Plasma Levels Of IL-17A Research Articles

Elevated plasma levels of Th17-related cytokines are associated with increased risk of atrial fibrillation.

We performed a matched case-control study using a propensity score matching, to assess the association of Th17-related cytokines, including interleukin (IL) 17A (IL-17A), IL-17F, IL-21, IL-22 and IL-6, along with interferon-γ (IFN-γ), IL-10, IL-9, and IL-4, with the risk of AF. A total of 336 patients with AF were matched 1:1 with patients without AF. Plasma levels of cytokines were measured using Luminex xMAP assays. The plasma levels of all examined cytokines were significantly higher in AF patients than controls (P < 0.05), and these cytokines were highly correlated with each other (P < 0.01). A multivariate conditional logistic regression analysis showed that elevated plasma levels of IL-17A, IL-17F, IL-21, IL-22, IFN-γ, IL-10, IL-9 and IL-6 were significantly associated with AF risk independently of potential confounders. There were no significant differences in plasma levels of examined cytokines between paroxysmal and chronic AF patients. IL-17A, IL-21, IL-10 and IL-6 levels were positively correlated with left atrial diameter; IL-17F level was negatively correlated with left ventricle ejection fraction among AF patients (P < 0.05). Elevated plasma levels of Th17-related cytokines were independently associated with increased an risk of AF; hence, Th17-related cytokines may be involved in the pathogenesis of AF.

RS8193036 POLYMORPHISM OF IL-17A GENE IN A KAZAKH POPULATION AND ITS ASSOCIATION WITH PLASMA IL-17A AMONG ERYSIPELAS PATIENTS

We studied associations between rs8193036 polymorphism of IL-17A gene (C737T) and plasma levels of IL-17A in patients with erysipelas and healthy subjects in a Kazakh population. The rs8193036 polymorphism was assessed in 95 patients with erysipelas and 383 control subjects. The IL-17A (rs8193036) polymorphism was studied by a real time polymerase chain reaction. Plasma levels of IL-17A were assessed in 90 patients with erysipelas and 90 healthy subjects by enzyme immunoassay. Categorical data were analyzed using Pearson's Chi tests and odds ratios (OR) with 95 % confidence intervals (CI). Continuous data were studied using Kruskal -Wallis and Mann-Whitney tests with Bonferroni correction. We found that T allele occurred more frequently (OR = 1.41; 95 % CI: 0.21-0.92) while allele C (OR = 0.71; 95 % CI: 0.51-0.99) and genotype CC (OR = 0.44; 95% CI: 0.21-0.92) occurred less frequently in cases than in controls. In erysipelas patients with CC genotype the level of IL-17A was significantly higher (p = 0.010) compared to the carriers of CT genotype. Also, the levels of IL-17A in patients with erysipelas was higher than among controls in groups with both CC and CT genotypes (p = 0.023 and p = 0.020, respectively). These data suggest that the rs8193036 polymorphism of IL-17A gene may play a role in the etiology of erysipelas, but other factors are also involved.

Experimental Persistent Infection of BALB/c Mice with Small-Colony Variants of Burkholderia pseudomallei Leads to Concurrent Upregulation of PD-1 on T Cells and Skewed Th1 and Th17 Responses.

BackgroundBurkholderia pseudomallei (B. pseudomallei), the causative agent of melioidosis, is a deadly pathogen endemic across parts of tropical South East Asia and Northern Australia. B. pseudomallei can remain latent within the intracellular compartment of the host cell over prolonged periods of time, and cause persistent disease leading to treatment difficulties. Understanding the immunological mechanisms behind persistent infection can result in improved treatment strategies in clinical melioidosis.MethodsTen-day LD50 was determined for the small-colony variant (SCV) and its parental wild-type (WT) via intranasal route in experimental BALB/c mice. Persistent B. pseudomallei infection was generated by administrating sub-lethal dose of the two strains based on previously determined LD50. After two months, peripheral blood mononuclear cells (PBMCs) and plasma were obtained to investigate host immune responses against persistent B. pseudomallei infection. Lungs, livers, and spleens were harvested and bacterial loads in these organs were determined.ResultsBased on the ten-day LD50, the SCV was ~20-fold less virulent than the WT. The SCV caused higher bacterial loads in spleens compared to its WT counterparts with persistent B. pseudomallei infection. We found that the CD4+ T-cell frequencies were decreased, and the expressions of PD-1, but not CTLA-4 were significantly increased on the CD4+ and CD8+ T cells of these mice. Notably, persistent infection with the SCV led to significantly higher levels of PD-1 than the WT B. pseudomallei. Plasma IFN-γ, IL-6, and IL-17A levels were elevated only in SCV-infected mice. In addition, skewed plasma Th1 and Th17 responses were observed in SCV-infected mice relative to WT-infected and uninfected mice.ConclusionB. pseudomallei appears to upregulate the expression of PD-1 on T cells to evade host immune responses, which likely facilitates bacterial persistence in the host. SCVs cause distinct pathology and immune responses in the host as compared to WT B. pseudomallei.

