CXCL10 Concentrations Research Articles

CCR8/CCL1 and CXCR3/CXCL10 axis mediated memory T cell activations in recalcitrant drug-induced hypersensitivity patients.

As a drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) is potentially fatal. Most patients with DRESS recover within a few weeks; however, some patients may suffer from a prolonged disease course and develop autoimmune sequelae. We investigated the immune mechanism and therapeutic targets of patients with recalcitrant DRESS with a prolonged disease course. A total of 32 patients with recalcitrant DRESS with a prolonged treatment course ≥8 weeks, 28 patients with short-duration DRESS with a treatment course <2 weeks, and 26 healthy individuals were enrolled in the study for analysis. Bulk transcriptome results demonstrated that mRNA expression levels of CCR8 and CXCR3 were significantly increased in the blood samples from patients in the acute stage of prolonged DRESS (adjusted p-values: CCR8=1.50×10-9 and CXCR3=2.60×10-4, respectively, for comparison of patients with prolonged DRESS to the healthy donor group). Serum and skin lesional concentrations of CCL1 and CXCL10, as the ligands of CCR8 and CXCR3, respectively, were significantly elevated in patients with prolonged DRESS as compared to those patients with short-duration DRESS. The results from high-parameter flow cytometry and autoantibody screening also identified significant escalations of CD8+ GNLY+CXCR3+effector memory T cells, CD8+central memory T cells, CD4+CCR8+Th2 cells, and IgG-anti-HES6 autoantibodies in patients with prolonged DRESS. Furthermore, in vitro blocking assays revealed that JAK inhibitors (mainly tofacitinib and upadacitinib) significantly decreased the release of CCL1 and CXCL10, and some patients with prolonged DRESS were successfully treated with JAK inhibitors. JAK inhibitors (tofacitinib and upadacitinib) were associated with decreased concentrations of CCL1 and CXCL10, suggesting that they may attenuate CCR8/CCL1- and CXCR3/CXCL10-axis-mediated memory T cell activation, which contribute to disease pathogenesis for patients with recalcitrant DRESS and a long-term treatment course.

Impact of CCR5Δ32 on the risk of infection, Staphylococcus aureus carriage, and plasma concentrations of chemokines in Danish blood donors

The CC chemokine receptor 5 (CCR5) is a suggested receptor for Staphylococcus aureus leukotoxin ED. Homozygosity for the Δ32 deletion (CCR5Δ32) protects against human immunodeficiency virus infection and possibly also against leukotoxin ED. We examined the impact of CCR5Δ32 on the susceptibility to S.aureus infection, all-cause infections, and S.aureus nasal carriage, respectively, and on the concentrations of circulating chemokines in blood donors. We included 95,406 participants from the Danish Blood Donor Study (DBDS) genotyped for >650,000 single nucleotide polymorphisms. The CCR5Δ32 (rs333, MAF: 0.12) was imputed from a reference panel and validated. Infectious outcomes were identified by diagnosis codes and redeemed prescription of antibiotics in national health registers. Data on S.aureus nasal carriage and forty-seven inflammatory biomarkers were available for 6721 and 7811 participants, respectively. Cox, logistic, and linear regression models adjusted for relevant confounders were used to explore said associations. During more than 700,000 person-years of observation, we found that CCR5Δ32 was associated with neither an increased risk of redeemed dicloxacillin, hospital-treated S.aureus-associated infection (replicated in 345,996 Icelanders), redeemed antibiotics, all-cause infection, and nor with S.aureus nasal carriage. We discovered an association between CCR5Δ32 and elevated CCL4 concentrations, which were 1.26-fold higher in Δ32-heterozygotes (95%-CI: 1.23-1.30) and 2.64-fold higher in Δ32-homozygotes (95%-CI: 2.41-2.90) compared with wildtype homozygotes. Conversely, concentrations of CCL2, CXCL-10, and CCL11 were slightly lower among Δ32-heterozygotes. Results from this CCR5Δ32 high-prevalent cohort do not support the idea that CCR5Δ32 affects the risk of S.aureus carriage or infection to any relevant degree, in this northern European context. CCL4 was the main chemokine affected by CCR5Δ32 and was observed in higher concentration among Δ32-carriers. This study cannot rule out that S.aureus is a previous driver of CCR5Δ32 selection. The Health Research Fund of Central Denmark Region, Aarhus University, Danish Administrative Regions, Bio- and Genome Bank Denmark, Danish Blood Donor Research Foundation, Aase & Ejnar Danielsens Foundation, Højmosegård Grant, National Institute of Allergy and Infectious Diseases, and A.P. Møller Foundation for the Advancement of Medical Science.

