 3 segments) (n = 6), longitudinal extensive transverse myelitis (LETM) (n = 2), multifocal spinal cord lesions (n = 1), and myelitis involving dorsal and lateral columns (n = 2). The most pronounced response to treatment was observed in patients with partial transverse myelitis and patients with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies (MOG Abs). Multiple comparisons have demonstrated decreased levels of interleukin-10 (IL-10), interferon-α2 (IFN-α2), IFN-β, and thymic stromal lymphopoietin (TSLP), and increased IL-19 and B cell activating factor (BAFF) in patients with COVID-19 myelitis (CM) compared to the MS group. The highest BAFF and a proliferation-inducing ligand (APRIL) concentrations were found in patients with the most profound neurological disability. Conclusions: Myelitis associated with COVID-19 is clinically and radiologically heterogeneous. Evaluation of cytokine profiles in patients with myelitis associated with COVID-19 revealed their relative similarity with ones of MS patients, except for a few cytokines. BAFF/APRIL system as well as IL-10 is well-known for the role in the development and progression of autoimmune diseases, however, their links with COVID-19 and effects on the development of immune-mediated central nervous system (CNS) disorders after SARS-CoV-2 remain to be further studied.

The aim of the study was to investigate the effect on the psycho-emotional state and adherence to treatment in patients with pulmonary tuberculosis of remaxol inclusion in the accompanying therapy regimens.Material and methods. The data from 326 patients (252 men and 74 women) with various forms of pulmonary tuberculosis treated at the Regional Clinical Tuberculosis Dispensary were analyzed; the average age of patients was 41.3±1.6 years. A low level of adherence to treatment, as well as clinical and laboratory signs of grade I hepatotoxicity were revealed in patients receiving a course of etiotropic therapy in the main group (N=72). In this regard, in addition to the psychological support for the main course of treatment, accompanying therapy was prescribed: remaxol 400 ml intravenous drip every other day (course No. 5), after-wards — 1 time a week (course No. 4). Patients in the comparison group (N=254) received standard treatment. In addition to the standard examination, the cytokine profile (the level of IL-1β, 4, 6), TNF-α and IFN-γ) was determined in dynamics according to the indications in patients. The level of adherence to the treatment was also determined in dynamics through testing according to the original methodology.Results. The study revealed that the inclusion of remaxol in the treatment regimens facilitated more pronounced positive dynamics in clinical and laboratory data compared with the standard regimen: a decrease in signs of hepatotoxicosis and a tendency towards improvement in cytokine profile parameters. This contributed to maintaining the etiotropic therapy regimen and improving the well-being of patients, which, in turn, increased the level of adherence and therefore the effectiveness of treatment in patients.Conclusions. The combination of positive effects of remaxol use in patients with pulmonary tuberculosis contributes to an increase in their psycho-emotional state and thereby increases adherence to treatment and its effectiveness.

Objective: is to assess parameters of cytokine profile, and some biomarkers of hemogram, cytogenetic damage, and oxidative stress to determine their associations with clinical symptoms and identify early prognostic factors for tick-borne encephalitis febrile form compared with Lyme borreliosis non-erythemal form at the onset of the disease.Materials and methods. In 25 patients with febrile tickborne encephalitis (mean age: 49.51 years), 24 patients with Lyme borreliosis non-erythemal form (mean age: 46.70 years) and 14 healthy donors (mean age: 47.20 years), the following parameters were analyzed: hemogram, blood leukocyte indices, cytokine profile, the levels of micronucleated T-lymphocytes, malondialdehyde and total immunoglobulin (Ig) G. For statistical analysis, the Mann–Whitney U-test, Pearson’s goodness-of-fit test, Spearman’s correlation coefficient, and ROC assay with AUC assessment were used.Results. In the tick-borne encephalitis patient group compared to the controls, the following parameters were increased: neutrophil count, blood leukocyte indices, the levels of micronucleated T-lymphocytes, malondialdehyde and proinflammatory cytokines in the blood, which directly correlated with maximal pyrexia levels. Prognostic value for early preliminary diagnosis of tick-borne encephalitis compared with borreliosis showed the following blood parameters: increases in neutrophil count and the levels of micronucleated T-cells, neutrophils to monocytes ratio, neutrophils to lymphocytes ratio, concentrations of malondialdehyde, tumor necrosis factor (TNF)-α, interleukins (IL)-8, IL-6, IL-10, and TNF-α/IL-4 ratio as well as decreases in the levels of IL-4 and total serum IgG. The parameters showed from average to excellent predictive ability as well as high positive and negative predictive values.Conclusion. In patients with tick-borne encephalitis, we detected correlations between the pyrexia levels and the biomarkers of inflammation, oxidative stress, and cytogenetic damage as well as it were found some differences in these parameters from the group of borreliosis patients, which probably had prognostic significance.

Cytokines are the key mediators which control and regulate immune and inflammatory responses via complex networks and serve as biomarkers of many diseases. Quantitative determination of cytokines is helpful in assessing immune status and adjusting therapy for various inflammatory diseases, such as sepsis and pneumonia. Since community-acquired pneumonia remains a common cause of childhood morbidity and mortality. At the present stage, prognosis of the disease severity in children is an urgent problem. The aim of our study was to identify associations between cytokine levels in healthy children and in children with community-acquired pneumonia (CAP), depending on the age of patients and severity of the pathological process. The work was carried out at the Department of Microbiology, Virology and Immunology, Department of Propaedeutics of Childhood Diseases and Pediatrics, and at the Research Institute of Immunology at the South Ural State Medical University. The study included 117 children aged 1 to 18 years with radiologically confirmed diagnosis of CAP, either severe or mild degree. The comparison group was composed from 28 healthy children who did not have community-acquired pneumonia, as well as other signs of acute respiratory viral infection at the time of examination, being observed for any chronic disorders. The levels of IL-1β, IFNγ, IL-6, IL-4, IL-10, IL-2, TNFα, IFNλ2 (IL-28A), IFNλ3 (IL-28B), IL-8, MCP-1, IL-17AF, GM-CSF were determined in blood serum by means of ELISA test systems (a “sandwich” technique with peroxidase as an indicator enzyme). For statistical analysis, a multidimensional method was used, i.e., non-linear analysis of the principal components using the CATPCA algorithm. Among the children with CAP, our study revealed a consistent increase of IL-1ß, IL-4, IL-10, IL-2, TNFα, IFNλ2 (IL-28A), IFNλ3 (IL-28B), IL-8, MCP-1, IL-17AF, GM-CSF in blood serum. The highest correlation with severity was shown for IFNλ2 (IL-28A), IFNλ3 (IL-28B) and MCP-1, which may be considered additional biomarkers of the CAP severity. There was also a significant variability of the cytokine profile in healthy children and its significant skewing in pneumonia, especially in severe cases.