IL-23/Th17 axis is not influenced by TNF-blocking agents in ankylosing spondylitis patients.

BackgroundAdvances in pathophysiology and treatment of ankylosing spondylitis (AS) was recently demonstrated. However, the effect of anti-TNF in the newly described inflammatory pathways involved pathogenesis of this disease remains to be determined. The aim of our study was, therefore, to investigate long-term influence of anti-TNF drugs in IL-23/IL-17 axis of AS patients and their possible correlation with treatment, clinical, laboratory and radiographic parameters.MethodsEighty-six AS anti-TNF naïve patients, 47 referred for anti-TNF therapy (active-AS; BASDAI ≥ 4) and 39 with BASDAI < 4 (control-AS) were included. The active group was evaluated at baseline, 12-months and 24-months after TNF blockade and compared at baseline to control-AS group and to 47 healthy age- and gender-matched controls. Plasma levels of IL-17A, IL-22, IL-23 and PGE2 were measured. Non-steroidal anti-inflammatory drugs (NSAIDs) intake were recorded every 6 months. Radiographic severity and progression was assessed by mSASSS at baseline and 24 months after therapy.ResultsAt baseline, active-AS group presented higher IL-23 and PGE2 levels compared to control-AS group (p < 0.001 and p = 0.008) and to healthy controls (p < 0.001 and p = 0.02). After 24-months of TNF blockade, IL-23 and PGE2 remained elevated with higher levels compared with the healthy group (p < 0.001 and p = 0.03) in spite of significant improvements in all clinical/inflammatory parameters (p < 0.001). Further analysis of 27 anti-TNF-treated patients who achieved a good response (ASDAS-CRP < 2.1,with a drop ≥ 1.1) at 24-months revealed that IL-23 plasma levels remained higher than healthy controls (p < 0.001) and higher than control-AS group with similar disease activity (ASDAS-CRP < 2.1, p = 0.01). In active-AS group (n = 47), there was a strong correlation between IL-23 and IL-17A at baseline, 12-months and 24-months after anti-TNF therapy (p ≤ 0.001).ConclusionThis study provides novel data demonstrating that the IL-23/IL-17 axis is not influenced by TNF blockade in AS patients despite clinical and inflammation improvements and NSAID intake.

Faecalibacterium prausnitzii supernatant ameliorates dextran sulfate sodium induced colitis by regulating Th17 cell differentiation.

To explore the preventive and therapeutic effects of Faecalibacterium prausnitzii (F. prausnitzii) supernatant on dextran sulfate sodium (DSS) induced colitis in mice. Forty C57BL/6J male mice were randomly divided into four groups: control group, model group, treatment group, and prevention group. Mice were weighed daily. On day 10, the colon length was measured, the colorectal histopathologic damage score (HDS) was assessed, and plasma interleukin (IL)-17A, IL-6, and IL-4 levels were detected by enzyme-linked immunosorbent assay. The expression of transcription factor retinoic acid-related orphan receptor-γt (RORγt) and IL-17A in colon inflammatory mucosa tissue were determined by immunohistochemical assay, and the expression levels of RORγt mRNA, IL-17A mRNA, and IL-6 mRNA were detected by real-time quantitative polymerase chain reaction (PCR). The proportion of Th17 in mononuclear cells in spleen was assayed by fluorescence activated cell sorter. When compared with the model group, the colon length (P < 0.05) and body weight (P < 0.01) in the treatment and prevention groups were significantly increased, and the colon HDS was decreased (P < 0.05 and P < 0.01). There was no statistical difference between the treatment group and prevention group. After treatment with F. prausnitzii supernatant, the plasma levels of IL-17A and IL-6 (P < 0.05), the protein and mRNA expression of IL-17A and RORγt, and the Th17 cell ratio of spleen cells (P < 0.01) were significantly decreased compared to the model group. Plasma IL-4 level in the prevention group was significantly higher than that in the model group (P < 0.05), but there was no significant difference between these two groups in the expression of IL-6 in both the plasma and colon mucosa tissues. F. prausnitzii supernatant exerts protective and therapeutic effects on DSS-induced colitis in mice, probably via inhibition of Th17 differentiation and IL-17A secretion in the plasma and colon mucosa tissues. It can also improve colitis in mice by downregulating IL-6 and prevent colitis by upregulating IL-4.

