CXCL10 Concentrations Research Articles

A Multiparameter Prognostic Risk Score of Chronic Graft-versus-Host Disease Based on CXCL10 and Plasmacytoid Dendritic Cell Levels in the Peripheral Blood at 3 Months after Allogeneic Hematopoietic Stem Cell Transplantation

Chronic GVHD (cGVHD) is the major cause of long-term morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). There are no biomarkers that can consistently predict its occurrence. We aimed to evaluate whether numbers of antigen-presenting cell subsets in peripheral blood (PB) or serum chemokine concentrations are biomarkers of cGVHD occurrence. The study cohort comprised 101 consecutive patients undergoing allogeneic HSCT between January 2007 and 2011. cGVHD was diagnosed by both modified Seattle criteria and National Institutes of Health (NIH) criteria. Multicolor flow cytometry was used to determine the number of PB myeloid dendritic cells (DCs), plasmacytoid DCs, CD16+ DCs, and CD16+ and CD16- monocytes, as well as CD4+ and CD8+ T cells, CD56+ natural killer cells, and CD19+ B cells. Serum concentrations of CXCL8, CXCL10, CCL2, CCL3, CCL4, and CCL5 were measured by a cytometry bead array assay. At a median of 60 days after enrollment, 37 patients had developed cGVHD. Patients with cGVHD and those without cGVHD had comparable clinical characteristics. However, previous acute GVHD (aGVHD) was strongly correlated with later cGVHD (57% versus 24%, respectively; P=.0024). Each potential biomarker was screened for its association with cGVHD using the Mann-Whitney U test. Biomarkers that differed significantly (P < .05) between patients with cGVHD and those without cGVHD were analyzed by receiver operating characteristic (ROC) curve analysis to select the variables predicting cGVHD with an area under the ROC curve (AUC) >.5 and a P value <.05. A multivariate Fine-Gray model identified the following variables as independently associated with the risk of cGVHD: CXCL10 ≥592.650 pg/mL (hazard ratio [HR], 2.655; 95% confidence interval [CI], 1.298 to 5.433; P=.008), pDC ≥2.448/μL (HR, .286; 95% CI, .142 to .577; P < .001) and previous aGVHD (HR, 2.635; 95% CI, 1.298 to 5.347; P=.007). A risk score was derived based on the weighted coefficients of each variable (2 points each), resulting in the identification of 4 cohorts of patients (scores of 0, 2, 4, and 6). In a competing risk analysis to stratify patients at differing risk levels of cGVHD, the cumulative incidence of cGVHD was 9.7%, 34.3%, 57.7%, and 100% in patients with scores of 0, 2, 4, and 6, respectively (P < .0001). The score could nicely stratify the patients based on the risk of extensive cGVHD as well as NIH-based global and moderate to severe cGVHD. Based on ROC analysis, the score could predict the occurrence of cGVHD with an AUC of .791 (95% CI, .703 to .880; P < .001). Finally, a cutoff score ≥4 was identified as the optimal cutoff by Youden J index with a sensitivity of 57.1% and a specificity of 85.0%. A multiparameter score including a history of previous aGVHD, serum CXCL10 concentration, and number of pDCs in the PB at 3 months post-HSCT stratify patients at varying risk levels of cGVHD. However, the score needs to be validated in a much larger independent and possibly multicenter cohort of patients undergoing transplantation from different donor types and with distinct GVHD prophylaxis regimens.

Initial investigation of molecular phenotypes of airway mast cells and cytokine profiles in equine asthma.

Equine asthma is a naturally occurring lung disease characterized by chronic, partially reversible airway obstruction, pulmonary remodeling, and lower airway inflammation. Asthma is currently divided into two major groups, mild to moderate asthma (mEA) and severe asthma (sEA), but further subtyping by phenotype (i.e., clinical presentation) and/or endotype (i.e., cellular mechanisms) may be warranted. For this study, we were interested in further investigation of cellular and inflammatory characteristics of EA, including airway mast cells. The purpose of this study was to: (1) compare mast cell protease mRNA expression between healthy and asthmatic horses, (2) analyze the cytokine profile present in BALF of currently defined equine asthma groups, and (3) use these data to evaluate potential biomarkers of defined asthma groups. We hypothesized that there would be significant differences in the cellular mast cell phenotypes (i.e., mucosal vs. connective tissue) and cytokine profiles in the BALF of asthmatic vs. healthy horses and across asthma groups. We assert these characteristics may inform additional subtypes of equine asthma. Adult horses were recruited from the institution's teaching herd and clinical caseload. Mast cell protease gene expression of the BALF cellular component and multiplex bead immunoassay for cytokine concentrations in the BALF supernatant were investigated. Airway mast cells primarily expressed tryptase, with low levels of chymase. No significant changes in protease expression were detected across groups. Horses with severe asthma had increased TNF-α, CXCL-8, and IFN-γ concentrations in BALF supernatant. Multidimensional analysis demonstrated healthy and mEA horses have overlapping characteristics, with sEA separating from the other groups. This difference was primarily due to BALF neutrophil and lymphocyte concentrations. These study results further inform understanding of EA immunopathology, and future studies designed to investigate asthma phenotypes and endotypes. Ultimately, a better understanding of these groups could help identify novel therapeutic strategies.