Hyperhomocysteinemia (HHcy) is now being actively studied as a potential risk factor and/or biomarker for numerous pathological conditions, including brain diseases. This study aimed to analyze the proteolytic processes in the brains of rats with HHcy. Total proteolytic activity, metal-dependent, and serine proteases activities, the content of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases-1, cytokines, serine proteases, total protein and medium and low molecular-weight substances (MLMWS), were evaluated. HHcy was induced by DL-homocysteine thiolactone (HTL) daily intragastric administration (200 mg·kg–1 of body weight) to young and adult albino non-linear male rats for 8 weeks following rat sacrifice and brain harvesting. It was established that HHcy causes an increase in total proteolytic activity and a rise in MLMWS levels in rat brains. Serine protease activity increased to a greater extent compared to metal-dependent one, and bigger changes were observed in young rats. Rise in MMP-9 and -10 levels (in young animals), a decline in MMP-3 and -8 levels, and a decrease in the content of interleukin-1β, interferon-γ, interleukin-4 and tumor necrosis factor-α (the last two in young animals) was also detected. No significant changes were found in serine protease content. Therefore, proteolysis intensification in the brain of rats with HHcy is more likely caused by protease up-regulation through mechanisms stimulated by homocysteine, HTL, and oxidative stress, without involving pro-inflammatory signaling pathways.

Hyperhomocysteinemia (HHcy) is now being actively studied as a potential risk factor and/or biomarker for numerous pathological conditions, including brain diseases. This study aimed to analyze the proteolytic processes in the brains of rats with HHcy. Total proteolytic activity, metal-dependent, and serine proteases activities, the content of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases-1, cytokines, serine proteases, total protein and medium and low molecular-weight substances (MLMWS), were evaluated. HHcy was induced by DL-homocysteine thiolactone (HTL) daily intragastric administration (200 mg·kg-1 of body weight) to young and adult albino non-linear male rats for 8 weeks following rat sacrifice and brain harvesting. It was established that HHcy causes an increase in total proteolytic activity and a rise in MLMWS levels in rat brains. Serine protease activity increased to a greater extent compared to metal-dependent one, and bigger changes were observed in young rats. Rise in MMP-9 and -10 levels (in young animals), a decline in MMP-3 and -8 levels, and a decrease in the content of interleukin-1ß, interferon-γ, interleukin-4 and tumor necrosis factor-a (the last two in young animals) was also detected. No significant changes were found in serine protease content. Therefore, proteolysis intensification in the brain of rats with HHcy is more likely caused by protease up-regulation through mechanisms stimulated by homocysteine, HTL, and oxidative stress, without involving pro-inflammatory signaling pathways. [ABSTRACT FROM AUTHOR]

The aim of the work is to determine the relationship between the levels of cytokines of proinflammatory and anti-inflammatory action during the clinical course of hemorrhagic fever with renal syndrome (HFRS) and the previously described characteristics of the phenotypic composition of blood lymphocytes in disease of various severity. Materials and methods. 65 patients with a serologically verified diagnosis of HFRS were under observation. The control group included 15 conditionally healthy people. Determination of cytokines in the blood of patients with HFRS was carried out by the enzyme immunoassay method at the different stages of the disease. The phenotypic composition of blood lymphocytes was assessed by flow cytofluorimetry. Results. At the different stages of the disease, there was a quantitatively different increase in the content of cytokines in the blood associated with cytotoxic immune reactions (IL-12, IFN, TNFa, TNF), as well as IL-10 and IL-6 correlated with each other in severe cases, against the background of a drop in blood levels of IL-4 and IL-1. In the moderate course of HFRS, correlations of IL-12 and IL-4 with NKG2D+ CTL, the relationship of IL-12 with almost all other cytokines, and the correlation of CD8+ Treg with IL-6 and TNF levels were observed. In severe cases, the formation of a complex that included interconnected IL-6 and IL-10 correlating with the number of NKG2D+ CTL, CD8+ Treg, NKT was noted. Conclusion. The pathogenetically significant mechanism of HFRS is realized with the predominant participation of cytokines of the cellular immune response and IL-6, correlatively associated with NKG2D+ CTL, CD8+ Treg, NKT, which, in case of a favorable outcome, contribute to the active formation of a pool of CD8+ memory cells, disrupted presumably by excessive secretion of IL-10.

ObjectivesTo investigate the characteristic cytokine profile of the aqueous humor in eyes with congenital cataract and pre-existing posterior capsule dysfunction (PCD).MethodsIn this cross-sectional study, the enrolled eyes with congenital cataract and PCD were included in the PCD group, while those with an intact posterior capsule were included in the control group. Demographic data and biometric parameters were recorded. The levels of 17 inflammatory factors in the aqueous humor collected from the enrolled eyes were detected using Luminex xMAP technology, and intergroup differences in the collected data were analyzed.ResultsThe PCD group comprised 41 eyes from 31 patients with congenital cataract and PCD, whereas the control group comprised 42 eyes from 27 patients with congenital cataract and an intact posterior capsule. Lens thickness was significantly thinner in the PCD group than in the control group. However, the levels of monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-β2 (TGF-β2), and vascular endothelial growth factor (VEGF) were significantly higher in the PCD group than in the control group. Multivariate logistic regression confirmed that lens thickness and TGF-β2 level were independent risk factors for PCD.ConclusionA thinner lens thickness in eyes with congenital cataract and PCD could serve as a biometric feature of these eyes. The higher levels of MCP-1, TGF-β2, and VEGF in eyes with PCD indicated a change in their intraocular inflammatory microenvironment, which possibly led to cataract progression. Lens thickness and TGF-β2 level are independent risk factors for PCD.