Interferon-gamma driven elevation of CXCL9: a new sepsis endotype independently associated with mortality

Endotype classification becomes the cornerstone of understanding sepsis pathogenesis. Macrophage activation-like syndrome (MALS) and immunoparalysis are the best recognized major endotypes, so far. Interferon-gamma (IFNγ) action on tissue macrophages stimulates the release of the cytotoxic chemokine CXCL9. It was investigated if this mechanism may be an independent sepsis endotype. In this cohort study, 14 patient cohorts from Greece, Germany and Italy were studied. The cohorts were 2:1 randomly split into discovery and validation sets. Sepsis was defined by the Sepsis-3 definitions and blood was sampled the first 24h from meeting the Sepsis-3 definitions. Concentrations of IFNγ, CXCL9, IP-10 (IFNγ induced protein-10), soluble CD163 and ferritin were measured. The endotype of IFNγ-driven sepsis (IDS) was defined in the discovery set as the combination of a) blood IFNγ above a specified cut-off associated with the minimal risk for immunoparalysis (defined as ≥8000 HLA-DR receptors on CD45/CD14-monoytes); and b) increase of CXCL9. Results were compared to the validation set. 5503 patients were studied; 3670 in the discovery set and 1833 in the validation set. IDS was defined as IFNγ more than 3pg/ml and CXCL9 more than 2200pg/ml. The frequency of IDS in the discovery set was 19.9% (732 patients; 95% confidence intervals-CIs 18.7-21.3%) and in the validation set 20.0% (366 patients; 95% CIs 18.2-21.9%). Soluble CD163, a marker of macrophage activation, was greater in IDS and IDS had features distinct from MALS. The mortality in IDS patients was 43.0% (315 patients; 95% CIs 39.5-46.6%) in the discovery set and 40.4% in the validation set (148 patients; 95% CIs 35.5-45.5%) (p=0.44 compared to patients of the discovery set). IDS was an independent risk factor for death in the presence of other endotypes, severity scores and organ dysfunctions of the multivariate model [hazard ratio 1.71 (95% CIs 1.45-2.01) in the discovery set and 1.70 (95% CIs 1.34-2.16) in the validation set]. Decreases of IFNγ and CXCL9 blood levels within the first 72h were associated with better outcome. IDS is a new sepsis endotype independently associated with unfavorable outcome. Hellenic Institute for the Study of Sepsis; Horizon 2020 project ImmunoSep; Swedish Orphan BioVitrum AB (publ) and German Federal Ministry of Education and Research.

Nasal Mucosal Cytokines as Potential Biomarkers for Assessing Disease Severity and Class of Pathogen in Children with Community-Acquired Pneumonia.

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality in children. Assessing disease severity and etiology remains challenging in the clinical setting. The objective of this study was to identify mucosal biomarkers that could potentially assist with patient classification. We analyzed mucosal concentrations of cytokines in nasopharyngeal samples obtained from a convenience sample of 182 children with CAP and 26 matched healthy controls. Pathogens were identified by cultures and molecular assays. Severe disease was defined by hospital stay ≥ 3 days, and/or PICU admission. Data were analyzed according to identified pathogens and disease severity. Children with CAP and detected atypical bacteria had significantly higher concentrations of MCP-2, IFN-γ and CXCL10 among others compared with those with typical bacteria. Children with influenza virus had significantly higher concentrations of MCP-2, CXCL10, CXCL11, CX3CL1, and IFN-γ than those with typical bacteria. Additionally, children with severe CAP had significantly higher concentrations of CCL23 than children with mild/moderate disease, irrespective of the pathogen(s) identified. We identified differences in mucosal concentrations of inflammatory and antiviral cytokines in children with CAP according to disease severity and detected pathogens. Mucosal biomarkers represent a promising approach to help assessing disease severity and etiology.