Use of cerebrospinal fluid CXCL13 concentration for diagnosis and monitoring of neurosyphilis: a three-case report

Introduction: Previous retrospective studies have demonstrated that the concentration of chemokine ligand CXCL13 in cerebrospinal fluid (CSF-CXCL13) is a promising biomarker in the diagnosis of neurosyphilis and, additionally, in the monitoring of therapeutic efficacy. Objective: To describe three cases of patients with neurosyphilis (NS) treated at Hospital Universitário Gaffrée e Guinle, in Rio de Janeiro, Brazil, with suspected active syphilis with neurological symptoms. Case report: Three patients from Rio de Janeiro, Brazil, were investigated for symptomatic NS. The concentration of CSF-CXCL13 was prospectively performed by enzyme-linked immunosorbent assay (ELISA) in all participants at baseline and in follow-up visits at 3 months after therapy. CSF-CXCL13 concentrations were significantly higher in all three patients with established NS. The CSF-CXCL13 concentrations decreased after 3 months of therapy compared to baseline in all cases reported. The added high concentration of CSF-CXCL13 plus CSF-TPHA reactivity above 1:40 titer agreed with the diagnosis of NS in 100% of the cases. Conclusion: In this case series, we present three cases of NS diagnosed using CXCL13 in CSF as a complementary test. These case series suggest that the clinical use of CSF-CXCL13 is useful as a supplementary biomarker for NS and for monitoring the effectiveness of NS therapy, especially in patients with nonreactive CSF-VDRL, excluding other neurologic diseases.

Značaj dijagnostike neuroborelioze u Republici Srbiji

Lyme neuroborreliosis (LNB) is the most common disseminated form of LB in Europe. It is a tick transmitted disease, caused by Borrelia burgdorferi sensu lato complex (Bb). There are numerous tests on the market for neuroborreliosis diagnostics, but none is reliable enough to confirm the diagnosis of LNB alone. Measuring antibody index (AI), although a gold standard test, is unable to distinguish current infection from a resolved one. Support can partially be found in CXCL-13 concentration follow up, which will decrease after successful therapy. Microbiology testing is just a support in establishing LNB diagnosis, and must be considered in conjunction with exposure history, clinical presentation, and other laboratory findings.

Cerebrospinal fluid cytokines after autologous haematopoietic stem cell transplantation and intrathecal rituximab treatment for multiple sclerosis.

Multiple sclerosis has been established as an inflammatory disease of the central nervous system. Many aspects of the pathophysiology are still unknown and it is presently unclear how different treatments affect the immunopathology of multiple sclerosis. In this study, we explored cytokines discriminating between individuals with multiple sclerosis and healthy controls and then how these cytokines were affected by treatment intervention with autologous haematopoietic stem cell transplantation or intrathecal rituximab. CSF from individuals with multiple sclerosis and healthy controls were analysed with a proximity extension assay to simultaneously determine the level of 92 cytokines and other inflammation-related proteins. In total, CSF from 158 multiple sclerosis patients and 53 healthy controls were analysed. Sixty-four patients with relapsing-remitting multiple sclerosis and 27 with progressive multiple sclerosis took part in a cross-sectional study and underwent lumbar puncture on a single occasion. Forty-five patients with relapsing-remitting multiple sclerosis were treated with autologous haematopoietic stem cell transplantation and underwent lumbar puncture at baseline and then at follow-up visits made at 1-, 2- and 5 years. Twenty-two patients with progressive multiple sclerosis were treated with intrathecal rituximab and followed with lumbar punctures at baseline and then at follow-up visits made at 3-, 6- and 12 months. Of the 92 studied cytokines, 16 were found to be altered in multiple sclerosis and 11 were decreased after treatment with autologous haematopoietic stem cell transplantation. None of the studied cytokines was affected by treatment with intrathecal rituximab for progressive multiple sclerosis. Some proteins were highly associated with each other. Therefore, a cluster analysis was made and then the highest-ranked protein from the four highest-ranked clusters was used for the subsequent analyses. CCL3, IL-12B, CXCL10 and IL-8 discriminated between multiple sclerosis patients and controls, but only IL-12B differed between patients with relapsing-remitting and progressive multiple sclerosis. The CSF concentrations of CCL3, IL-12B and CXCL10 were decreased after autologous haematopoietic stem cell transplantation, whereas IL-8 appeared to be unaffected by this intervention. High concentrations of IL-8 were associated with worse outcome in both treatment groups. Overall, the results suggest a profound effect of autologous haematopoietic stem cell transplantation on the inflammatory milieu of the CSF in multiple sclerosis.