Decreased circulating Th22 and Th17 cells in patients with aplastic anemia

BackgroundAplastic anemia (AA) is an immune-mediated disorder and mainly related to active destruction of hematopoietic cells by effector T lymphocytes. T helper (Th) 22 cells characterized as a novel subset of CD4+ T cells participate in the pathogenesis of autoimmune and hematological diseases. However, the role of Th22 subset in AA remains unknown. Methods31 untreated AA patients and 30 healthy controls were included in this study. The percentages of Th22, Th17 and pure Th17 cells in peripheral blood were detected by flow cytometry. ELISA to measure interleukin (IL)-22 and IL-17A plasma levels and qRT-PCR for the mRNA levels of Th22 and Th17 related molecules were performed. ResultsThe proportions of Th22, pure Th17, Th17 cells and plasma levels of IL-22 were significantly lower in untreated AA patients than those in normal controls. A positive correlation was found between Th22 and pure Th17 cells in AA. Moreover, percentages of Th22 cells correlated positively with reticulocyte counts and percentages. In addition, STAT3/STAT5 mRNA expression ratio was elevated in AA patients. ConclusionTogether, our results showed Th22 cells correlating with clinical characteristics of AA patients, indicating a possible role of Th22 immune response in the pathogenesis and therapeutic intervention of AA.

Increased miR-155 Expression in Peripheral Blood Mononuclear Cells of Primary Immune Thrombocytopenia Patients Was Correlated with Serum Cytokine Profiles

We investigated the possible pathogenic role of a microRNA (miR-155) in primary immune thrombocytopenia (ITP). We used quantitative real-time PCR to determine the relative expression of miR-155 and SOCS1 (suppressor of cytokine signaling) mRNA in peripheral blood mononuclear cells (PBMCs) from 28 ITP patients and 28 healthy controls. Cytokine plasma levels were determined by ELISA. Possible associations between miR-155 levels and serum cytokine concentrations were assessed using Spearman or Pearson correlation analysis. Seven naive ITP patients were followed and the effects of medical treatment on miR-155 levels were assessed. Compared to healthy controls, ITP patients had increased miR-155 and decreased SOCS1 mRNA levels. ITP patients also had increased plasma IL-17A and decreased IL-4, IL-10 and TGF-β₁ levels. miR-155 levels were negatively correlated with platelet counts, SOCS1 mRNA levels, and the plasma levels of IL-4, IL-10 and TGF-β₁, but positively correlated with plasma IL-17A levels. Medical treatment for ITP decreased miR-155 levels. Thus, our results suggest that miR-155 might be involved in the pathogenesis of ITP by regulating cytokine profiles, which may be mediated by miR-155 targeting SOCS1. © 2014 S. Karger AG, Basel

Increased plasma IL-17F levels in rheumatoid arthritis patients are responsive to methotrexate, anti-TNF, and T cell costimulatory modulation.