Diagnoses Bacterial Wound Infection and Detection of Some Immune Parameters in its

This study aims to diagnoses bacterial wound infection and to estimate the serum levels of TLR-3, CXCL8, TGF-β1, IL-8, IL-17 and IL-22 in wound patients. This study had been included 140 samples (blood and swab) obtained from patients found in Baquba-Teaching Hospital from 15/ 6 /2023 to 20 /3 /2024. Swab samples taken from wound were culture on the blood agar and MacConkey agar, and then Bacteria diagnoses was done by using an automatic VITEK 2 system. The serum levels of immune parameters done by ELISA. The results shown that sixty isolates were grow in culture, the results indicated of 38(63.3%) isolates of gram-negative bacteria, represented by: 12 (20%) isolates E. coli, 18 (30%) Pseudomonas aeruginosa, 6 (10%) Protus spp., 2 (3.3%) Acinetobacter spp. the results indicated of 22 (36.6%) isolates of gram-positive bacteria, represented by: 16 (26.6%) isolates Staphylococcus aureus, 4 (6.6 %) another Staphylococcus spp., 2 (3.3%) Enterococcus spp. The study also shown the a increase in the concentration of TLR-3 , CXCL8 , IL-2 , IL-17 and IL-22 in the serum of bacterial patients compared with the healthy, Where the results of the current study show decreases in the concentration of TGF-β1 among compared with healthy. In conclusion, it was discovered that the infection of bacteria in wound infection was lower in females than males. Pseudomonas aeruginosa and S. aureus were found to be the highly isolated bacteria wound infection, with increases levels of TLR-3, CXCL8, IL-17 and IL-22 in serum in patients and decreases level of TGF-β1 in serum of patients.

Endocrine immune-related adverse events by immune checkpoint inhibitors and potential predictive markers: a prospective study from a single tertiary center.

Immune checkpoint inhibitors (ICIs) can trigger immune-related adverse events (irAEs). The appearance pattern of irAEs, who is prone to them, and their mechanisms are still uncertain. In this study, we aimed to monitor patients initiated on ICIs for endocrinological aspects and to investigate the potential predictive markers in the development of endocrine-irAEs. The study prospectively included 43 patients with metastatic disease scheduled for anti-PD-1/L1 therapy. Endocrinological follow-up was conducted at specified intervals as well as in response to any additional reported complaints. Serum concentrations of CXCL10, IL-1beta, and IL-17A were measured prior to ICI and during the endocrine-irAEs. A total of 39.5% of the patients experienced endocrine-irAEs, with a median onset time of 3 months. Among patients, 34.9% developed thyroid-related adverse events, and 4.6% experienced hypophysitis. Thyroid autoantibodies were associated with a higher incidence of thyroid-related irAEs (P = 0.004). In the irAE group, median pre-ICI CXCL10 and baseline thyroid stimulating hormone (TSH) levels were significantly higher, baseline total testosterone level in men was lower than in the non-irAE group (P < 0.05), whereas IL-1beta and IL-17A levels did not differ (P > 0.05). Serum CXCL10, IL-1beta, and IL-17A concentrations did not differ significantly pre-ICI and during adverse events (P > 0.05). Pre-ICI CXCL10 concentration was correlated positively with anti-TPO levels in patients with at least one thyroid autoantibody positivity (r = 0.706, P = 0.01) and negatively with baseline total testosterone level of men (r = 0.509, P = 0.002). Our results suggest that higher pre-ICI serum CXCL10 and TSH levels might have a predictive role in the development of endocrinopathies. Besides, baseline thyroid antibody measurements could be beneficial in predicting thyroid dysfunction.

Prognostic and therapeutic monitoring value of plasma and urinary cytokine profile in primary membranous nephropathy: the STARMEN trial cohort

Abstract Background and hypothesis Primary membranous nephropathy (PMN) is usually caused by anti-PLA2R autoantibodies. There are different therapeutic options according to baseline risk. Novel biomarkers are needed to optimize risk stratification, and predict and monitor the response to therapy, as proteinuria responses may be delayed. We hypothesized that plasma or urinary cytokines may provide insight into the course and response to therapy in PMN. Methods Overall, 192 data-points from 34 participants in the STARMEN trial, randomized to tacrolimus-rituximab (TAC-RTX) or corticosteroids-cyclophosphamide (GC-CYC), were analyzed for plasma and urine cytokines using a highly sensitive chemiluminescence immunoassay providing a high-throughput multiplex analysis. Results Baseline (pretreatment) urinary CXCL13 predicted the therapeutic response to TAC-RTX. Cytokine levels evolved over the course of therapy. The levels of nine plasma and six urinary cytokines correlated with analytical parameters of kidney damage and disease activity, such as proteinuria, eGFR and circulating anti-PLA2R levels. The correlation with these parameters was most consistent for plasma and urinary GDF15, plasma TNF-α and urinary TWEAK. Decreasing plasma GDF15 levels were associated to response to GC-CYC. Four clusters of cytokines were associated to different stages of response to therapy in the full cohort, with the less inflammatory cluster associated to remission. Conclusion In conclusion, PMN displayed characteristic plasma and urine cytokine patterns that evolved over time as patients responded to therapy. Baseline urinary CXCL13 concentration could be a prognostic marker of response to TAC-RTX.