Nasal host response-based screening for undiagnosed respiratory viruses: a pathogen surveillance and detection study

Symptomatic patients who test negative for common viruses are an important possible source of unrecognised or emerging pathogens, but metagenomic sequencing of all samples is inefficient because of the low likelihood of finding a pathogen in any given sample. We aimed to determine whether nasopharyngeal CXCL10 screening could be used as a strategy to enrich for samples containing undiagnosed viruses. In this pathogen surveillance and detection study, we measured CXCL10 concentrations from nasopharyngeal swabs from patients in the Yale New Haven health-care system, which had been tested at the Yale New Haven Hospital Clinical Virology Laboratory (New Haven, CT, USA). Patients who tested negative for a panel of respiratory viruses using multiplex PCR during Jan 23-29, 2017, or March 3-14, 2020, were included. We performed host and pathogen RNA sequencing (RNA-Seq) and analysis for viral reads on samples with CXCL10 higher than 1 ng/mL or CXCL10 testing and quantitative RT-PCR (RT-qPCR) for SARS-CoV-2. We used RNA-Seq and cytokine profiling to compare the host response to infection in samples that were virus positive (rhinovirus, seasonal coronavirus CoV-NL63, or SARS-CoV-2) and virus negative (controls). During Jan 23-29, 2017, 359 samples were tested for ten viruses on the multiplex PCR respiratory virus panel (RVP). 251 (70%) were RVP negative. 60 (24%) of 251 samples had CXCL10 higher than 150 pg/mL and were identified for further analysis. 28 (47%) of 60 CXCL10-high samples were positive for seasonal coronaviruses. 223 (89%) of 251 samples were PCR negative for 15 viruses and, of these, CXCL10-based screening identified 32 (13%) samples for further analysis. Of these 32 samples, eight (25%) with CXCL10 concentrations higher than 1 ng/mL and sufficient RNA were selected for RNA-Seq. Microbial RNA analysis showed the presence of influenza C virus in one sample and revealed RNA reads from bacterial pathobionts in four (50%) of eight samples. Between March 3 and March 14, 2020, 375 (59%) of 641 samples tested negative for 15 viruses on the RVP. 32 (9%) of 375 samples had CXCL10 concentrations ranging from 100 pg/mL to 1000 pg/mL and four of those were positive for SARS-CoV-2. CXCL10 elevation was statistically significant, and a distinguishing feature was found in 28 (8%) of 375 SARS-CoV-2-negative samples versus all four SARS-CoV-2-positive samples (p=4·4 × 10-5). Transcriptomic signatures showed an interferon response in virus-positive samples and an additional neutrophil-high hyperinflammatory signature in samples with high amounts of bacterial pathobionts. The CXCL10 cutoff for detecting a virus was 166·5 pg/mL for optimal sensitivity and 1091·0 pg/mL for specificity using a clinic-ready automated microfluidics-based immunoassay. These results confirm CXCL10 as a robust nasopharyngeal biomarker of viral respiratory infection and support host response-based screening followed by metagenomic sequencing of CXCL10-high samples as a practical approach to incorporate clinical samples into pathogen discovery and surveillance efforts. National Institutes of Health, the Hartwell Foundation, the Gruber Foundation, Fast Grants for COVID-19 research from the Mercatus Center, and the Huffman Family Donor Advised Fund.

Comparison between Clinical Utility of CXCL-8 and Clinical Practice Tumor Markers for Colorectal Cancer Diagnosis.

Owing to the high incidence and mortality rates of colorectal cancer (CRC), novel biomarkers for CRC diagnosis are critically needed. Therefore, this study is aimed at exploring the clinical utility of serum C-X-C motif chemokine 8 (CXCL-8) for CRC diagnosis and progression compared to the routinely used biomarkers, carcinoembryonic antigen (CEA), and carbohydrate antigen-19-9 (CA19-9). This study included 227 patients with CRC, 110 patients with colorectal adenoma (CA), and 123 healthy participants, who were recruited from the Fujian Medical University Union Hospital from July 1, 2019 to October 31, 2020. Serum concentrations of CXCL-8, CEA, and CA19-9 were detected using enzyme-linked immunosorbent assay and chemiluminescent microparticle immunoassay. Clinicopathological features of patients with CRC were collected and analyzed. The diagnostic efficacy of CXCL-8, CEA, and CA19-9 for CRC was evaluated using receiver operating characteristic (ROC) curves. We found that the serum concentrations of CXCL-8, CEA, and CA19-9 were significantly higher in patients with CRC than those in patients with CA and healthy controls. The diagnostic sensitivity of CXCL-8 alone was higher than those of CEA and CA19-9 both and when combined; thus, CXCL-8 may be better at discriminating patients with CRC from healthy controls and patients with CA. Moreover, combining CXCL-8 with CEA or CA19-9 improved their respective diagnostic performances in distinguishing patients with CRC from CA patients and healthy participants. Notably, we also found that serum concentrations of CXCL-8 were positively correlated with metastases and tumor size. Therefore, our study suggests that serum CXCL-8 may serve as an improved biomarker for CRC diagnosis compared to the traditional tumor markers CEA and CA19-9. Moreover, our findings indicate the potential efficacy of serum CXCL-8 levels as a CRC prognostic biomarker.