Abstract—The data on cytokine expression in humans and animals after radiation exposure is reviewed. Cytokines are biologically active hormone-like proteins regulating a wide range of processes in the body. The main functions of cytokines are regulation of the immune response and inflammatory processes and participation in embryogenesis. Cytokines can affect the cell radiosensitivity, the frequency and type of radiation-induced tissue reactions, and damage to the genome. Changes in the expression of cytokines can persist for a long time after radiation exposure and are mainly pro-inflammatory in nature. The study of cytokine helps to understand the mechanisms of development of the immediate and long-term effects of radiation exposure in order to minimize or prevent them. [ABSTRACT FROM AUTHOR]

Introduction: Pure Neural Leprosy (PNL) is a form of this long time known disease that affects only the peripheral nervous system. Since it is a rare form of the disease, its pathophisiology is still poorly understood. Objective: Describe the cytokines profile in patients with PNL. Methods: 30 Patients diagnosed with PNL in the Souza Araujo Outpatient Clinic and with cytokines evaluated were selected. They were evaluated by neurologists and diagnosed after a nerve biopsy. Serum levels of IL-1 b, IL-6, IL-10, IL-17, TNF, CCL-2/MCP-1, IFN-1, CXCL-10/IP-10 and TGF-b were evaluates at the moment of the diagnosis. Results: Neural thickening was a common clinical finding in this groups of patients. Small and medium sensitive fibers signs and symptoms were present in 92% of the patients and motor involvement in 53%. 43% of patients presented neuropathic pain and no one had neuritis TGF-beta, IL-17, CCl-2 and IP-10. CCL-2 levels were associated with demyelinating patters and IP-10 and IL-1o were associated with axonal patterns at NCS. Discussion: PNL patients' cytokine profile appears to be different of other clinical forms of leprosy, with the presence of cytokines described in both tuberculoid and lepromatous leprosy. High levels of CCl-2 may be related to the presence of silent neuritis as well as the presence of IL-10. PNL is unique a form of leprosy, therefore, understanding its immunological profiles essential to better understand the disease itself. [ABSTRACT FROM AUTHOR]

To clarify the differences and similarities in the cytokine profiles of macrophage activating syndrome (MAS) between systemic lupus erythematosus (SLE) and adult-onset Still's disease (AOSD). The study participants included 9 patients with MAS-SLE, 22 with non-MAS-SLE, 9 with MAS-AOSD, and 13 with non-MAS-AOSD. Serum cytokine levels were measured using a multiplex bead assay. Cytokine levels were compared between patients with SLE and AOSD with/without MAS. Moreover, cytokine patterns were examined using principal component analysis (PCA) and cluster analysis. IL-6, IL-8, IL-18, and TNF-α levels were elevated in patients with SLE and AOSD. IFN-α levels were elevated in SLE, whereas IL-1β and IL-18 levels were elevated in AOSD. In SLE, IFN-α and IL-10 levels were higher in MAS than in non-MAS and controls. PCA revealed distinctive cytokine patterns in SLE and AOSD, SLE with IFN-α and IP-10, AOSD with IL-1β, IL-6, and IL-18, and enhanced cytokine production in MAS. PCA and cluster analysis showed no differences in cytokine patterns between the MAS and non-MAS groups. However, serum ferritin levels were correlated with IFN-α levels in SLE. Cytokine profiles differed between SLE and AOSD but not between MAS and non-MAS. MAS is induced by the enhancement of underlying cytokine abnormalities rather than by MAS-specific cytokine profiles. Type I IFN may be involved in MAS development in patients with SLE. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the deadliest cancers worldwide. The dysregulation of secretory pathways is a crucial driver of CRC progression, since it modulates cell proliferation, angiogenesis and survival. This study explores the changes in the CRC cytokine profile depending on the culture conditions and the presence of fibroblasts and macrophages as cellular components of the tumor microenvironment in 2D and in 3D formed spheroids. Upon analysis of 45 different cytokines, chemokines and growth factors, 20 CRC cell lines were categorized into high and low secretors. In the high secretor group cytokines related to angiogenesis, EMT and invasion were significantly upregulated. LIF and HFG were identified as the best discriminator between both groups. Independent of this grouping, the addition of normal as well as cancer-associated fibroblasts had a similar impact on the cytokine profile by increasing the total amount of secreted cytokines in most of the investigated cell lines. In contrast, the differentiation and polarization of macrophages was modulated differently by normal vs. cancer-associated fibroblasts. In summary, we identified two groups of CRC cell lines that differ in their cytokine profile. The dependance of this profile was analyzed in detail—not only from the tumor cell line but as well from the culture condition in vitro. Key cytokines that discriminate the two groups were identified and their importance as promising biomarker candidates for CRC discussed. [ABSTRACT FROM AUTHOR]

