High level of plasma TILRR protein is associated with faster HIV seroconversion.

BACKGROUND: TILRR (Toll-like Interleukin-1 Receptor Regulator) is a modulator of many genes in NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling. It promotes the production of inflammatory mediators and the migration of immune cells. Recently, we showed that TILRR protein circulates in human blood. Thus, it could influence systemic inflammation. Systemic and mucosal inflammations increase the susceptibility to HIV infection. In this study, we analyzed the TILRR protein levels of the archived plasma samples of women enrolled in the Pumwani cohort to determine whether the plasma TILRR protein levels before seroconversion are correlated with differential risk of HIV seroconversion. METHODS: TILRR protein of 941 archived HIV negative plasma samples from 390 women who were HIV negative at the cohort enrollment was quantified with an in-house developed multiplex bead array method. Proinflammatory cytokines/chemokines were measured using a 14-plex bead array method. Spearman rank correlation analysis was used to determine the correlation between plasma TILRR protein and proinflammatory cytokines/chemokines. Kaplan-Meier survival analysis was conducted to evaluate whether the median plasma TILRR protein levels correlate with increased risk of HIV seroconversion. FINDINGS: The level of plasma TILRR protein was positively correlated with plasma IL-1ß (rho: 0.2593, p<0.0001), MCP-1 (rho: 0.2377, p<0.0001), and IL-17A (rho: 0.1225, p=0.0216). Women with median plasma TILRR protein levels ≥100 ng/ml seroconverted significantly faster than women with plasma TILRR protein levels <100 ng/ml (log-rank= 100.124, p<0.0001; relative risk= 3.72 and odds ratio= 15.29). Furthermore, the factors causing genital inflammation, such as STIs (sexually transmitted infections), vaginal discharge, and genital ulcers were not statistically significantly different among women with different median plasma TILRR protein levels. INTERPRETATION: The high plasma TILRR protein levels are highly correlated with several plasma proinflammatory cytokines/chemokines. High median plasma TILRR protein (≥100 ng/ml) strongly predicted an increased risk of HIV seroconversion. Reducing plasma TILRR protein levels may reduce the risk of HIV acquisition. FUNDING: The study was funded by an operating grant from the Canadian Institutes of Health Research (CIHR), operating grant-PA: CHVI Vaccine Discovery and Social Research (http://www.cihr-irsc.gc.ca/e/193.html), and National Microbiology Laboratory of Canada.

IL-23R gene polymorphisms in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease in which many different genetic variants of functional gene polymorphisms may play a culprit role in the underlying pathogenetic mechanism. The recent studies suggest that interleukin-23 receptor (IL-23R) gene polymorphisms may increase susceptibility to the development of various autoimmune diseases. We aimed to examine the possible relationship of nine single nucleotide polymorphisms (SNPs) in the IL-23R gene to susceptibility to rheumatoid arthritis and their associations with disease characteristics in the South Aegean region of Turkey. We enrolled 100 rheumatoid arthritis patients and age- and sex-matched 96 healthy subjects in the study. After deoxyribonucleic acid (DNA) isolation was performed, a 'Restriction Fragment Length Polymorphism' (RFLP) method was used for the investigation of polymorphisms associated with the IL-23R gene. Allele identification and genotyping were obtained from polymerase chain reaction (PCR) products using gel electrophoresis. Allele frequencies and detected genotypes were compared between groups. All statistical analyses were performed using SPSS 25.0 (IBM SPSS Statistics 25 software (Armonk, NY: IBM Corp.)). Continuous variables were defined by the mean ± standard deviation and categorical variables were defined by number and percent. Logistic Regression Analysis was used for determining which variables affect the presence of RA. Differences between categorical variables were analyzed with Chi-square analysis. Statistical significance was determined as p < 0.05. The mean age was 53.48 ± 11.7 years in the RA group, whereas 52.55 ± 12.7 years in the healthy control group. The genotypes of IL-23R with rs11805303(TT), rs10889677(AA), rs1004819(AA), and rs7530511(CT) polymorphisms were seen more often in RA patients than healthy controls. Having the AA genotype of IL-23R rs1004819 and the CT genotype of Il-23R rs7530511 increase the development risk of RA with a statistical significance (OR: 3.416 p = 0.003 and OR: 4.899 p = 0.0001, respectively). RA patients with the CC genotype of Il-23R with rs11805303, the CC genotype with rs10889677, and the TT genotype with rs2201841 of the IL-23R gene had higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels than with other genotypes. RA patients with the CC genotype rs11805303 and the GG genotype rs1004819 of the IL-23R gene had more active disease. Our findings suggest that all of the nine analyzed IL-23R gene polymorphisms are seen more frequently than healthy controls in our study population. Besides, some SNPs were related to higher acute phase reactants and higher disease activity scores.