2160. Mucosal Antiviral Cytokine Responses Are Impaired in Children and Adolescents with Severe COVID-19

Abstract Background The factors associated with severe COVID-19 in pediatric patients remain poorly understood. We sought to determine whether mucosal innate immunity cytokines were associated with disease severity in children and adolescents with acute COVID-19. Methods Single-center, prospective study including children and adolescents &amp;lt; 21 years of age hospitalized because of symptomatic COVID-19 from 3/2020 to 1/2021, and age, sex and race matched pre-pandemic (2016-2019) healthy controls. Nasopharyngeal (NP) samples were obtained at enrollment for measurement of SARS-CoV-2 viral loads by rt-PCR and cytokine concentrations using a 92-plex inflammation/antiviral panel (Olink). Disease severity was assessed by the need for supplemental oxygen or PICU admission, and patients classified as severe and non-severe based on these two parameters. Statistical analyses were performed in R studio and Benjamini-Hochberg applied to adjust for multiple comparisons. Results Of the 75 children with acute COVID-19 (median IQR age: 3.4 [0.2-15.3] years), 28 (37%) were classified as severe COVID-19 (19 PICU; 25 supplemental oxygen) and 47 (63%) were non-severe. Children with severe COVID-19 were predominantly male and had an underlying condition more frequently than those with non-severe disease (79% vs 49% respectively; p&amp;lt; 0.01, Table 1). SARS-CoV-2 viral loads were comparable between groups, yet patients with severe COVID-19 had significantly higher concentrations of C-reactive protein (p=0.04), more frequent lymphopenia (p=0.03) and cardiac involvement (p=0.04), and received COVID-19 directed therapies more commonly (p&amp;lt; 0.001). Comparative analyses identified 24 cytokines that were significantly different between children with acute COVID-19 versus 45 healthy controls. Of those, concentrations of IFN-γ (p=0.004), CXCL10 (p=0.01), CXCL11 (p=0.02) and CCL19 (p=0.02) were significantly lower in children with severe versus those with non-severe COVID-19 (Fig 1). Table 1.Demographic and clinical characteristics in children with symptomatic COVID-19*Bolded p-values indicates statistical significance. Abbreviations: N, number. CRP, C-Reactive protein; PICU, pediatric intensive care unit.**Other including the following underlying conditions: prematurity, endocrine conditions, immunocompromising conditions, prematurity, trisomy 21 and complex care. Ł Lymphopenia defined as an ALC of &amp;lt;4,500 cells/μl in infants, and &amp;lt;1,500 cells /μl in children &amp;gt;12 months of age Continuous variables displayed as medians and 25%-75% interquartile ranges (IQR), Mann-Whitney test was used to determine differences between two groups; Kruskal-Wallis &amp; Dunn’s multiple test correction was used to determine differences between three groups (p-values*). Categorical data expressed as numbers and proportions (in parenthesis) and analyzed by Fisher’s exact test or Chi square test. Figure 1.Nasal mucosal concentrations of antiviral/regulatory cytokines in children with symptomatic COVID-19 according to disease severity Conclusion Mucosal concentrations of antiviral/regulatory cytokines were decreased in children with severe COVID-19. These findings suggest that impaired mucosal innate immune responses might favor SARS-CoV-2 disease progression and severity in children. Disclosures Amy Leber, PhD, BioFire: Advisor/Consultant|BioFire: Grant/Research Support|Biorad: Advisor/Consultant|Cepheid: Grant/Research Support Octavio Ramilo, MD, Adagio: Advisor/Consultant|Bill &amp; Melinda Gates Foundation: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Lilly: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|NIH: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Honoraria Asuncion Mejias, MD, PhD, MsCS, AstraZeneca: Honoraria|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Roche: Advisor/Consultant|Sanofi-Pasteur: Advisor/Consultant|Sanofi-Pasteur: Honoraria.

Analysis of Treponema pallidum DNA and CXCL13 in Cerebrospinal Fluid in HIV-Negative Syphilis Patients.