Background: Cytokines are actively involved in the regulation of the inflammatory and immune responses and have crucial importance in the outcome of spinal cord injuries (SCIs). Examining more objective and representative indicators of the patient's condition is still required to reveal the fundamental patterns of the abovementioned posttraumatic processes, including the identification of changes in the expression of cytokines. Methods: We performed a dynamic (3, 7, and 14 days post-injury (dpi)) extended multiplex analysis of cytokine profiles in both CSF and blood serum of SCI patients with baseline American Spinal Injury Association Impairment Scale grades of A. Results: The data obtained showed a large elevation of IL6 (>58 fold) in CSF and IFN-γ (>14 fold) in blood serum at 3 dpi with a downward trend as the post-traumatic period increases. The level of cytokine CCL26 was significantly elevated in both CSF and blood serum at 3 days post-SCI, while other cytokines did not show the same trend in the different biosamples. Conclusions: The dynamic changes in cytokine levels observed in our study can explore the relationships with the SCI region and injury severity, paving the way for a better understanding of the pathophysiology of SCI and potentially more targeted and personalized therapeutic interventions. [ABSTRACT FROM AUTHOR]

Physical exercise generates a systemic response in the immune system. It has been observed that cell populations respond to exercise stimuli, especially Natural Killer cells, whose number increase within minutes of starting physical exertion. This study aimed to evaluate the acute effect of moderate- and high-intensity exercise on immunological markers in healthy women. As specific objectives, the percentages of CD3-CD56+ Natural Killer total cells, CD56brightCD16dim effector subpopulation, CD56dimCD16bright cytotoxic subpopulation, NKG2A inhibition receptor, NKG2D activation receptor, and NKT cells were analyzed. In addition, the levels of the cytokines IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNF and the chemokines CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10 were also analyzed. Natural Killer total cells showed an increase in their percentage in both exercise protocols (p = 0.001 for the moderate-intensity group and p = 0.023 for the high-intensity group); however, only in the high-intensity exercise session was there an increase in the CD56dimCD16bright cytotoxic subpopulation (p = 0.014), as well as a decrease in CD56brightCD16dim effector subpopulation (p = 0.001) and their NKG2A inhibition receptor (p = 0.043). An increase in IL-6 was observed after the high-intensity exercise session (p = 0.025). Conclusions. Physical exercise influences immunological markers and shows an acute response to moderate- or high-intensity exercise. [ABSTRACT FROM AUTHOR]

Abstract COVID-19-related acute respiratory distress syndrome (CARDS) is associated with high mortality rates. We still have limited knowledge of the complex alterations developing in the lung microenvironment. The goal of the present study was to comprehensively analyze the cellular components, inflammatory signature, and respiratory pathogens in bronchoalveolar lavage (BAL) of CARDS patients (16) in comparison to those of other invasively mechanically ventilated patients (24). In CARDS patients, BAL analysis revealed: SARS-CoV-2 infection frequently associated with other respiratory pathogens, significantly higher neutrophil granulocyte percentage, remarkably low interferon-gamma expression, and high levels of interleukins (IL)-1β and IL-9. The most important predictive variables for worse outcomes were age, IL-18 expression, and BAL neutrophilia. To the best of our knowledge, this is the first study that was able to identify, through a comprehensive analysis of BAL, several aspects relevant to the complex pathophysiology of CARDS.

The aim of the study: to evaluate the cytokine profile state in pregnant women with non-alcoholic fatty liver disease (NAFLD) at the stage of non-alcoholic steatohepatitis (NASH) with varying degrees of obesity under the influence of the developed complex therapy program. Material and methods. We examined 197 pregnant women with NAFLD at the stage of NASH in combination with obesity. The main group I consisted of 98 pregnant women with NAFLD at the stage of NASH with varying degrees of obesity, who were divided into 3 subgroups depending on body mass index (BMI). Among them, 26 pregnant women with BMI of 25.0–29.9 kg/m2 were included in IA group, 48 pregnant women with BMI of 30.0–34.9 kg/m2 were included in IB group, and 24 pregnant women with BMI of 35.0–39.9 kg/m2 – in IC group. All pregnant women in the main group were prescribed complex therapy including vitamin E at a dose of 400 IU/day, ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg/day, and L-carnitine at a dose of 3 g per day. The comparison group consisted of 69 women with NAFLD at the stage of NASH and abdominal obesity, who corresponded to subgroups of the main group (IIA – 23 patients, IIB – 25 women, IIC – 21 pregnant women) and received basic therapy. The control group consisted of 30 healthy women. To evaluate the cytokine profile, levels of IL-1β, IL-6, IL-10 and TNF-α were determined by ELISPOT. Results. Analysis of the cytokine profile in women with NASH and obesity showed the presence of systemic inflammation links in the examined groups, which was manifested by increased levels of pro-inflammatory and decreased levels of anti-inflammatory interleukins in blood serum of pregnant women. A prescription of the complex treatment contributed to a decreased activity of the inflammatory response, which was manifested by an improvement in the levels of cytokine profile indicators. Conclusions. NASH during pregnancy is accompanied by significant changes in the cytokine profile. The prescription of complex therapy in the form of vitamin E, UDCA and L-carnitine is effective in the treatment of pregnant women with NAFLD at the stage of NASH due to cumulative and potentiating effects, reducing manifestations of systemic inflammation by normalizing the level of cytokines.

IntroductionPure Neural Leprosy (PNL) is a form of this long time known disease that affects only the peripheral nervous system. Since it is a rare form of the disease, its pathophisiology is still poorly understood.ObjectiveDescribe the cytokines profile in patients with PNL.Methods30 Patients diagnosed with PNL in the Souza Araujo Outpatient Clinic and with cytokines evaluated were selected. They were evaluated by neurologists and diagnosed after a nerve biopsy. Serum levels of IL-1 β, IL-6, IL-10, IL-17, TNF, CCL-2/MCP-1, IFN-ϒ, CXCL-10/IP-10 and TGF-β were evaluates at the moment of the diagnosis.ResultsNeural thickening was a common clinical finding in this groups of patients. Small and medium sensitive fibers signs and symptoms were present in 92% of the patients and motor involvement in 53%. 43% of patients presented neuropathic pain and no one had neuritis TGF-beta, IL-17, CCl-2 and IP-10. CCL-2 levels were associated with demyelinating patters and IP-10 and IL-1o were associated with axonal patterns at NCS.DiscussionPNL patients’ cytokine profile appears to be different of other clinical forms of leprosy, with the presence of cytokines described in both tuberculoid and lepromatous leprosy. High levels of CCl-2 may be related to the presence of silent neuritis as well as the presence of IL-10. PNL is unique a form of leprosy, therefore, understanding its immunological profiles essential to better understand the disease itself.