The aims of this study are to compare plasma levels of IL17A, A/F, and F biomarkers in RA patients versus controls, and to determine responsiveness to methotrexate (MTX), anti-TNFs, and abatacept. We selected plasma samples from RA cohorts consisting of a cross-sectional RA cohort (N = 78) not receiving DMARDs at the time of sampling, as well as from longitudinal drug start cohorts (N = 71 patients) with pre/post samples including anti-TNF, abatacept, and MTX-treated patients. We assayed IL-17A, IL-17F, and IL17-A/F using a highly sensitive immunoassay system. Plasma levels of IL-17A, IL-17A/F, and IL-17F were all significantly increased in RA versus controls. The difference was largest in IL-17F, with median IL-17F levels in RA patients being approximately 18-fold higher than controls (81 pg/mL in RA vs. 4.4 pg/mL in controls, p < 0.001). Among the forms of IL-17, only IL-17F was decreased after therapy in the MTX cohort (p = 0.006), abatacept cohort (p < 0.001), and anti-TNF cohorts (p = 0.02), whereas IL-17A and IL-17A/F were not significantly decreased for any of the three drug cohorts. Synovial fluid analysis demonstrated higher IL-17F levels in RA (p = 0.016) than healthy controls. These results suggest a specific role for IL-17F in human RA pathogenesis and as a therapeutic target.

Interleukin-1 receptor antagonist correlates with hepatic venous pressure gradient and predicts occurrence of overall complications and bacterial infections in patients with cirrhosis.

The plasma levels of interleukin (IL)-1α, IL-1β and IL-1 receptor antagonist (IL-1Ra) are increased in cirrhotic patients. We aimed to investigate whether these cytokines correlate with hepatic venous pressure gradient (HVPG), the severity of liver cirrhosis and complications of cirrhosis. Sixty-three cirrhotic patients that underwent hemodynamic studies in Taipei Veterans General hospital were enrolled retrospectively. Plasma levels of IL-1α, IL-1β, IL-1Ra and endotoxin were assessed by enzyme-linked immunosorbent assay. Plasma obtained from 11 healthy subjects served as normal controls. Plasma levels of IL-1α, IL-1β and IL-1Ra were increased in cirrhotic patients compared with controls. IL-1Ra levels significantly correlated with plasma endotoxin levels, Child-Pugh scores, Model of End-Stage Liver Disease (MELD) scores and HVPG. On multivariate analysis, higher IL-1Ra levels (≥760 pg/mL) predicted the occurrence of portal hypertension-related complications and the development of bacterial infections independently of the MELD scores and portal pressure. Furthermore, higher IL-1Ra levels also predicted the survival in patients without hepatocellular carcinoma. The plasma IL-1Ra level correlates with HVPG. Additionally, it may predict the occurrence of portal hypertension-related complications and bacterial infections in cirrhotic patients and the survival in patients without hepatocellular carcinoma.

Plasma levels of IL-37 and correlation with TNF-α, IL-17A, and disease activity during DMARD treatment of rheumatoid arthritis.

The aim of this study was to assess the change of IL-37 concentrations in rheumatoid arthritis (RA) patients under Disease-modifying anti-rheumatic drug (DMARD) therapy, and to establish a correlation between Interleukin-37 and pro-inflammatory cytokines in plasma and disease activity. The plasma level of IL-37 was determined using ELISA in 50 newly diagnosed RA patients and 30 healthy controls (HC). Plasma levels of IL-17A, IL-6 and TNF-α were measured using flow a cytometric bead array assay. We found that the concentrations of IL-37, as well as IL-17A, IL-6 and TNF-α, were higher in plasma of RA patients compared to HCs. Compared to patients who did not respond to DMARD treatment, treatment of patients responsive to DMARDs resulted in down-regulation of IL-17A, IL-6 and TNF-α expression. The plasma level of the anti-inflammatory cytokine IL-37 was also decreased in drug responders after DMARD treatment. The plasma level of IL-37 in RA patients was positively correlated with pro-inflammatory cytokines (IL-17A, TNF-α) and disease activity (CRP, DAS28) in RA patients. IL-37 expression in RA and during DMARD treatment appears to be controlled by the level of pro-inflammatory cytokines. This results in a strong correlation between plasma levels of IL-37 and disease activity in RA patients.