Neurosyphilis (NS) is a chronic infectious disease associated with Treponema pallidum subsp. pallidum (TP) infection of the central nervous system. The purpose of this study was to offer evidence for the diagnosis and treatment of NS by revealing the detection of TP DNA and CXCL13 concentration in the cerebrospinal fluid (CSF) of HIV-negative syphilis patients. This study included 75 syphilis patients. The frequency of TP invasion into the CSF was detected by nested PCR. ELISA was performed to detect CSF CXCL13 concentrations, and ROC analysis was performed to assess diagnostic accuracy. Sociodemographic data, clinical symptoms, and laboratory indices of patients were collected. CSF CXCL13 levels and clinical characteristics of syphilis patients were investigated retrospectively. The detection rate of CSF DNA of TP by nested PCR was 5.3% and 16.7% in HIV-negative syphilis patients and NS patients, respectively. There was a significant difference between the NS and non-NS groups in terms of neurological symptoms, CSF TPPA, CSF TRUST, CSF nucleated cells, CSF protein, and CSF CXCL13 levels (P<0.05). ROC curve analysis showed that the AUC for CSF CXCL13 levels was 0.906 (95% CI 0.832-0.981, P <0.0001), with an optimal critical value of 57.85 pg/mL and sensitivity and specificity of 88.89% and 78.95%, respectively. Nested PCR can be used as an auxiliary diagnosis of NS, and CSF CXCL13 >60 pg/mL has high sensitivity and specificity for NS patients and non-NS patients. CXCL13 may be a useful marker to distinguish NS from non-NS syphilis in HIV-negative patients.

Plasma Levels of CXC Motif Chemokine 1 (CXCL1) and Chemokine 8 (CXCL8) as Diagnostic Biomarkers in Luminal A and B Breast Cancer.

Chemokines are involved in the regulation of immune balance and in triggering an immune response. CXCL1 and CXCL8 belong to the ELR-motif-containing group of CXC chemokines, which, in breast cancer (BC), stimulate angiogenesis and increase migration and invasiveness of tumor cells. The aim of this study was to evaluate CXCL1, CXCL8 and comparative marker CA 15-3 plasma concentrations in BC patients with luminal subtypes A and B. The study group consisted of 100 patients with BC, and the control group of 50 subjects with benign breast lesions and 50 healthy women. Chemokines concentrations were determined by ELISA method; CA15-3-by CMIA. Concentrations of CXCL8 and CA15-3 were significantly higher in BC total group and luminal B (for CA15-3 also in luminal A) subtype of BC than in healthy controls and subjects with benign lesions. In the total BC group, the highest SE, PPV and NPV were observed for CXCL8 (70%, 77.78%, 50%, resp.). A combined analysis of tested chemokines with CA 15-3 increased SE and NPV values (96%, 69.23%, resp.). The diagnostic power of the test (measured by area under ROC curve (AUC)) showed the highest value for CXCL8 in the total BC group (0.6410), luminal A (0.6120) and B subgroup of BC (0.6700). For the combined parameter, the AUC was increasing and reached the highest value for CXCL1 + CXCL8 + CA15-3 combination (0.7024). In light of these results, we suggest that CXCL8 could be used as an additional diagnostic marker that would positively influence the diagnostic utility of CA 15-3, especially in luminal B subtype of BC.

ISL1/SHH/CXCL12 signaling regulates myogenic cell migration during mouse tongue development.

Migration of myoblasts derived from the occipital somites is essential for tongue morphogenesis. However, the molecular mechanisms of myoblast migration remain elusive. In this study, we report that deletion of Isl1 in the mouse mandibular epithelium leads to aglossia due to myoblast migration defects. Isl1 regulates the expression pattern of chemokine ligand 12 (Cxcl12) in the first branchial arch through the Shh/Wnt5a cascade. Cxcl12+ mesenchymal cells in Isl1ShhCre embryos were unable to migrate to the distal region, but instead clustered in a relatively small proximal domain of the mandible. CXCL12 serves as a bidirectional cue for myoblasts expressing its receptor CXCR4 in a concentration-dependent manner, attracting Cxcr4+ myoblast invasion at low concentrations but repelling at high concentrations. The accumulation of Cxcl12+ mesenchymal cells resulted in high local concentrations of CXCL12, which prevented Cxcr4+ myoblast invasion. Furthermore, transgenic activation of Ihh alleviated defects in tongue development and rescued myoblast migration, confirming the functional involvement of Hedgehog signaling in tongue development. In summary, this study provides the first line of genetic evidence that the ISL1/SHH/CXCL12 axis regulates myoblast migration during tongue development.

CSF CXCL13 and Chitinase 3-like-1 Levels Predict Disease Course in Relapsing Multiple Sclerosis