Post-COVID-19 conditions are the subject of extensive scientific study. It is known that system disorders may persist in people who recover from COVID-19 for 3 to 12 months (in most cases). The first line of systemic disorders is dysfunction of the immune system, especially the cytokine profile. The mechanism of the launch of immune complications is currently unknown. We hypothesized that anti-SARS-CoV-2 IgG might trigger the development of post-COVID-19 complications. Our research aimed to study the cytokine profile (including IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12β, TNF-α, IFN-γ) and the transcription factor NF-kB in the blood plasma of donor groups depending on various titers of anti-SARS-CoV-2 IgG. We determined the qualitative values of the cytokine parameters using ELISA (Enzyme Linked Immunosorbent Assay). We estimated the changes in the cytokine profiles in all donor groups. Differences between donor groups were established for each research parameter. We detected changes in NF-κB levels as a key transcription factor for the expression of inflammatory cytokines. The highest level was found in the donor group with a titer of anti-SARS-CoV-2 IgG 75 ± 5 Index (S/C). We detected some differences between donor groups in the levels of pro-inflammatory cytokines compared to a reference point. IL-1β, IL-6, IL-8, INF-γ, and TNF-α levels changed in most donor groups with titers of anti-SARS-CoV-2 IgG ≥ 10 ± 3 Index (S/C). In addition, we showed that the decrease in anti-inflammatory cytokine IL-4 in donor groups ranged from the titer of anti-SARS-CoV-2 IgG 55 ± 5 Index (S/C) to 85 ± 5 Index (S/C), but these changes for the anti-inflammatory cytokine IL-10 were not detected. We found that the cytokine profile may be affected during post-COVID-19 conditions. The cytokine profiles of the donor groups changed depending on the titers of anti-SARS-CoV-2 IgG. The obtained results testify to the fact that the antibody subpopulation may be a key reason for immune dysfunction, influencing the development of other pathological processes.

Introduction: Controlling pulmonary Mycobacterium avium complex (MAC) disease is difficult because there is no way to know the clinical stage accurately. There have been few attempts to use cell-mediated immunity for diagnosing the stage. The objective of this study was to characterize cytokine profiles of CD4+T and CD19+B cells that recognize various Mycobacterium avium-associated antigens in different clinical stages of MAC. Methods: A total of 47 MAC patients at different stages based on clinical information (14 before-treatment, 16 on-treatment, and 17 after-treatment) and 17 healthy controls were recruited. Peripheral blood mononuclear cells were cultured with specific antigens (MAV0968, 1160, 1276, and 4925), and the cytokine profiles (IFN-γ, TNF-α, IL-2, IL-10, IL-13, and IL-17) of CD4+/CD3+ and CD19+ cells were analyzed by flow cytometry. Results: The response of Th1 cytokines such as IFN-g and TNF-a against various antigens was significantly higher in both the on-treatment and after-treatment groups than in the before-treatment group and control (P < 0.01-0.0001 and P < 0.05-0.0001). An analysis of polyfunctional T cells suggested that the presence of IL-2 is closely related to the stage after the start of treatment (P = 0.0309-P < 0.0001) and is involved in memory function. Non-Th1 cytokines, such as IL-10 and IL-17, showed significantly higher responses in the before-treatment group (P < 0.0001 and P < 0.01-0.0001). These responses were not observed with purified protein derivative (PPD). CD19+B cells showed a response similar to that of CD4+T cells. Conclusion: There is a characteristic cytokine profile at each clinical stage of MAC. [ABSTRACT FROM AUTHOR]

Post-COVID-19 conditions are the subject of extensive scientific study. It is known that system disorders may persist in people who recover from COVID-19 for 3 to 12 months (in most cases). The first line of systemic disorders is dysfunction of the immune system, especially the cytokine profile. The mechanism of the launch of immune complications is currently unknown. We hypothesized that anti-SARS-CoV-2 IgG might trigger the development of post-COVID-19 complications. Our research aimed to study the cytokine profile (including IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12ß, TNF-a, IFN-γ) and the transcription factor NF-kB in the blood plasma of donor groups depending on various titers of anti-SARS-CoV-2 IgG. We determined the qualitative values of the cytokine parameters using ELISA (Enzyme Linked Immunosorbent Assay). We estimated the changes in the cytokine profiles in all donor groups. Differences between donor groups were established for each research parameter. We detected changes in NF-κB levels as a key transcription factor for the expression of inflammatory cytokines. The highest level was found in the donor group with a titer of anti-SARS-CoV-2 IgG 75±5 Index (S/C). We detected some differences between donor groups in the levels of pro-inflammatory cytokines compared to a reference point. IL-1ß, IL-6, IL-8, INF-γ, and TNF-a levels changed in most donor groups with titers of anti-SARS-CoV-2 IgG = 10±3 Index (S/C). In addition, we showed that the decrease in anti-inflammatory cytokine IL-4 in donor groups ranged from the titer of anti-SARS-CoV-2 IgG 55±5 Index (S/C) to 85±5 Index (S/C), but these changes for the anti-inflammatory cytokine IL-10 were not detected. We found that the cytokine profile may be affected during post-COVID-19 conditions. The cytokine profiles of the donor groups changed depending on the titers of anti-SARS-CoV-2 IgG. The obtained results testify to the fact that the antibody subpopulation may be a key reason for immune dysfunction, influencing the development of other pathological processes. [ABSTRACT FROM AUTHOR]