Blood levels of cytokines in children with idiopathic partial and generalized epilepsy

PurposeAntiepileptic drugs have been reported to reduce the levels of serum immunoglobulins and affect the production and levels of certain cytokines. We investigated the effects of valproic acid (VPA) and topiramate (TPM) on the blood levels of interleukin (IL)-1α, IL-1β, IL-6, IL-10, and TNF-α in children with idiopathic generalized and partial epilepsy. MethodsForty prepubertal children aged 6–12 (mean 8.3±1.7) years, 19/40 (47.5%) female and 21/40 (52.5%) male, with idiopathic generalized or partial epilepsy diagnosed in the child neurology outpatient clinic were included. The patients were divided into two treatment groups: 20 were treated with VPA and 20 with TPM. The plasma levels of IL-1α, IL-1β, IL-6, IL-10, TNF-α were measured using ELISA method before the initiation of treatment and at the 6th and 12th months of the treatment. The Chi-square test was used to compare qualitative data. To compare the periods, recurrence measurements were done using variance analysis and Freidman 2-sided variance analysis. p<0.05 was considered as statistically significant. ResultsIn the VPA group, the levels of IL-1α significantly increased at 12 months while the levels of IL-10 decreased at 6 months of treatment compared to values before treatment (p<0.05). There was no significant difference in levels of IL-1β, IL-6, TNF-α (p>0.05). In the TPM group, lower levels of IL-10 were observed at 6th and 12th months compared to the onset of treatment (p<0.05). ConclusionThe results of this study demonstrated that VPA and TPM might lead to changes in the levels of cytokines in epileptic patients. The next step would be to investigate the relation of these findings to the outcome of epilepsy and response to treatment.

Interleukin‐17A plays an important role in endothelial cell activation and atherogenesis in ApoE−/− mice

Interleukin‐17 (IL‐17) cytokines are a family of pro‐inflammatory cytokines. IL‐17A has been implicated in numerous autoimmune and inflammatory diseases including atherosclerosis. However, the role of IL‐17A in early atherogenesis remained to be determined. The objective of our study is to determine the role of IL‐17A in early atherogenesis. Previously, using a bioinformatics approach, we found that IL‐17 receptors A and C, and adaptor protein, ACT1, are expressed in human vascular tissue, suggesting that IL‐17A has a role in chronic vascular inflammation. The data for the expression of these receptors and ACT1 were not available in mouse vascular tissue; however, using immunostaining, we found that IL‐17RA is expressed in mouse aorta. Moreover, plasma levels of IL‐17A are found to be increased in atherogenic ApoE−/− mice compared with wild type mice. IL‐17A treatment was found to induce pro‐inflammatory cytokines production in mouse aortic cells. Furthermore, to elucidate the role of IL‐17A in atherogenesis in ApoE−/− mice, we cross‐bred IL‐17A−/− mice with ApoE−/− mice to generate our double knock‐out mouse model, ApoE−/−IL‐17A−/− mice. Our data suggest that IL‐17A have an important role in early atherogenesis and with our novel mouse model we will be able to elucidate the function as well as the mechanism of IL‐17A in the endothelial cell activation and development of atherosclerosis in ApoE−/− mice.

Paneth Cell–Mediated Multiorgan Dysfunction after Acute Kidney Injury

Acute kidney injury (AKI) is frequently complicated by extrarenal multiorgan injury, including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of proinflammatory mediators drives multiorgan injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage-depleted mice decreased markedly. In addition, intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI.

IL-17A facilitates platelet function through the ERK2 signaling pathway in patients with acute coronary syndrome.

BackgroundPlatelet aggregation mediated by inflammation played a critical role in the development of coronary heart diseases (CHD). Our previous clinical researches showed that Th17 cells and their characteristic cytokine IL-17A were associated with the plaque destabilization in patients with acute coronary syndrome (ACS). However, the potent effect of IL-17A on platelets-induced atherothrombosis remains unknown.Methods and ResultsIn this study, we detected the plasma IL-17A levels and platelet aggregation in patients with stable angina (SA), unstable angina (UA), acute myocardial infarction (AMI) and chest pain syndrome (CPS). In addition, the markers of platelet activation (CD62P/PAC-1) and the mitogen-activated protein kinases (MAPKs) pathway were detected in platelets from ACS patients. We found that plasma IL-17A levels and platelet aggregation in patients with ACS (UA and AMI) were significantly higher than patients with SA and CPS, and the plasma IL-17A levels were positively correlated with the platelet aggregation (R = 0.47, P<0.01). In addition, in patients with ACS, the platelet aggregation, CD62P/PAC-1 and the phosphorylation of ERK2 signaling pathway were obviously elevated in platelets pre-stimulated with IL-17A in vitro. Furthermore, the specific inhibitor of ERK2 could attenuate platelet aggregation and activation triggered by IL-17A.ConclusionOur experiment firstly proved that IL-17A could promote platelet function in patients with ACS via activating platelets ERK2 signaling pathway and may provide a novel target for antiplatelet therapies in CHD.