Several biomarkers from multiple sclerosis (MS) patients’ biological fluids have been considered to support diagnosis, predict disease course, and evaluate treatment response. In this study, we assessed the CSF concentration of selected molecules implicated in the MS pathological process. To investigate the diagnostic and prognostic significance of CSF concentration of target candidate biomarkers in both relapsing (RMS, n = 107) and progressive (PMS, n = 18) MS patients and in other inflammatory (OIND, n = 10) and non-inflammatory (ONIND, n = 15) neurological disorders. We measured the CSF concentration of APRIL, BAFF, CHI3L1, CCL-2, CXCL-8, CXCL-10, CXCL-12, CXCL-13 through a Luminex Assay. MS patients were prospectively evaluated, and clinical and radiological activity were recorded. CHI3L1 and CXCL13 CSF levels were significantly higher in both MS groups compared to control groups, while CCL2, BAFF, and APRIL concentrations were lower in RMS patients compared to PMS and OIND. Considering RMS patients with a single demyelinating event, higher concentrations of CHI3L1, CXCL10, CXCL12, and CXCL13 were recorded in patients who converted to clinically defined MS(CDMS). RMS patients in the CXCL13 and CHI3L1 high concentration group had a significantly higher risk of relapse (HR 12.61 and 4.57), MRI activity (HR 7.04 and 2.46), and of any evidence of disease activity (HR 12.13 and 2.90) during follow-up. CSF CXCL13 and CHI3L1 levels represent very good prognostic biomarkers in RMS patients, and therefore can be helpful in the treatment choice. Higher CSF concentrations of neuro-inflammatory biomarkers were associated with a higher risk of conversion to CDMS in patients with a first clinical demyelinating event. Differential CSF BAFF and APRIL levels between RMS and PMS suggest a different modulation of B-cells pathways in the different phases of the disease.

Cytokine Patterns in COVID-19 Patients: Which Cytokines Predict Mortality and Which Protect Against?

(1) Background/Aim: People infected with SARS-CoV-2 may develop COVID-19 in a wide range of clinical severity. Pulmonary fibrosis is characterized by several grades of chronic inflammation and collagen deposition in the interalveolar space. SARS-CoV-2 infection has been demonstrated to cause lung fibrosis without a currently elucidated mechanism. Some studies emphasize the role of proinflammatory cytokines. This research studies the correlation of the released cytokines with mortality or lung injury in COVID-19 patients. (2) Methods: Electronic medical record data from 40 patients diagnosed with COVID-19 in the COVID-19 Department, Galilee Medical Center, Nahariya, Israel, were collected. Epidemiological, clinical, laboratory, and imaging variables were analyzed. The cytokine levels were measured upon admission and discharge. A correlation between cytokine levels and severity and mortality or lung involvement was undertaken. (3) Results: IFN-gamma and IL-10 are the most powerful risk factors for mortality in the COVID-19 patient groups in a multivariate analysis. However, in a univariate analysis, TGF-β, CXCL-10, IFN gamma, and IL-7 affected mortality in COVID-19 patients. MMP-7 was significantly correlated with a cytokine storm and a high 4-C (severity) score in COVID-19 patients. MMP-7, TGF-β, IL-10, IL-7, TNF-α, and IL-6 were correlated with high lung involvement in COVID-19 patients. Serum concentrations of IGF-1 were significantly increased upon discharge, but MMP-7 was decreased. (4) Conclusions: Proinflammatory cytokines predict clinical severity, lung fibrosis, and mortality in COVID-19 patients. High concentrations of TGF-β, CXCL-10, IL-10, IL-6, and TNF-α are correlated to severity and lung injury. However, certain cytokines have protective effects and higher levels of these cytokines increase survival levels and lower lung damage. High levels of INF-γ, IL-7, MMP-7, and IGF-1 have protection probabilities against lung injury and severity.

Type III Interferons, Viral Loads, Age, and Disease Severity in Young Children With Respiratory Syncytial Virus Infection.

The interplay among respiratory syncytial virus (RSV) loads, mucosal interferons (IFN), and disease severity in RSV-infected children is poorly understood. Children <2 years of age with mild (outpatients) or severe (inpatients) RSV infection and healthy controls were enrolled, and nasopharyngeal samples obtained for RSV loads and innate cytokines quantification. Patients were stratified by age (0-6 and >6-24 months) and multivariable analyses performed to identify predictors of disease severity. In 2015-2019 we enrolled 219 RSV-infected children (78 outpatients; 141 inpatients) and 34 healthy controls. Type I, II, and III IFN concentrations were higher in children aged >6 versus 0-6 months and, like CXCL10, they were higher in outpatients than inpatients and correlated with RSV loads (P < .05). Higher IL6 concentrations increased the odds of hospitalization (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.07-5.36) only in children >6 months, while higher IFN-λ2/3 concentrations had the opposite effect irrespective of age (OR, 0.38; 95% CI, .15-.86). Likewise, higher CXCL10 concentrations decreased the odds of hospitalization (OR, 0.21; 95% CI, .08-.48), oxygen administration (OR, 0.42; 95% CI, .21-.80),PICU admission (OR, 0.39; 95% CI, .20-.73), and prolonged hospitalization (OR, 0.57; 95% CI, .32-.98) irrespective of age. Children with milder RSV infection and those aged >6 months had higher concentrations of mucosal IFNs, suggesting that maturation of mucosal IFN responses are associated with protection against severe RSV disease.

IL-4, IL-10, CCL2 and TGF-β as potential biomarkers for severity in Plasmodium vivax malaria.