Mediators of monocyte chemotaxis and matrix remodeling are associated with mortality and pulmonary fibroproliferation in patients with severe COVID-19.

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. Pulmonary fibrosis following COVID-19 pneumonia has been described at autopsy and following lung transplantation. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop features of pulmonary fibroproliferation. We enrolled COVID-19 patients admitted to the ICU with hypoxemic respiratory failure. (n = 195). Plasma was collected within 24h of ICU admission and at 7d. In mechanically ventilated patients, endotracheal aspirates (ETA) were collected. Protein concentrations were measured by immunoassay. We tested for associations between protein concentrations and respiratory outcomes using logistic regression adjusting for age, sex, treatment with steroids, and APACHE III score. In a subset of patients who had CT scans during hospitalization (n = 75), we tested for associations between protein concentrations and radiographic features of fibroproliferation. Among the entire cohort, plasma IL-6, TNF-α, CCL2, and Amphiregulin levels were significantly associated with in-hospital mortality. In addition, higher plasma concentrations of CCL2, IL-6, TNF-α, Amphiregulin, and CXCL12 were associated with fewer ventilator-free days. We identified 20/75 patients (26%) with features of fibroproliferation. Within 24h of ICU admission, no measured plasma proteins were associated with a fibroproliferative response. However, when measured 96h-128h after admission, Amphiregulin was elevated in those that developed fibroproliferation. ETAs were not correlated with plasma measurements and did not show any association with mortality, ventilator-free days (VFDs), or fibroproliferative response. This cohort study identifies proteins of tissue remodeling and monocyte recruitment are associated with in-hospital mortality, fewer VFDs, and radiographic fibroproliferative response. Measuring changes in these proteins over time may allow for early identification of patients with severe COVID-19 at risk for fibroproliferation.

Comprehensive analysis of CXCL10 and MIP-3a reveals their potential clinical application in hepatocellular carcinoma

Chemokines play a crucial role in the pathogenesis of patients with hepatocellular carcinoma (HCC). The expression levels of interferon-γ-induced protein-10 (CXCL10) and macrophage inflammatory protein-3α (MIP-3a) were investigated to clarify their clinical significance in HCC.The protein levels of CXCL10 and MIP-3a in the serum of 105 HBV-associated HCC patients, 50 patients with liver cirrhosis (LC), 50 patients with chronic hepatitis B (CHB) and 50 healthy donors (HC) were detected by liquid chip technology (Luminex) or ELISA. In addition, their mRNA levels were also determined in liver cancer and adjacent cancer tissue (paracancer; ParaCa) from 65 HCC patients. The online database UALCAN was used to analyze the association between CXCL10 and pathological manifestations of liver cancer. In addition, the diagnostic value of CXCL10/MIP-3a and AFP in HCC patients was determined by analyzing the Receiver Operating Characteristic Curve (ROC).The protein concentrations of CXCL10 and MIP-3a were significantly higher in the HCC group than in the LC, CHB and HC groups. CXCL10 in sera and liver cancer tissues is significantly positively correlated with ALT, but no significance between CXCL10 in ParaCa tissues and sera-ALT. Their mRNA is significantly higher in cancer tissues than in ParaCa tissues. The areas under the ROC curve of CXCL10, MIP-3a, CXCL10 and MIP-3a combined and AFP were 0.9169, 0.9261, 0.9299 and 0.7880, respectively. Elevated chemokines CXCL10 and MIP-3a in HCC patients may be associated with the clinical manifestation of HCC and could be a potential molecular marker for prognostic evaluation or a therapeutic target for HCC.

Prof Analysis of CXCL12 and S100A12 levels in peripheral blood and synovial fluid and their correlation with severity in patients with knee osteoarthritis