Th17/IL-17 Might Play a Protective Role in CLL Immunity

Abstract 2843 Background:Immune system disorders play an important role in the development and progression of CLL. Many deficiencies, contributing to disease progression, were found in T cell populations. Th17 cells represent a recently-discovered distinct lineage of helper T-cells, characterized by IL-17 secretion. IL-17 play an active role in inflammation and autoimmune diseases, however the role of IL-17 and Th17 cells in CLL immunopathogenesis remains undefined. We investigated IL-17A mRNA and IL-17A protein expression in peripheral blood (PB) CD4+ T cells and the plasma levels of IL-17 in 70 untreated patients with CLL in the context of clinical and immunological parameters. Th17 cell percentage was measured also in the bone marrow of CLL patients. The control group consisted of 20 healthy age-matched subjects. Materials and methods:Quantitative ‘real-time' reverse transcription-polymerase chain reaction (qRT-PCR) was used for the analysis of IL-17A mRNA in PB CD4+ T-cells. Intracellular IL-17A expression in CD3+/CD4+cells was analyzed using a three-color flow cytometry technique. Plasma levels of IL-17A, IL-4 and IL-10 were measured by ELISA. Results:None of the CD4+ T cells in the samples obtained from healthy volunteers (HV) contained detectable amounts of IL-17 mRNA, whereas it could be found in 5 out of 70 CLL samples. All CLL patients with detectable IL-17 mRNA in T-cells were in 0 Rai stage and negative both for ZAP-70 and CD38 expression. It is possible that IL-17 mRNA in these cells is expressed only for a short time thus evading detection by PCR, or that CLL cells contain low amounts of the IL-17 transcript and the RT-PCR method was not sufficiently sensitive to detect these small amounts. Frequently, in HV as well as in CLL patients, the percentage of CD4+ T cells with intracellular IL-17 expression in non-activation assays was lower than 1%, comparable to the level of autofluorescence. Despite the fact that IL-17 mRNA was not detected in the T cells of the majority of CLL patients, IL-17 protein was present in T cells after PMA and ionomycin stimulation. We found a significantly higher median percentage of CD4+/CD3+/IL-17+ cells in CLL patients (18.2%) than in HV (2.9%) (p<0.01). Median percentage of Th17 cells was significantly higher in CLL patients in stages 0–1 according to Rai, as compared with stages 2–4 (36.2% vs 4.5%, p<0.05). There were no differences in Th17 percentages between the PB and BM of CLL patients. Accordingly, the IL-17 plasma level was significantly higher in CLL patients than in HV (101.9 pg/ml vs 75.6 pg/ml; p<0.05) and there was a significant correlation between Th17 cell percentage and IL-17 plasma level. There was also significant correlation between the percentages of Th17 and iNKT cells (R=0.56; p<0.05), and inverse correlations between the percentage of Th17 and: Treg cells (R=−0.28; p<0.05), CD4+IL-4+ (R=−0.55; p<0.05) and CD4+TNF+ T cells (R=−0.59; p<0.01). The percentage of Th17 inversely correlated with β2-microglobulin serum level (R=−0.29; p<0.05) and the expression of ZAP-70 (R=−0.244; p<0.05) and CD38 (R=−0.33; p<0.01). The plasma level of IL-17 inversely correlated with the stage of disease (R=−0.23; p<0.05), IL-10 (R=−0.56; p<0.01) and TNF (R=−0.66; p<0.01) plasma levels, CD38 antigen (R=−0.25; p<0.05) and ZAP-70 expression (R=−0.28; p<0.05). In patients requiring therapy during the observation period, the median percentage of Th17 cells and median plasma IL-17 level were significantly lower comparing to untreated ones (5.7% vs 23.1%, p<0.05; 53.8 vs 95.6 pg/ml, p<0.05; respectively). Moreover, median plasma IL-17A level correlated with the time from CLL diagnosis to the start of therapy (R=0.49; p<0.01). Conclusions: both the Th17 cell percentage, and the IL-17 plasma level are significantly higher in the PB of untreated CLL patients compared with the HV, and IL-17 mRNA expression was found only in the T cell of CLL patients, but not in the control group. Correlations found with disease activity parameters, the subsets of T cells involved in tumor surveillance, and also with the length of time from diagnosis to the start of therapy, suggest an important protective role for Th17 cells in CLL immunity. Disclosures:No relevant conflicts of interest to declare.