IL-23/IL-17 axis and soluble receptors isoforms sIL-23R and sIL-17RA in patients with rheumatoid arthritis-presenting periodontitis.

BACKGROUND: Rheumatoid arthritis (RA) and periodontitis (P) are chronic inflammatory diseases characterized by joint and radiographic bone loss, respectively. IL-23 and IL-17 have an essential role in the immunopathogenesis of RA, and P. IL-23 stimulates Th17 cells through which produces IL-17, IL-21, and RANKL. IL-17 stimulates fibroblasts to produce RANKL, which initiates bone loss in the joints in RA and the periodontal tissue in periodontitis. The aim of this study was to determine the expression pattern of IL-23/IL-17 axis and soluble receptors isoforms sIL-23R and sIL-17RA of patients with RA presenting P (RAP). MATERIAL AND METHODS: Healthy subjects (HS) (n = 42), patients with P (n = 40), RA (n = 20), and patients with RAP (n = 40) were included. Plasma samples were obtained to evaluate the IL-23, IL-17A, sIL-23R, and sIL-17RA by ELISA technique. A nonparametric Mann-Whitney U test was used to compare the differences between groups. A Chi-square was used to compare gender, grade and stage of periodontitis, and DAS28-ESR between the groups. Spearman's rank correlation coefficient was used to study the association between the molecules and clinical parameters. RESULTS: IL-23 levels were increased in the RAP group, and lower sIL-23R levels were found in the RAP groups. However, IL-17A was lower in the P and RAP group but not in RA patients. RAP group showed a decrease IL-17A levels in advanced stages of the periodontal disease. CONCLUSION: These results suggest that IL-23 and IL-17A tend to downregulate their expression patterns when patients present both rheumatoid arthritis and periodontitis.

Electroacupuncture inhibits IL-17/IL-17R and post-receptor MAPK signaling pathways in a rat model of chronic obstructive pulmonary disease.

OBJECTIVE: Interleukin (IL)-17, as a T-helper 17 cell (Th17) cytokine, plays a key role in chronic obstructive pulmonary disease (COPD) pathophysiology including chronic inflammation and airway obstruction, which lead to decreased pulmonary function. The aim of this study was to investigate the effect of acupuncture on IL-17, its receptor (IL-17R) and the mitogen-activated protein kinase (MAPK) signaling pathway, in a rat model of COPD. METHODS: The COPD model was induced in Sprague Dawley rats by exposure to cigarette smoke for 12 weeks. The model rats were treated with electroacupuncture (EA) at BL13 and ST36. The lung function and histology of the rats were observed. IL-17, tumor necrosis factor (TNF)-α, and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA) in bronchoalveolar lavage fluid (BALF) and in plasma. The leukocytes and macrophages in the BALF were counted. The expression levels of IL-17R were assayed in lung tissue by real-time polymerase chain reaction (PCR), western blotting, and immunohistochemistry. MAPK signaling pathway molecules including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK)1/2 and p38, and their phosphorylated forms, were observed in the lung by western blotting. RESULTS: Compared with the control group rats, lung function decreased and there was a severe inflammatory infiltration of the pulmonary parenchyma in the COPD rats. EA effectively improved lung function and alleviated the inflammatory infiltration in the lungs of COPD rats. EA also reversed the elevated total leukocyte and macrophage counts, the high levels of IL-17 and TNF-α, and the low IL-10 content in COPD rats. Meanwhile, EA downregulated the increased mRNA and protein expression of IL-17R, and significantly inhibited the elevated levels of phosphorylated JNK, ERK1/2, and p38 in the lungs of COPD rats. CONCLUSION: Our results suggest that the protective effects of acupuncture therapy on the lungs of COPD rats are likely related to inhibition of IL-17/IL-17R and the post-receptor MAPK signaling pathways.