Cytokines and chemokines are immune response molecules that display diverse functions, such as inflammation and immune regulation. In Plasmodium vivax infections, the uncontrolled production of these molecules is thought to contribute to pathogenesis and has been proposed as a possible predictor for disease complications. The objective of this study was to evaluate the cytokine profile of P. vivax malaria patients with different clinical outcomes to identify possible immune biomarkers for severe P. vivax malaria. The study included patients with non-severe (n = 56), or severe (n = 50) P. vivax malaria and healthy controls (n = 50). Patient plasma concentrations of IL-4, IL-2, CXCL10, IL-1β, TNF-α, CCL2, IL-17A, IL-6, IL-10, IFN-γ, IL-12p70, CXCL8 and active TGF-β1 were determined through flow cytometry. The levels of several cytokines and chemokines, CXCL10, IL-10, IL-6, IL-4, CCL2 and IFN-γ were found to be significantly higher in severe, compared to non-severe P. vivax malaria patients. Severe thrombocytopenia was positively correlated with IL-4, CXCL10, IL-6, IL-10 and IFN-γ levels, renal dysfunction was related to an increase in IL-2, IL-1β, IL-17A and IL-8, and hepatic impairment with CXCL10, MCP-1, IL-6 and IFN-γ. A Lasso regression model suggests that IL-4, IL-10, CCL2 and TGF-β might be developed as biomarkers for severity in P. vivax malaria. Severe P. vivax malaria patients present specific cytokine and chemokine profiles that are different from non-severe patients and that could potentially be developed as biomarkers for disease severity.

CXCL8, CCL2, and CMV Seropositivity as New Prognostic Factors for a Severe COVID-19 Course.

The exact pathophysiology of severe COVID-19 is not entirely elucidated, but it has been established that hyperinflammatory responses and cytokine storms play important roles. The aim of this study was to examine CMV status, select chemokines, and complement components in COVID-19, and how concentrations of given molecules differ over time at both molecular and proteomic levels. A total of 210 COVID-19 patients (50 ICU and 160 non-ICU patients) and 80 healthy controls were enrolled in this study. Concentrations of select chemokines (CXCL8, CXCL10, CCL2, CCL3, CCR1) and complement factors (C2, C9, CFD, C4BPA, C5AR1, CR1) were examined at mRNA and protein levels with regard to a COVID-19 course (ICU vs. non-ICU group) and CMV status at different time intervals. We detected several significant differences in chemokines and complement profiles between ICU and non-ICU groups. Pro-inflammatory chemokines and the complement system appeared to greatly contribute to the pathogenesis and development of severe COVID-19. Higher concentrations of CXCL8 and CCL2 in the plasma, with reduced mRNA expression presumably through negative feedback mechanisms, as well as CMV-positive status, correlated with more severe courses of COVID-19. Therefore, CXCL8, CCL2, and CMV seropositivity should be considered as new prognostic factors for severe COVID-19 courses. However, more in-depth research is needed.

PSV-B-16 Correlation between Plasma, Uterine, and Vaginal Cytokine Concentrations in Postpartum Beef Cows Prior to Artificial Insemination

Abstract Cytokines have a vital role in reproductive immune environment during the postpartum period. Previous data evaluated uterine and vaginal cytokine concentrations prior to insemination; however, was unable to correlate these data with plasma cytokine concentrations. The objective of this study was to determine relationships between uterine, vaginal, and plasma pro- and anti-inflammatory cytokine concentrations in postpartum beef cows prior to timed artificial insemination (TAI). Bos indicus-influenced beef cows (n=20) free of any physical, health or reproductive-related issues were subjected to the Bee Synch II protocol 8 days prior (d-8) to TAI (d0). Uterine and vaginal flushes and blood were collected on d-3 and d-1. Pregnancy was determined by transrectal ultrasonography on d28 (Pregnant, n=7; Open, n=13). Using the RayBiotech Quantibody Bovine Cytokine Array 1 the following cytokines concentrations were determined: interferon (IFN)-α, IFN-γ, interleukin (IL)-13, IL-1α, IL-1-F5, IL-21, tumor necrosis factor (TNF)-α, chemokine ligand (CXCL)-9, CXCL-10, and chemokine ligand 4 (CCL4). Concentration data were analyzed using PROC GLM and correlations using Pearson correlation in SAS. For plasma samples, 8 pro-inflammatory cytokines (IFN-α, IFN-γ, IL-13, IL-1α, IL-1-F5, IL-21, CXCL-9, and TNF-α) had greater (P&amp;lt; 0.05) concentrations in open cows compared with pregnant cows. For uterine flushes, 3 pro-inflammatory cytokines (IFN-γ, IL-1α, and IL-21) had greater (P&amp;lt; 0.05) concentrations in open cows compared with pregnant cows. For vaginal flushes, IFN-α concentrations were greater (P&amp;lt; 0.05) in open cows, while CXCL-10 concentrations were greater in pregnant cows. There were no significant correlations between plasma and uterine or vaginal samples (P&amp;gt;0.05). Interestingly, for open cows there were correlations for IFN-α (r=0.46; P=0.02), IFN-γ (r=0.58; P=0.002), and IL-21 (r=0.54; P=0.004) between uterine and vaginal samples; however, no correlations were observed for pregnant cows. These results suggest a greater abundance of pro-inflammatory cytokines within the uterus, vagina, and in peripheral circulation for resulting open cows prior to TAI.