Abstract: To investigate the expression of CXCL12 and S100A12 in peripheral blood (PB) and synovial fluid (SF) of patients with knee osteoarthritis (OS) and to analyze the correlation between them and the severity of knee OS. 60 patients with kneeOS treated in our hospital from January 2020 to December 2022 were selected as the experimental group, and 60 healthy knee joints with similar age were selected as the control group. The fasting venous blood of 120 subjects was drawn in the early morning, and the SF was extracted during joint operation or sodium hyaluronate injection. Put the collected PB and SF in the refrigerator at-80℃. The levels of CXCL12 and S100A12 in PB and SF were detected by enzyme linked immunosorbent assay (Elisa). The correlation between the levels of CXCL12 and S100A12 in PB and SF and Kmurl L grade and WOMAC score. The levels of CXCL12 and S100A12 in PB and SF in the observation group were raised than those in the control group. There were significant differences in the levels of CXCL12 and S100A12 in PB and SF in the experimental group. The higher the Kmurl grade of knee OS, the higher the concentration of CXCL12 and S100A12 in PB and SF. The levels of CXCL12 and S100A12 in PB of knee OS were positively correlated with WOMAC score (r = 0.767, 0.521 respectively, P &lt; 0.05), see figure 1. The levels of CXCL12 and S100A12 in SF of knee OS were positively correlated with WOMAC score (r = 0.663, 0.357 respectively, P &lt; 0.05). The levels of CXCL12 and S100A12 in PB and SF are positively correlated with the severity of knee OS. The levels of CXCL12 and S100A12 in PB and SF can provide basis for the evaluation and prognosis of knee OS.

Serum Concentrations of Chemokines CCL20, CXCL8 and CXCL10 in Relapsing-Remitting Multiple Sclerosis and Their Association with Presence of Antibodies against Epstein-Barr Virus.

Epstein-Barr virus (EBV) infection and various chemokines, including CCL20, CXCL8 and CXCL10 are considered to participate in the pathogenesis of multiple sclerosis (MS), and several studies point to a direct regulatory effect of EBV on the expression of these chemokines. In our study we hypothesized that serum concentrations of CCL20, CXCL8 and CXCL0 are induced in patients with relapsing-remitting MS (RRMS) in comparison to healthy individuals, and that they are associated with EBV infection. Serum concentrations of CXCL8 and CXCL10 were lower in RRMS patients in relapse in comparison to healthy controls. Although potential effects of corticosteroid therapy introduced in a subgroup of RRMS patients prior to sampling were excluded by subgroup comparison, this possibility has to be considered while interpreting the results. We found an inverse association between serum concentrations of CXCL8 and anti-Epstein-Barr Virus Nuclear Antigen (EBNA) IgG and decreased expression of CXCL8 in peripheral blood mononuclear cells (PBMC) in relapse compared to remission. Lower serum concentrations of CXCL8 and CXCL10 in RRMS patients and decreased peripheral production of CXCL8 in relapse may indicate compensatory anti-inflammatory counter-regulation in MS.

Distinct inflammatory markers in primary and secondary dengue infection: can cytokines CXCL5, CXCL9, and CCL17 act as surrogate markers?

ABSTRACT Dengue fever poses a significant global health threat, with symptoms including dengue hemorrhagic fever and dengue shock syndrome. Each year, India experiences fatal dengue outbreaks with severe manifestations. The primary cause of severe inflammatory responses in dengue is a cytokine storm. Individuals with a secondary dengue infection of a different serotype face an increased risk of complications due to antibody-dependent enhancement. Therefore, it is crucial to identify potential risk factors and biomarkers for effective disease management. In the current study, we assessed the prevalence of dengue infection in and around Aligarh, India, and explored the role of cytokines, including CXCL5, CXCL9, and CCL17, in primary and secondary dengue infections, correlating them with various clinical indices. Among 1,500 suspected cases, 367 tested positive for dengue using Real-Time PCR and ELISA. In secondary dengue infections, the serum levels of CXCL5, CXCL9, and CCL17 were significantly higher than in primary infections (P < 0.05). Dengue virus (DENV)-2 showed the highest concentrations of CXCL5 and CCL17, whereas DENV-1 showed the highest concentrations of CXCL9. Early detection of these cytokines could serve as potential biomarkers for diagnosing severe dengue, and downregulation of these cytokines may prove beneficial for the treatment of severe dengue infections.

ACKR3 Antagonism Enhances the Repair of Demyelinated Lesions Through Both Immunomodulatory and Remyelinating Effects

Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored. This study assessed the therapeutic effect of ACT-1004-1239 in two demyelinating disease models. In the proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) model, ACT-1004-1239 administered upon the detection of the first signs of paralysis, resulted in a dose-dependent reduction in EAE disease severity, concomitant with diminished immune cell infiltrates in the CNS and reduced demyelination. Notably, efficacy correlated with elevated plasma concentrations of CXCL11 and CXCL12, two pharmacodynamic biomarkers of ACKR3 antagonism. Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. In the cuprizone-induced demyelination model, ACT-1004-1239 administered after 5 weeks of cuprizone exposure, significantly accelerated remyelination, already quantifiable one week after cuprizone withdrawal. Additionally, ACT-1004-1239 penetrated the CNS, elevating brain CXCL12 concentrations. These results demonstrate that ACKR3 antagonism significantly reduces the severity of experimental demyelinating diseases, even when treatment is initiated therapeutically, after the occurrence of lesions. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases.