TH17/IL23 cytokine gene polymorphisms in bullous pemphigoid.

BACKGROUND: TH17/IL-23 immune axis is considered to be involved in the pathogenesis of autoimmune and chronic inflammatory diseases. Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease, characterized by the presence of autoantibodies against the components of the dermal-epidermal junction. Animal studies and characterization of patient samples point toward a contribution of TH17 cells in BP pathogenesis. However, genetic polymorphisms in the genes of TH17/IL-23 cytokines have not yet been well investigated in BP. METHODS: Detection of polymorphisms in IL-17A (rs2275913 and rs3819025), IL-17F (rs2397084 and rs763780), IL-17RA (rs2229151), and IL-23R (rs2201841, rs7530511, rs11209026, and rs10889677) genes were performed following the collection of blood samples and DNA extraction from BP patients and controls. Gene expression of IL-23R was determined by quantitative RT-PCR analysis. RESULTS: The prevalence of IL-23R rs7530511 genotypes and alleles, as well as IL-23R rs2201841 alleles, is significantly different between the BP patients and controls. While the minor C-allele of IL-23R rs7530511 is highly present in the patients, the G-allele distribution of IL-23R rs2201841 is significantly more prevalent in the control individuals compared to the BP patients. Genotypes and alleles of other SNPs in IL-17A, IL-17F, and IL-17RA were similarly distributed in patients and controls. CONCLUSIONS: No alteration was found in the gene expression between wild and polymorphic genotypes of IL-23R (rs2201841 and rs7530511) variations, indicating they do not contribute to altering the levels of gene expression in blood. In summary, our data show that the alleles of two SNPs in IL-23R rs2201841 and rs7530511 are associated with BP.

Low Interleukin-22 Binding Protein Is Associated With High Mortality in Alcoholic Hepatitis and Modulates Interleukin-22 Receptor Expression.

INTRODUCTION: In alcoholic hepatitis (AH), high interleukin (IL)-22 production is associated with disease improvement, purportedly through enhanced infection resistance and liver regeneration. IL-22 binding protein (BP) binds and antagonizes IL-22 bioactivity, but data on IL-22BP in liver disease suggest a complex interplay. Despite the scarcity of human data, IL-22 is in clinical trial as treatment of AH. We, therefore, in patients with AH, described the IL-22 system focusing on IL-22BP and associations with disease course, and mechanistically pursued the human associations in vitro. METHODS: We prospectively studied 41 consecutive patients with AH at diagnosis, days 7 and 90, and followed them for up to 1 year. We measured IL-22 pathway proteins in liver biopsies and blood and investigated IL-22BP effects on IL-22 in hepatocyte cultures. RESULTS: IL-22BP was produced in the gut and was identifiable in the patients with AH' livers. Plasma IL-22BP was only 50% of controls and the IL-22/IL-22BP ratio thus elevated. Consistently, IL-22-inducible genes were upregulated in AH livers at diagnosis. Low plasma IL-22BP was closely associated with high 1-year mortality. In vitro, IL-22 stimulation reduced IL-22 receptor (R) expression, but coincubation with IL-22BP sustained IL-22R expression. In the AH livers, IL-22R mRNA expression was similar to healthy livers, although IL-22R liver protein was higher at diagnosis. DISCUSSION: Plasma IL-22BP was associated with an adverse disease course, possibly because its low level reduces IL-22R expression so that IL-22 bioactivity was reduced. This suggests the IL-BP interplay to be central in AH pathogenesis, and in future treatment trials (see Visual abstract, Supplementary Digital Content 5, http://links.lww.com/CTG/A338).