Disease-modifying therapies (DMTs) impact the cellular immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (pwMS). In this study, we aim to elucidate the characteristics of the involved antigen-specific T cells via the measurement of broad cytokine profiles in pwMS on various DMTs. We examined SARS-CoV-2-specific T cell responses in whole blood cultures characterized by the release of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, IL-17A, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), as well as antibodies (AB) targeting the SARS-CoV-2 spike protein in pwMS following either two or three doses of mRNA or viral vector vaccines (VVV). For mRNA vaccination non-responders, the NVX-CoV2373 protein-based vaccine was administered, and immune responses were evaluated. Our findings indicate that immune responses to SARS-CoV-2 vaccines in pwMS are skewed towards a Th1 phenotype, characterized by IL-2 and IFN-γ. Additionally, a Th2 response characterized by IL-5, and to a lesser extent IL-4, IL-10, and IL-13, is observed. Therefore, the measurement of IL-2 and IL-5 levels could complement traditional IFN-γ assays to more comprehensively characterize the cellular responses to SARS-CoV-2 vaccines. Our results provide a comprehensive cytokine profile for pwMS receiving different DMTs and offer valuable insights for designing vaccination strategies in this patient population.

Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, abnormalities of the cytokine profiles are deeply involved in its pathophysiology. Therefore, an approach focused on the cytokine profile of individual patients with UC is ideal. Recent studies have demonstrated that molecular analysis of cytokine profiles in UC can predict response to each advanced therapy. This narrative review summarizes the molecules involved in the efficacy of various advanced therapies for UC. Understanding these associations may be helpful in selecting optimal therapeutic agents.

Abstract The β2AR is a prototypical G protein‐coupled receptor (GPCR) known to orchestrate different cellular responses by the stimulation of specific signaling pathways. The best‐established signaling pathways for the β2AR are the canonical Gs pathway and the alternative β arrestin 2 (βarr2) pathway. Exploring each pathway separately remains a challenging task due to the dynamic nature of the receptor. Here, we fused the β2AR with its cognate transducers, Gαs and βarr2, using short linkers as a novel approach for restricting the conformation of the receptor and preferentially activating one of its two signaling pathways. We characterized the behavior of our fusion proteins β2AR‐Gαs and β2AR‐βarr2 in HEK293 cells by measuring their constitutive activity, transducer recruitment, and pharmacological modulation. Our fusion proteins show (a) steric hindrance from the reciprocal endogenous transducers, (b) constitutive activity of the β2AR for the signaling pathway activated by the tethered transducer, and (c) pharmacologic modulation by β2AR ligands. Based on these characteristics, we further explored the possibility of a gain‐of‐function mechanism in the human lung non‐tumorigenic epithelial cell line, BEAS‐2B cells. This immortalized human bronchial epithelial cell line has immunomodulatory properties through cytokine release mediated by β2AR stimulation. Our findings suggest that each signaling pathway of the β2AR is biased toward either the Th1 or Th2 inflammatory response suggesting a role in regulating the immune phenotype of respiratory diseases. Our data imply that our fusion proteins can be used as tools to isolate the function elicited by a single signaling pathway in physiologically relevant cell types.

Abstract Background The risk of hypertensive disorders of pregnancy (HDP) varies in women with gestational diabetes mellitus (GDM), depending on the degree of insulin resistance and is also influenced by obesity. The aim of this study was to evaluate clinical features, blood pressure (BP) profiles and inflammatory markers, to identify patients with an elevated risk of developing HDP. Methods A total of 146 normotensive pregnant women were studied. We analysed the relationships of BP profiles detected by ambulatory blood pressure monitoring (ABPM) with serum biomarkers and angiogenic factors and their association with the development of HDP. Results Fourteen (9.6%) women developed HDP, of which 11 had GDM and 8 had obesity. Women with HDP had higher values of 24-h and daytime systolic/diastolic BP (113/69 vs. 104/64; 115/72 vs. 106/66 mmHg, respectively; p

The pandemic caused by a new strain of the SARS-CoV-2 coronavirus has swept the whole world but effective methods for treating this severe pathology have not yet been created. It has now been established that a risk of a severe course of COVID-19 is not so much a patient's age itself, but so-called age-related diseases; the renin-angiotensin system (RAS) is directly or indirectly involved into their development. The SARS-CoV-19 virus interacts with one of the main regulatory elements of this system, ACE2, and disrupts the balance between the two RAS branches. This ultimately manifests itself in an increase in levels of angiotensin II, which, through binding to the angiotensin type 1 receptor (AT1R), causes a number of pathological conditions, including hypertension, atherosclerosis, and cardiovascular diseases, enhances cell proliferation, apoptosis, death of vascular endothelial cells, etc. This process has been described in many reviews by Russian and foreign authors. However, cells of innate and adaptive immunity are another less well-described but no less important target of angiotensin II. The consequences of this interaction are analyzed in detail in this review. With COVID-19, dendritic cells are activated, macrophage proliferation and neutrophil infiltration increase with further involvement of CD4-lymphocytes and other cellular elements of the adaptive immunity in this process. Hyperactivation of the immune system is accompanied with the release of a large amount of pro-inflammatory cytokines, which can lead to the occurrence of a cytokine storm. The picture is aggravated by the inhibitory effect produced by the virus itself on the synthesis of signaling interferons at initial stages in its internalization into the cell. A separate section in the review ad-dresses the problem how to predict a risk of a developing serious condition and search for its predictors by analyzing the state of the RAS and ratios of key cellular elements in the immune system. This is extremely important for making decisions concerning the amount of necessary medical care and strategies for subsequent treatment.