Chemokines in diabetic eye disease

BackgroundDiabetic eye disease is a common micro-vascular complication of diabetes and a leading cause of decreased vision and blindness in people of working age worldwide.Although previous studies have shown that chemokines system may be a player in pathogenesis of diabetic eye disease, it is unclear which chemokines play the most important role.To date, there is no meta-analysis which has investigated the role of chemokines in diabetic eye disease.We hope this study will contribute to a better understanding of both the signaling pathways of the chemokines in the pathophysiological process, and more reliable therapeutic targets for diabetic eye disease.MethodsEmbase, PubMed, Web of Science and Cochrane Library systematically searched for relevant studies from inception to Sep 1, 2023. A random-effect model was used and standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated to summarize the associated measure between chemokines concentrations and diabetic eye disease. Network meta-analysis to rank chemokines-effect values according to ranked probabilities.ResultsA total of 33 different chemokines involving 11,465 subjects (6559 cases and 4906 controls) were included in the meta-analysis. Results of the meta-analysis showed that concentrations of CC and CXC chemokines in the diabetic eye disease patients were significantly higher than those in the controls. Moreover, network meta-analysis showed that the effect of CCL8, CCL2, CXCL8 and CXCL10 were ranked highest in terms of probabilities. Concentrations of CCL8, CCL2, CXCL8 and CXCL10 may be associated with diabetic eye disease, especially in diabetic retinopathy and diabetic macular edema.ConclusionOur study suggests that CCL2 and CXCL8 may play key roles in pathogenesis of diabetic eye disease. Future research should explore putative mechanisms underlying these links, with the commitment to develop novel prophylactic and therapeutic for diabetic eye disease.

Altered serum concentrations of IL-8, IL-32 and IL-10 in patients with lung impairment 6 months after COVID-19

Post-COVID symptoms are reported in 10–35 % of patients not requiring hospitalization, and in up to 80 % of hospitalized patients and patients with severe disease. The pathogenesis of post-COVID syndrome remains largely unknown. Some evidence suggests that prolonged inflammation has a key role in the pathogenesis of most post-COVID manifestations. We evaluated a panel of inflammatory and immune-mediated cytokines in individuals with altered HRCT features and in patients without any long-term COVID symptoms. Blood samples of 89 adult patients previously hospitalized with COVID-19 were collected and stratified as patients with and without HRCT evidence of fibrotic lung alterations. Serum analyte concentrations of IL-4, IL-2, CXCL10 (IP-10), IL-1β, TNF-α, CCL2 (MCP-1), IL-17A, IL-6, IL-10, IFN-γ, IL-12p70 and TGF-β1 (free active form) were quantified by bead-based multiplex assay. Clinical and functional data were recorded in a database.With the use of machine learning approach, IL-32, IL-8, and IL-10 proved to be associated with the development of HRCT evidence of lung sequelae at follow-up. Direct comparison of cytokine levels in the two groups showed increased levels of IL-32 and decreased levels of IL-8 in patients with lung impairment. After further stratification of patients by severity (severe versus mild/moderate) during hospitalization, IL-10 emerged as the only cytokine showing decreased levels in severe patients. These findings contribute to a better understanding of the immune response and potential prognostic markers in patients with lung sequelae after COVID-19.

Early cognitive dysfunction development immunological predictors in the ischemic stroke acute period

The purpose of the study is activity identification CXC family cytokines in patients with cognitive impairments in the acute period of ischemic stroke.Material and methods. 78 patients with diagnosis “Ischemic stroke” were examined. Depending on cognitive impairment (Montreal Cognitive Assessment (MoCA)) patients were divided into two groups: the 1st group — 58 patients with cognitive decline (MoCA ≤ 25 points); the 2nd group — 20 patients without cognitive decline. Neuropsychologic testing was performed on the second day of hospitalisation and included episodic memory, executive function, speech, gnosis, praxis and IQCODE parameters examination. Laboratory diagnosis consisted of level assessing of CXC family chemokines (CXCL10, CXCL11, CXCL9, CXCL1, CXCL8) and TNF-α cytokine in patients’ plasma on the second day of hospitalisation. Statistical analysis was employed using the Python programing language and its libraries Pandas and SciPy.Results. Statistical analysis revealed the highest level of IP-10/CXCL10 chemokines (p = 0.002) and Gro-a/CXCL1 (p = 0.044) in patients of the 1st group, statistically significant correlations of MoCA and IQCODE with IP-10/CXCL10 and Gro-a/CXCL1 concentrations, correlations of IP-10/CXCL10 concentrations with semantic information processing functions (r = –0.512), subject gnosis (r = –0.211), memory (r = 0.275), speech (r = –0.400), and Gro-a/ CXCL1 level with semantic information processing (r = –0.418).Conclusion. The study of chemokines of the CXC cluster represents a relevant and promising direction in the diagnosis and assessment of progression of early post-stroke cognitive impairment of mixed genesis due to minimal invasiveness and high specificity. Further studies are needed to verify CXCL chemokines, particularly IP-10/CXCL10 and Gro-a/CXCL1 as potential molecular markers of neurological damage in neurodegenerative and inflammatory diseases of the central nervous system.