Systemic Th17 response in the presence of periodontal inflammation.

BACKGROUND: The relationship between periodontitis and the pathogenesis of other inflammatory diseases, such as diabetes, rheumatoid arthritis and obesity has been an important topic of study in recent decades. The Th17 pathway plays a significant role in how local inflammation can influence systemic inflammation in the absence of systemic pathology. OBJECTIVE: To determine Th17 biased-cells in systemically healthy patients in the presence of generalized chronic periodontitis. METHODOLOGY: A total of 28 patients were recruited without systemic inflammatory pathology, which was determined by clinical history, the Health Assessment Questionnaire (HAQ) and rheumatoid factor detection. Of these patients, 13 were diagnosed as healthy/gingivitis (H/G) and 15 as generalized chronic periodontitis (GCP). Th17 (CD4+CD161+) cells and Th17IL23R+ (CD4+CD161+IL-23R+) cells were quantified by flow cytometry, based on the total cells and on the lymphocyte region, termed the "enriched population" (50,000 events for each). RESULTS: The percentages of Th17 cells of the H/G and periodontitis groups were similar on total cells and enriched population (19 vs 21.8; p=4.134 and 19.6 vs 21.8; p=0.55). However, Th17IL23R+ cells differ significantly between periodontally healthy patients and generalized chronic periodontitis patients in both total cell (0.22% vs 0.65%; p=0.0004) and enriched populations (0.2% vs 0.75%; p=0.0266). CONCLUSIONS: GCP patients (otherwise systemically healthy) were characterized by increased Th17-proinflammatory cell phenotype positive for the IL-23 receptor in peripheral blood. The proportion of Th17 cells that are negative for the IL-23 receptor in the peripheral blood of systemically healthy patients seemed to be unaffected by the presence or absence of chronic periodontitis.

Prognostic value of serum soluble interleukin-23 receptor and related T-helper 17 cell cytokines in non-small cell lung carcinoma.

The signaling of interleukin (IL)-23 and its receptor (IL-23R) play a crucial role in the development of cancers. However, the clinical significance of human serum soluble IL-23R (sIL-23R) and its relationship with IL-23 are still not explored in non-small cell lung cancer (NSCLC). In our study, sIL-23R was first identified in the serum of NSCLC patients, but not in healthy controls, by proteomics. The IL-23R mRNA and protein were upregulated in NSCLC cell lines and tissues tested by quantitative PCR, western blot analysis and immunohistochemistry. The levels of sIL-23R, IL-23, and IL-17 in 195 NSCLC patients' serum were determined by ELISA, and high levels of sIL-23R were significantly associated with advanced N stage (P = .039), clinical stage (P = .007), and poor 5-year survival rate. In vitro, sIL-23R was shown binding to IL-23 and the balance could affect patients' N and T stage, overall survival, and downstream cytokine IL-17 in a potential antagonistic relationship. Although sIL-23R, IL-23, and IL-17 were all associated with poor prognosis, only the sIL-23R/IL-23 ratio (hazard ratio, 1.945; 95% confidence interval, 1.147-3.299; P = .014) was found to be an independent factor for prognosis. Therefore, we identified fragments of soluble cytokine receptor of IL-23R with affinity ability to its natural ligand IL-23 in NSCLC patients' serum. The balance between the 2 antagonists can work as a potential prognostic serum marker.

Dysregulation in IL-6 receptors is associated with upregulated IL-17A related signaling in CD4+ T cells of children with autism.