Abstract Background A crucial role for the immune system has been proposed in the establishment and progression of head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the cytokine and regulatory profiles of T cells in tumor draining lymph nodes (TDLNs) of patients with HNSCC. Results The frequencies of CD4+TNF-α+ and CD4+TNF-αhi negatively were associated with poor prognostic factors such as LN involvement (P = 0.015 and P = 0.019, respectively), stage of the disease (P = 0.032 and P = 0.010, respectively) and tumor size (P = 0.026 and P = 0.032, respectively). Frequencies of CD8+IFN-γ+ and CD8+IFN-γ+ TNF-α+ T cells showed negative relationship with tumor grade (P = 0.035 and P = 0.043, respectively). While, the frequencies of CD4+IL-4+, CD8+IL-10+, CD8+IL-4+T cells were higher in advanced stages of the disease (P = 0.042, P = 0.041 and P = 0.030, respectively) and CD4+IFN-γ+TNF-α−, CD8+IL-4+ and CD8+IFN-γ+TNF-α− T cells were higher in patients with larger tumor size (P = 0.026 and P = 0.032, respectively). Negative associations were found between the frequencies of CD4+CD25+Foxp3+ and CD4+CD25+Foxp3+CD127low/− Treg cells and cancer stage (P = 0.015 and P = 0.059). Conclusion This study shed more lights on the changes in immune profile of T cells in TDLNs of HNSCC. Larger tumor size and/or LN involvement were associated with lower frequencies of CD4+TNF-α+, CD8+IFN-γ+ and CD8+IFN-γ+TNF-α+ but higher frequency of CD4+IL-4+ T cells. Moreover, Foxp3+Tregs correlated with good prognostic indicators.

Abstract Background Lymphomatoid papulosis (LyP) is a rare condition in pediatrics; LyP histological type D has been reported in only 7 children. The differential diagnosis of LyP in the spectrum of lymphoid proliferation remains controversial. Case presentation A 6-year-old boy presented to Emergency Department with a 3-week history of an erythematous papulo-vesicular itchy eruption over the submandibular regions, trunk and extremities. History, symptoms and laboratory tests were unremarkable. SARS-CoV-2 antigen was negative. The clinical suspicion of pityriasis lichenoides et varioliformis acuta (PLEVA) was posed, and topical steroids were introduced. One week after, he returned with an extensive painful scaly papulo-erythematous rash, with some ulcerated and necrotic lesions, and fever; therefore the child was hospitalized. Biochemical results were within reference limits, except for high level of C-reactive protein, aspartate aminotransferase, alanine transaminase and bilirubin. Due to a persistently high fever, systemic corticosteroid treatment was administered, with a good clinical response and an improvement of the skin lesions. Anti-PVB-19 Immunoglobulin M was detected. Elevated levels of IL-6, IL-10 and IFN-γ were also recorded. Five days post-admission, most of the lesions had cleared, and the child was discharged. Methotrexate was started, with a positive response. At skin biopsy a “PLEVA-like” pattern was apparent, with a dense, wedge shaped lymphoid infiltrate featuring epidermotropism and morphologically comprising pleomorphic and blastic cells. The pattern of infiltration was highlighted by immunohistochemical stains, which prove the process to feature a CD8+/CD30 + phenotype, the latter being intense on larger cells, with antigenic loss. Polymerase chain reaction for T-cell receptor gamma (TCRG) chain clonality assessment documented a monoclonal peak. A diagnosis of LyP type D was favored. Conclusion The reported case encompasses most of the critical features of two separated entities—PLEVA and LyP—thus providing further support to the concept of them representing declinations within a sole spectrum of disease. Studying the role of infectious agents as trigger potential in lymphoproliferative cutaneous disorders and detecting novel markers of disease, such as cytokines, could have a crucial impact on pathogenic disease mechanisms and perspective therapies.

BackgroundInflammaging is a phenomenon that has been associated with the development and progression of sarcopenia and frailty syndrome. According to the literature, on the one side, the increase in body fat is associated with a systemic pro-inflammatory status, which consequently favors inflammaging, and on the other side, the regular practice of physical exercise can mitigate the development of this scenario. Therefore, here, we aimed to evaluate the association between inflammaging and physical factors, both body and functional, in a group of physically active older women.MethodsSeventy older women (mean age 72.66 ± 6.17 years) participated in this observational cross-sectional and were separated into the eutrophic, overweight, and obese groups. It was assessed: by bioimpedance—body fat percentage (Fat%) and total (Fat kg), skeletal muscle mass (muscle), and free fat mass both in percentage (FFM%) and total (FFMkg); by the International Physical Activity Questionnaire (IPAQ)—the time of moderate-intensity physical activity per week; by physical tests—handgrip (HG), sit-up-stand-on-the-chair in 5 repetitions (Sit-up) and vertical squat jump test (SJ); in addition to the determination of serum cytokine concentration (IL-6, TNF-α, IL-10, and IL-8), and also body mass index (BMI) and calf circumference (Calf).ResultsHigher FFM% and lower body fat (both kg and %) were found in the eutrophic group than in the other groups. The eutrophic group also performed more weekly physical activity, jumped higher, and presented not only higher serum IL-6 concentration but also an increased ratio of IL-10/IL-6, IL-10/TNF-α, IL-10/IL-8 as compared to the values found in the overweight group. The obese group presented higher body fat (kg and %) and lower FFM% than the other groups and also higher serum IL-6 concentration than the overweight group. Interestingly, several significant negative and positive correlations between body composition, physical tests, and serum cytokine concentrations were found in the eutrophic and obese groups.ConclusionWhile the eutrophic older women group showed a remarkable regulation of the systemic inflammatory status with positive associations in the physical parameters assessed, the overweight and obese groups presented impairment regulations of the inflammaging, which could be related to less weekly physical activity and higher body fat.