Immune checkpoint inhibitors induce acute interstitial nephritis in mice with increased urinary MCP1 and PD-1 glomerular expression

IntroductionImmune checkpoint inhibitors (ICIs) induce acute interstitial nephritis (AIN) in 2–5% of patients, with a clearly higher incidence when they are combined with platinum derivatives. Unfortunately, suitable disease models and non-invasive biomarkers are lacking. To fill this gap in our understanding, we investigated the renal effects of cisplatin and anti-PD-L1 antibodies in mice, assessing PD-1 renal expression and cytokine levels in mice with AIN, and then we compared these findings with those in AIN-diagnosed cancer patients.MethodsTwenty C57BL6J mice received 200 µg of anti-PD-L1 antibody and 5 mg/kg cisplatin intraperitoneally and were compared with those receiving cisplatin (n = 6), anti-PD-L1 (n = 7), or saline (n = 6). After 7 days, the mice were euthanized. Serum and urinary concentrations of TNFα, CXCL10, IL-6, and MCP-1 were measured by Luminex. The kidney sections were stained to determine PD-1 tissue expression. Thirty-nine cancer patients with AKI were enrolled (AIN n = 33, acute tubular necrosis (ATN) n = 6), urine MCP-1 (uMCP-1) was measured, and kidney sections were stained to assess PD-1 expression.ResultsCisplatin and anti PD-L1 treatment led to 40% AIN development (p = 0.03) in mice, accompanied by elevated serum creatinine and uMCP1. AIN-diagnosed cancer patients also had higher uMCP1 levels than ATN-diagnosed patients, confirming our previous findings. Mice with AIN exhibited interstitial PD-1 staining and stronger glomerular PD-1 expression, especially with combination treatment. Conversely, human AIN patients only showed interstitial PD-1 positivity.ConclusionsOnly mice receiving cisplatin and anti-PDL1 concomitantly developed AIN, accompanied with a more severe kidney injury. AIN induced by this drug combination was linked to elevated uMCP1, consistently with human AIN, suggesting that uMCP1 can be potentially used as an AIN biomarker.

CXCL13 as a biomarker in the diagnostics of European lyme Neuroborreliosis - A prospective multicentre study in Austria.

'Definite Neuroborreliosis (NB)' is diagnosed with the presence of NB-specific symptoms, cerebrospinal fluid (CSF) pleocytosis and an elevated Borrelia Burgdorferi antibody index. However, some diagnostic uncertainties exist. The B-cell chemokine CXCL13 represents an emerging biomarker for the diagnosis and treatment of NB because its intrathecal concentration rises prior to the Borrelia antibody index and drops rapidly after antibiotic therapy. Nevertheless, due to lacking prospective data, a definite CXCL13 cut-off for the diagnosis of NB is still pending. Definition of a CSF CXCL13 cut-off for the diagnosis of acute and untreated NB in a prospective study setting. This multicentre prospective study involved 6 neurological departments treating patients in the Lower Austria district (1.7 million inhabitants). The controls were patients scheduled for a spinal tap but not clinically diagnosed with NB. Demographic data, clinical characteristics and blood counts, as well as inflammatory CSF values and CSF CXCL13-concentration were analysed. We recruited 440 adult patients, of whom 42 have been diagnosed as having an acute and untreated 'definite NB'. Three hundred ninety-eight patients were assigned to the control group. The median intrathecal CXCL13 concentration was 2384 pg/ml for patients with NB and 0 pg/ml for controls. The difference was highly statistically significant (P ≤ .001). A CSF CXCL13 cut-off of 271 pg/ml resulted in a sensitivity of 95.2% and a specificity of 97.2% for the confirmation or exclusion of NB. Based on our results, we propose a CSF CXCL13 cut-off of 271 pg/ml with Euroimmun-Elisa for the diagnosis of acute and untreated NB. Due to its high sensitivity and specificity, CXCL13 is a strong candidate biomarker for routine NB assessment, especially in clinically unclear cases.