Autism spectrum disorder (ASD) is a heterogeneous syndrome characterized by dysregulations in speech and social interactions as well as repetitive and stereotypical behavioral patterns in which immune system plays a significant role. IL-6, an essential cytokine for polarization of Th0 cells into Th17 cells has been demonstrated to be crucial in the etiology of ASD in past studies both in humans and mice. Th17 cells are also believed to be central players in the pathogenesis of ASD through release of IL-17A. However, there is still insufficient data regarding identification of Th17 cells with respect to IL-6 signaling in ASD subjects. Therefore, this study explored IL-6 receptors (IL-6R/sIL-6R) and Th17 (p-STAT3/IL-17A/IL-23R) related markers comprehensively in the blood of typically-developing control (TDC, n = 35) and ASD children (n = 45). Our data show that there is enhanced sIL-6R levels in plasma and CD4+ T cells of ASD subjects as compared to TDC group. Increased sIL-6R signaling is associated with upregulated Th17 development in ASD subjects. Further, severe ASD subjects have higher inflammation in terms of IL-6/IL-17A related signaling as compared to moderate ASD patients. Furthermore, treatment of CD4 + T cells in vitro with IL-6 leads to much greater upregulation of p-STAT3, and IL-17A in ASD subjects than similarly treated CD4+ T cells in TDC group. Antagonism of IL-6 signaling by SC144 in vitro led to blockade of IL-6 mediated effects on CD4+ T cells. These data display unequivocally that IL-6 signaling components are dysregulated which play a crucial in enhancement of Th17 development in ASD subjects.

Systemic Th17 response in the presence of periodontal inflammation

Abstract The relationship between periodontitis and the pathogenesis of other inflammatory diseases, such as diabetes, rheumatoid arthritis and obesity has been an important topic of study in recent decades. The Th17 pathway plays a significant role in how local inflammation can influence systemic inflammation in the absence of systemic pathology. Objective: To determine Th17 biased-cells in systemically healthy patients in the presence of generalized chronic periodontitis. Methodology: A total of 28 patients were recruited without systemic inflammatory pathology, which was determined by clinical history, the Health Assessment Questionnaire (HAQ) and rheumatoid factor detection. Of these patients, 13 were diagnosed as healthy/gingivitis (H/G) and 15 as generalized chronic periodontitis (GCP). Th17 (CD4+CD161+) cells and Th17IL23R+ (CD4+CD161+IL-23R+) cells were quantified by flow cytometry, based on the total cells and on the lymphocyte region, termed the "enriched population" (50,000 events for each). Results: The percentages of Th17 cells of the H/G and periodontitis groups were similar on total cells and enriched population (19 vs 21.8; p=4.134 and 19.6 vs 21.8; p=0.55). However, Th17IL23R+ cells differ significantly between periodontally healthy patients and generalized chronic periodontitis patients in both total cell (0.22% vs 0.65%; p=0.0004) and enriched populations (0.2% vs 0.75%; p=0.0266). Conclusions: GCP patients (otherwise systemically healthy) were characterized by increased Th17-proinflammatory cell phenotype positive for the IL-23 receptor in peripheral blood. The proportion of Th17 cells that are negative for the IL-23 receptor in the peripheral blood of systemically healthy patients seemed to be unaffected by the presence or absence of chronic periodontitis.

A longitudinal study highlights shared aspects of the transcriptomic response to cardiogenic and septic shock.

BACKGROUND: Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock. METHODS: We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock. RESULTS: In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend. CONCLUSIONS: This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02141607. Registered 19 May 2014.

IL17RC affects the predisposition to thoracic ossification of the posterior longitudinal ligament.