COVID-19-related acute respiratory distress syndrome (CARDS) is associated with high mortality rates. We still have limited knowledge of the complex alterations developing in the lung microenvironment. The goal of the present study was to comprehensively analyze the cellular components, inflammatory signature, and respiratory pathogens in bronchoalveolar lavage (BAL) of CARDS patients (16) in comparison to those of other invasively mechanically ventilated patients (24). In CARDS patients, BAL analysis revealed: SARS-CoV-2 infection frequently associated with other respiratory pathogens, significantly higher neutrophil granulocyte percentage, remarkably low interferon-gamma expression, and high levels of interleukins (IL)-1β and IL-9. The most important predictive variables for worse outcomes were age, IL-18 expression, and BAL neutrophilia. To the best of our knowledge, this is the first study that was able to identify, through a comprehensive analysis of BAL, several aspects relevant to the complex pathophysiology of CARDS. [ABSTRACT FROM AUTHOR]

Endometrial receptivity (ER) is a key factor required for the successful implantation of the embryo. However, the evaluation of ER is challenging, as a nondisruptive sampling of endometrial biomaterial by conventional methods is only possible outside of the embryo transfer (ET) cycle. We propose a novel approach for the assessment of ER—microbiological and cytokine profiling of menstrual blood aspirated directly from the uterine cavity at the beginning of the cryo-ET cycle. The aim of the pilot study was to evaluate its prognostic potential regarding the outcome of the in vitro fertilization procedure. Samples collected from a cohort of 42 patients undergoing cryo-ET were analyzed by a multiplex immunoassay (48 various cytokines, chemokines, and growth factors) and a real-time PCR assay (28 relevant microbial taxa and 3 members of the Herpesviridae family). Significant differences between groups of patients who achieved and did not achieve pregnancy were observed for G-CSF, GRO-α, IL-6, IL-9, MCP-1, M-CSF, SDF-1α, TNF-β, TRAIL, SCF, IP-10, and MIG (p < 0.05), whereas microbial profiles were not associated with the outcome of cryo-ET. It appeared that levels of IP-10 and SCGF-β were significantly lower (p < 0.05), in patients with endometriosis. Menstrual blood may provide great opportunities to noninvasively investigate various parameters of the endometrium. [ABSTRACT FROM AUTHOR]

Pregnancy-specific beta-1-glycoprotein (PSG) is a protein with pleiotropic biological effects, particularly immunoregulatory and immunosuppressive potential. The use of recombinant PSG may exert therapeutic effects in experimental animals with induced autoimmune diseases. Recently, a search for the biological effects of short linear motifs (SLiMs) has become a new strategy for designing the pharmacological compounds. Tetrapeptide regions have been identified in the primary structure of several PSGs: YQCE, YECE and YACS, these SLiMs exhibit immunomodulatory activity. The aim of our study was to evaluate the prospectives for usage of PSG peptide fragments as pharmacological agents to modulate transplant immunity. We used an original model of host-versus-graft response in male Wistar rats transplanted with bone marrow, without prior conditioning treatment of recipients. We used a cocktail of the PSG peptide fragments administered to Wistar rats in the course of allogeneic bone marrow transplantation (BM) in dynamic manner, evaluating the cytokine profile as an integral index of immune response. Cytokine levels were determined by multiplex method using Bio-Plex ProTM Rat 23-Plex kit. Statistical processing of the data was performed by means of two-way analysis of variance and Tukey’s post hoc test for multiple comparisons. We have found that the levels of pro-inflammatory cytokines (IFNγ, IL-1α, IL-1β, IL-18), as well as the contents of G-CSF, GM-CSF and IL-7 were increased in the animals injected with BM only. In the group of animals injected with BM + PSG peptides, an increase in IFNγ, IL-6, TNFα was observed, which decreased by the end of the experiment. Increased levels of antiinflammatory cytokines IL-4 and IL-13 were detected in blood serum of the animals on day +14. Moreover, administration of PSG peptides also led to increase in IL-2, M-CSF, MCP-1, and RANTES levels on day 14 from the beginning of the experiment, and to a gradual decrease in their levels till the end of the experiment. Meanwhile, control group showed a marked tendency for increase of these and other cytokines. Thus, it was shown that the use of PSG peptides upon development of immune response to BM allograft may promote a return to normal levels for the most cytokines studied, thus presuming the immunopharmacological potential of these peptides. The obtained data can be used to develop a pharmacological preparation of the studied peptides to correct the imbalance of immune system.

Abstract Background Asthma is significantly related to chronic rhinosinusitis (CRS) both in prevalence and severity. However, the clinical patterns of uncontrolled asthma with and without comorbid CRS are still unclear. This study aimed to explore the clinical characteristics and cytokine patterns of patients with uncontrolled asthma, with and without comorbid CRS. Methods 22 parameters associated with demographic characteristics, CRS comorbidity, severity of airflow obstruction and airway inflammation, and inflammation type of asthma were collected and assessed in 143 patients with uncontrolled asthma. Different clusters were explored using two-step cluster analysis. Sputum samples were collected for assessment of Th1/Th2/Th17 and epithelium-derived cytokines. Results Comorbid CRS was identified as the most important variable for prediction of different clusters, followed by pulmonary function parameters and blood eosinophil level. Three clusters of patients were determined: Cluster 1 (n = 46) characterized by non-atopic patients with non-eosinophilic asthma without CRS, demonstrating moderate airflow limitation; Cluster 2 (n = 54) characterized by asthma patients with mild airflow limitation and CRS, demonstrating higher levels of blood eosinophils and immunoglobulin E (IgE) than cluster 1; Cluster 3 (n = 43) characterized by eosinophilic asthma patients with severe airflow limitation and CRS (46.5% with nasal polyps), demonstrating worst lung function, lowest partial pressure of oxygen (PaO2), and highest levels of eosinophils, fraction of exhaled nitric oxide (FeNO) and IgE. Sputum samples from Cluster 3 showed significantly higher levels of Interleukin (IL)-5, IL-13, IL-33, and tumor necrosis factor (TNF)-α than the other two clusters; and remarkably elevated IL-4, IL-17 and interferon (IFN)-γ compared with cluster 2. The levels of IL-10 and IL-25 were not significantly different among the three clusters. Conclusions Uncontrolled asthma may be endotyped into three clusters characterized by CRS comorbidity and inflammatory cytokine patterns. Furthermore, a united-airways approach may be especially necessary for management of asthma patients with Type 2 features.