Proinflammatory Chemokine Levels in Cerebrospinal Fluid of Patients with Neuroinvasive Flavivirus Infections.

Tick-borne encephalitis virus (TBEV) and West Nile virus (WNV) are the most important neuroinvasive arboviruses detected in Europe. In this study, we analyzed cerebrospinal fluid (CSF) concentrations of 12 proinflammatory chemokines (CCL2, CCL3, CCL4, CCL11, CCL17, CCL20, CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, and CXCL11) in 77 patients with neuroinvasive diseases (NIDs). Flavivirus infection was confirmed in 62 patients (TBEV and WNV in 31 patients each), while in 15 patients the etiology of NID was not determined (NDE). Similar patterns of high-level expression of chemokines regulating monocyte/macrophage responses (CCL2), neutrophil recruitment (CXCL1 and CXCL8), and interferon-inducible chemoattractants for leukocytes (CXCL10 and CXCL11) have been observed in WNV and TBEV groups. None of the tested chemokines significantly differed between patients with TBEV or WNV. Concentrations of CCL17, CCL20, CXCL5, CXCL10, and CXCL11 were significantly lower in both WNV and TBEV groups compared to NID NDE patients. The logistic regression model showed that CSF concentrations of CXCL11, CXCL5, and CXCL10 could potentially be used for the classification of patients into the WNV or TBEV group versus groups with other NIDs. This study identified, for the first time, similar patterns of CSF chemokine expression in WNV and TBEV infections, suggesting common immunopathogenic mechanisms in neuroinvasive flavivirus infections that should be further evaluated.

Abstract 3458: DNA methylation-predicted blood protein levels and breast cancer risk

Abstract Background: Blood DNA methylation (DNAm) profiles can be used to predict a variety of human physiologic traits that are associated with breast cancer incidence and plasma concentrations of over 100 proteins, including those involved in inflammation, coagulation, metabolism, and growth. DNAm predictions of circulating proteins, here referred to as “DNAm proteins,” may be useful in providing molecular insights into breast cancer etiology and could be a valuable resource for personalizing breast cancer risk prediction. Methods: The Sister Study is a nationwide, prospective cohort of 50,884 women with a family history of breast cancer designed to identify novel environmental and biological risk factors for breast cancer. Epigenome-wide DNAm data were previously generated using the HumanMethylation450 or MethylationEPIC arrays on baseline blood samples collected from two case-cohort samples, for a combined sample of 4,479 women. This sample included 2,151 (48%) women who were selected because they were diagnosed with breast cancer (1,673 invasive cancer and 478 ductal carcinomas in situ) in the 15 years (mean: 7.9 years) following blood draw. Blood levels of 109 DNAm proteins were estimated from DNAm profiles using the method developed by Gadd et al. (eLife, 2022). Weighted Cox regression models were used to estimate associations between these DNAm proteins and incident breast cancer; associations were considered statistically significant at a False Discovery Rate (q) ≤ 0.10. Results: In age and platform adjusted models, higher breast cancer rates were associated with higher DNAm-predicted blood concentrations of RARRES2, IGFBP4, and CCL21 and lower predicted concentrations of F7, SELL, CXCL9, CD48, and IL19. The strongest associations were observed for RARRES2 (per 1-SD increase, HR: 1.24, 95% CI: 1.10, 1.40, P= 6 × 10−4, q= 0.03) and F7 (per 1-SD increase, HR: 0.82, 95% CI: 0.74, 0.91, P= 3 × 10−4, q= 0.03). Estimates were similar after adjustment for known breast cancer risk factors and excluding those diagnosed within two years of their blood draw. Associations appeared stronger for invasive breast cancer. Conclusions: Using novel DNAm-based estimates of blood proteins, we identified associations between circulating proteins and breast cancer incidence. IGFBP4 and RARRES2 have previously been reported to be higher in newly-diagnosed breast cancer patients. We also identify new potential protein biomarkers related to immune response (CCL21, SELL, CXCL9, CD48, and IL19). Citation Format: Jacob K. Kresovich, Brett Reid, Doratha A. Byrd, Katie M. O'Brien, Zongli Xu, Clarice R. Weinberg, Dale P. Sandler, Jack A. Taylor. DNA methylation-predicted blood protein levels and breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3458.