BACKGROUND: Thoracic ossification of the posterior longitudinal ligament (T-OPLL) can cause thoracic spinal stenosis, which results in intractable myelopathy and radiculopathy. The etiology of T-OPLL is unknown and the condition is difficult to treat surgically. Whole-genome sequencing identified a genetic variant at rs199772854 of the interleukin 17 receptor C (IL17RC) gene as a potentially pathogenic locus associated with T-OPLL. We aimed to determine whether the rs199772854A site mutation causes abnormal expression of the IL17RC in Han Chinese patients with T-OPLL and predict the possible pathogenic mechanisms of T-OPLL. Analyses were performed to determine whether IL17RC is involved in the pathogenicity of T-OPLL. METHODS: Peripheral blood and OPLL tissue were collected from a total of 72 patients with T-OPLL disease (36 patients carrying the rs199772854A site mutation in IL17RC and 36 wild-type patients). The expression of IL17RC was analyzed by enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, immunohistochemistry, and Western blotting. RESULTS: rs199772854A mutation resulted in markedly increased IL17RC gene expression levels in peripheral blood samples and the OPLL tissue obtained following clinical surgery (P < 0.05). CONCLUSIONS: The results suggest that the rs199772854A site mutation of IL17RC can significantly increase the expression of IL17RC. The IL17RC gene rs199772854A site polymorphism is a potential pathogenic mutation in T-OPLL disease, which may be associated with the occurrence of T-OPLL.

The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.

BACKGROUND: Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD. OBJECTIVE: To analyze blood inflammatory proteins of early pediatric AD. METHODS: Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD. RESULTS: In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11). LIMITATIONS: Different baseline expression levels in healthy pediatric vs adult samples. CONCLUSIONS: Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.

Inflammation associated with volume reduction in the gray matter and hippocampus of older patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) and aging appear to be associated with inflammatory activation. Inflammatory processes might affect hippocampal function, neurogenesis, and gray matter loss. This study investigated the relationship between BD-specific brain regions and the total gray matter volume, peripheral inflammatory markers, and clinical features in older patients with BD. METHODS: We recruited euthymic patients with bipolar I disorder aged ≥50 years to undergo whole-brain magnetic resonance imaging. Each brain region was divided by an individual's total intracranial volume to obtain that brain region's volume in percentage relative to the total intracranial volume. We measured the plasma levels of soluble tumor necrosis factor receptor-1 (sTNF-R1), soluble interleukin (IL)-2 receptor (sIL-2R), sIL-6R, IL-1ß, and IL-1 receptor antagonist when patients were euthymic. Clinical data were obtained by reviewing available medical records and interviewing patients along with their reliable others. RESULTS: There were 32 patients with a mean age of 61.2 ±â€¯8.3 years and a mean age at illness onset of 33.4 ±â€¯13.8 years in this study. Stepwise regression showed that the right hippocampal volume was negatively associated with the levels of sIL-2R and sTNF-R1. The left hippocampal volume were negatively associated with the sIL-2R level and body mass index. The total gray matter volume had an inverse relationship with sTNF-R1 and IL-1ß levels. The duration of bipolar illness, lithium treatment, and antipsychotic use were not associated with hippocampal and total gray matter volumes. CONCLUSIONS: It is suggested that persistent inflammation is associated with reduction of hippocampal and gray matter volumes in older patients with BD. This phenomenon is supported by increases in sTNF-R1, sIL-2R, and IL-1ß levels. Neuroinflammation due to aging, obesity, and BD pathophysiology may play a role in BD neuroprogression across the life span.

Increased interleukin-23 receptor (IL-23R) expression is associated with disease severity in acute-on-chronic liver failure.