Immunogenicity profiling and distinct immune response in liver transplant recipients vaccinated with SARS-CoV-2 inactivated vaccines.

SARS-CoV-2 vaccination has been recommended for liver transplant (LT) recipients. However, our understanding of inactivated vaccine stimulation of the immune system in regulating humoral and cellular immunity among LT recipients is inadequate. Forty-six LT recipients who received two-dose inactivated vaccines according to the national vaccination schedule were enrolled. The clinical characteristics, antibody responses, single-cell peripheral immune profiling, and plasma cytokine/chemokine/growth factor levels were recorded. Sixteen (34.78%) LT recipients with positive neutralizing antibody (nAb) were present in the Type 1 group. Fourteen and 16 LT recipients with undetected nAb were present in the Type 2 and Type 3 groups, respectively. Time from transplant and lymphocyte count were different among the three groups. The levels of anti-RBD and anti-S1S2 decreased with decreasing neutralizing inhibition rates. Compared to the Type 2 and Type 3 groups, the Type 1 group had an enhanced innate immune response. The proportions of B, DNT, and CD3+CD19+ cells were increased in the Type 1 group, whereas monocytes and CD4+ T cells were decreased. High CD19, high CD8+CD45RA+ cells, and low effector memory CD4+/naïve CD4+ cells of the T-cell populations were present in the Type 1 group. The Type 1 group had higher concentrations of plasma CXCL10, MIP-1 beta, and TNF-alpha. No severe adverse events were reported in all LT recipients. We identified the immune responses induced by inactivated vaccines among LT recipients and provided insights into the identification of immunotypes associated with the responders.

CXCL13 is elevated in inflammatory bowel disease in mice and humans and is implicated in disease pathogenesis.

CXCL13 is a chemokine that is widely involved in the pathogenesis of autoimmune diseases, tumors and inflammatory diseases. In this study, we investigate the role of CXCL13 in the pathogenesis of inflammatory bowel disease using both clinical specimens and animal models. We found that the serum CXCL13 concentration in IBD patients was significantly higher than that in healthy controls, and correlated with that of CRP, neutrophils counts and hemoglobin. The increase of CXCL13 in IBD patients might be related to the significant decrease of circulating CD4+CXCR5+ T cells, the increase of CD19+CD5+ B cells and the enhancement of humoral immunity. In mice colitis model, we also found elevated levels of CXCL13 in colon tissue. Cxcl13-/- knockout mice exhibited a mild, self-limiting form of disease. Additionally, CXCL13 deficiency restricted CD4+CXCR5+ T cells migration in mesenteric lymph nodes, resulting locally regulatory B cells increased in colon. In conclusion, our findings raise the possibility that CXCL13 plays a critical role in the pathogenesis of IBD. We believe that our findings will contribute to the understanding of the etiology, and that antagonizing or inhibiting CXCL13 may work as a potential adjunctive therapy strategy for patients with IBD.

Cytokines and chemokines profile in encephalitis patients: A meta-analysis.

Encephalitis is caused by autoimmune or infectious agents marked by brain inflammation. Investigations have reported altered concentrations of the cytokines in encephalitis. This study was conducted to determine the relationship between encephalitis and alterations of cytokine levels in cerebrospinal fluid (CSF) and serum. We found possibly suitable studies by searching PubMed, Embase, Scopus, and Web of Science, systematically from inception to August 2021. 23 articles were included in the meta-analysis. To investigate sources of heterogeneity, subgroup analysis and sensitivity analysis were conducted. The protocol of the study has been registered in PROSPERO with a registration ID of CRD42021289298. A total of 23 met our eligibility criteria to be included in the meta-analysis. A total of 12 cytokines were included in the meta-analysis of CSF concentration. Moreover, 5 cytokines were also included in the serum/plasma concentration meta-analysis. According to the analyses, patients with encephalitis had higher CSF amounts of IL-6, IL-8, IL-10, CXCL10, and TNF-α than healthy controls. The alteration in the concentration of IL-2, IL-4, IL-17, CCL2, CXCL9, CXCL13, and IFN-γ was not significant. In addition, the serum/plasma levels of the TNF-α were increased in encephalitis patients, but serum/plasma concentration of the IL-6, IL-10, CXCL10, and CXCL13 remained unchanged. This meta-analysis provides evidence for higher CSF concentrations of IL-6, IL-8, IL-10, CXCL10, and TNF-α in encephalitis patients compared to controls. The diagnostic and prognostic value of these cytokines and chemokines should be investigated in future studies.