BACKGROUND: Th17 cells mediated immune response is important in chronic hepatitis B (CHB) infection and inflammation associated diseases; however, little is known about their immunopathogenic role in acute-on-chronic liver failure (ACLF). Interleukin-23 receptor (IL-23R) is essential for the generation of pathogenic Th17 cells; therefore, we aimed to evaluate IL-23R expression and its correlation with disease severity in ACLF. METHODS: Forty-two patients with ACLF (HBV and alcohol-related), thirty-two with CHB and twenty healthy controls (HC) were studied. Circulating and intrahepatic profile of Th17 cells and IL-23R was investigated. Association of IL-23R with disease severity was determined. RESULTS: Circulating Th17 cells were significantly increased in both ACLF groups (P = 0.03, P = 0.006) than CHB and HC. Percentage of Th17 cells was higher in liver than peripheral blood of ACLF patients (P = 0.04). Expression of IL-23R was immensely up-regulated on Th17 cells of ACLF patients. Importantly, IL-23R not only correlated with the increased percentage of Th17 cells but also had significant association with inflammation (P = 0.03) and clinical disease severity indices including Child-Turcotte-Pugh (P = 0.001) and Model for End-Stage Liver Disease (P = 0.002) scores. The ACLF non-survivors showed higher IL-23R expression (P = 0.01). Transcription factor retinoic acid receptor-related orphan nuclear receptor gamma-t (ROR-γt) was also high in circulation and in liver of ACLF patients and it positively correlated with ALT levels (P = 0.03). Surface receptors, including CCR6, IL-17R and pro-inflammatory cytokines IL-17A, IL-22, CXCL8 and GM-CSF were highly augmented in ACLF. CONCLUSION: ACLF patients express high IL-23R on Th17 cells which induces inflammation and strongly correlates with liver disease severity.

Soluble interleukin-27 receptor alpha is a valuable prognostic biomarker for acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after allogeneic haematopoietic stem cell transplantation. Interleukin-27 receptor alpha (IL-27Rα) is a co-receptor of IL-27, an inflammatory cytokine that possesses extensive immunological functions. It has been reported that IL-27Rα can exist in its soluble form (sIL-27Rα) in human serum and can function as a natural IL-27 antagonist. In this study, we examined serum sIL-27Rα levels and evaluated their prognostic value in aGVHD. A total of 152 subjects were prospectively recruited and separated into the training group (n = 72) and the validation group (n = 80). Serum sIL-27Rα at neutrophil engraftment was measured by ELISA. In the training set, a cut-off value of sIL-27Rα = 59.40 ng/ml was identified to predict grade II-IV aGVHD (AUC = 0.735, 95% CI 0.618-0.853, P = 0.001). Cumulative incidences of grade II-IV aGVHD (P = 0.004), relapse rate (P = 0.008), and non-relapse mortality (P = 0.008) in patients with low serum sIL-27Rα (≥59.40 ng/ml) were significantly higher than those of patients with high serum sIL-27Rα (<59.40 ng/ml). Multivariate analysis confirmed that low sIL-27Rα level (HR = 2.83 95% CI 1.29-6.19, P < 0.01) was an independent risk factor for predicting grade II-IV aGVHD. In addition, serum sIL-27Rα was positively correlated with IL-27 (R = 0.27, P = 0.029), IL-10 (R = 0.37, P = 0.0015) and HGF (R = 0.27, P = 0.0208), but was negatively correlated with TNFR1 (R = -0.365, P = 0.0022) and ST2 (R = -0.334, P = 0.0041), elafin (R = -0.29, P = 0.0117), and REG3α (R = -0.417, P = 0.0003). More importantly, the threshold value of sIL-27Rα was then validated in an independent cohort of 80 patients (AUC = 0.790, 95% CI 0.688-0.892, P < 0.001). Taken together, our findings suggested that serum sIL-27Rα at neutrophil engraftment maybe a valuable prognostic biomarker in predicting the incidence of moderate-to-severe aGVHD.

The role of IL-23/IL-17 axis in human kidney allograft rejection.

Th17 cell subset has been implicated in autoimmune diseases, tumor immunity and, transplant rejection. In order to investigate the role of IL-17/IL-23 pathway in allograft outcome, intragraft expression of IL-17 mRNA and single nucleotide polymorphisms (SNPs) of IL-17A, IL-17F, IL-17RC, and IL23R genes were evaluated with a quantification of IL-17A, IL-17F, and IL-23 plasma levels. This study revealed that recipients with acute rejection (AR) had a significant increase in IL-17A mRNA expression levels after transplantation compared to controls (P = 0.037). Moreover, IL-17A plasma levels were significantly higher in AR group; pretransplantation (Day-1 [D-1]): P = 0.00022 and posttransplantation (Day 7 [D7]): P < 10-14 . IL-17F and IL-23 plasma levels were significantly higher in AR at D7 only (47.86 vs. 22.99 pg/ml; and 33.82 vs. 18.811 pg/ml; P = 0.015 and P < 10-17 , respectively). Using receiver-operating characteristic curves, D7 IL-17A and IL-23 plasma levels exhibited excellent sensitivities and specificities for predicting AR. Genetic study revealed no association between IL-17A, IL-17F, IL-17RC, and IL23R studied SNPs and AR. Nevertheless, a significant improvement of graft survival was found in kidney transplant recipients carrying IL-17F-rs763780*A/A, IL-17RC*G/G, and *G/A genotypes. Besides, IL-17A mRNA levels were significantly higher in patients carrying the IL-23R*G/G genotype comparatively to those with *G/A genotype. Based on these findings, significant increase of IL-17A mRNA and protein levels in AR recipients that are genetically controlled highlights the role of this cytokine that can be a useful clinical biomarker to predict early acute renal allograft rejection.

Increased serum IL-36α and IL-36γ levels in patients with systemic lupus erythematosus: Association with disease activity and arthritis.

IL-36 cytokines (IL-36Ra, IL-36α, IL-36ß and IL-36γ) belong to the IL-1 family and have been linked to several autoimmune diseases. However, little is known about the relationships between systemic lupus erythematosus (SLE) and IL-36 cytokines. In this study, serum IL-36 cytokine levels were determined by enzyme-linked immunosorbent assay (ELISA), and their associations with SLE-related parameters were analyzed in 72 SLE patients and 63 healthy controls. Additionally, IL-36 cytokine mRNA levels were assessed in 30 of 72 SLE patients and 20 of 63 healthy controls using real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). Compared to healthy controls, SLE patients had significantly decreased serum IL-36Ra levels (P = 0.001) and markedly increased serum IL-36α and IL-36γ levels (P = 0.004 and P = 0.001, respectively). Serum IL-36α and IL-36γ levels were significantly higher in active SLE patients [SLE Disease Activity Index (SLEDAI) score ≥ 5] than in inactive patients (SLEDAI score ≤ 4) (P = 0.020 and P = 0.017, respectively). Serum IL-36α and IL-36γ levels were strongly correlated with SLEDAI score (r = 0.308, P = 0.008 and r = 0.400, P = 0.001, respectively) and complement C3 levels (r = -0.276, P = 0.019 and r = -0.314, P = 0.007, respectively). Moreover, SLE patients with arthritis had significantly higher serum IL-36α and IL-36γ levels than those without arthritis (P = 0.001 and P < 0.001, respectively). Our study indicates that the imbalanced antagonist/agonist profile of IL-36 cytokines may be linked to SLE pathogenesis. Furthermore, IL-36α and IL-36γ may participate in arthritis and may be good biomarkers of SLE disease activity.

Neuroinflammation, cortical activity, and fatiguing behaviour during self-paced exercise.

The present study aimed to identify whether or not the release of interleukin (IL)-6 and soluble (s) IL-6 receptor (R) is associated with fatiguing behaviour and changes in cortical activity during self-paced exercise. Relationships between the IL-6 and its soluble receptors, total work, reductions in power output, and changes in slow, alpha (α) and fast, beta (ß) brain waves during self-paced exercise were evaluated. Different intensities and environments were used to manipulate the release of IL-6, whereby seven active males cycled for 60 min in heat stress (HS) or thermoneutral (TN) environments at a clamped rating of perceived exertion (RPE) equating to low intensity (RPE = 12) or high intensity (RPE = 16). IL-6 and sIL-6R were positively associated with total work, but not with reductions in power output. There was greater α activity in high-intensity conditions, which was associated with the reduction in power output. Both high-intensity conditions appeared to have greater ß activity, and there was a positive correlation between ß activity and total work and ß activity and sIL-6R. We conclude that IL-6 and sIL-6R may contribute to perturbations in cortical activity and are associated with total work output, but reductions in power output are likely influenced greater by other internal and external factors.