IL-17A in LCH: Systemic Biomarker, Local Factor, or None of the Above?

Langerhans cell histiocytosis (LCH) is an enigmatic disease characterized by the infiltration of monocytes, macrophages, and dendritic cells, including Langerhans cells, into affected tissues. These immune cells traffic aberrantly, leaving inflammatory sequelae, organ dysfunction, endocrine deficits, and in rare cases a devastating neurodegenerative process in their wake. There remains much to learn about LCH, as debate persists as to whether it is a reactive disease of deregulated immune function or a bona fide neoplastic process; moreover, a molecular understanding of its pathobiology is lacking. Therefore, the finding from the Delprat group that interleukin (IL)-17A is elevated in the serum of LCH patients and may be involved in its pathogenesis was very welcome.1 However, in this issue, Peters et al. report that they have been unable to validate this finding, having failed to identify IL-17A at either the RNA or the protein level in a large number of LCH lesions.2 Just as independent validation of a novel biological finding is of principal importance in its garnering acceptance, so too should we value conflicting data and try to understand the discrepancies at hand.

Subcutaneous immunization with heat shock protein-65 reduces atherosclerosis in Apoe−/− mice

ObjectiveTo modulate atherosclerosis by combining subcutaneous immunization with heat shock protein 65 (hsp65) in alum adjuvant and anti-CD45RB monoclonal antibodies (mAb). Methods8 week old Apoe−/− mice on normal chow were treated for 12 weeks: group A received hsp65-alum immunization combined with anti-CD45RB mAb, group B hsp65-alum immunization combined with isotype control antibody, and group C mock vaccine combined with isotype control antibody. ResultsUnexpectedly, atherosclerotic lesions in the aortic root were significantly reduced in both hsp65-alum immunization groups (A and B) compared with the control group (C). Significantly elevated antibody titers against hsp65 were detected in both groups along with a significant increase in MHC class II expression on B cells. Body weight, total cholesterol and triglyceride levels were not different between groups. Treatment with anti-CD45RB antibody mediated a shift on CD4+ T cells from the CD45RBhigh to CD45RBlow isoform with a relative increase in CD4+Foxp3+ regulatory T cells (Treg) in an overall reduced T cell pool. Furthermore, anti-CD45RB treatment mediated a transient reduction of peripheral leukocytes and increased IFN-γ and IL-17A plasma levels. ConclusionsSubcutaneous immunization with hsp65-alum protects Apoe−/− mice against progression of early atherosclerosis. Administration of anti-CD45RB antibody provided no incremental benefit to the athero-protective effects of hsp65-alum treatment alone.

Decreased expression of interleukin‐27 in immune thrombocytopenia

Primary immune thrombocytopenia (ITP) is an immune-mediated disorder in which disturbed cytokine profiles have been found. Interleukin-27 (IL27) has been shown to bear both proinflammatory and anti-inflammtory effects. In the present study, plasma levels of IL27, interferon gamma (IFNG), IL4, and IL17A were determined by enzyme-linked immunosorbent assay in 23 active ITP patients, 20 patients in remission and 20 healthy controls. mRNA expression levels of IL27, EBI3, IL27 receptor (IL27RA), IL17A and RAR-related orphan receptor C (RORC) were determined by real-time quantitative polymerase chain reaction. Significantly lower levels of plasma IL27, IL4, mRNA expression of IL27, EBI3 and higher levels of plasma IFNG as well as mRNA expression of IL17A, RORC were observed in active ITP patients compared with healthy controls or patients in remission. No statistical difference was found in IL27RA mRNA expression or plasma IL17A levels among active ITP patients and controls. A negative correlation was found between the IL27 and RORC mRNA expression levels in active ITP patients. Our data demonstrated that active ITP patients had decreased plasma and mRNA expression levels of IL27, suggesting that it might be involved in the pathophysiological process of ITP.

Detrimental Functions of IL-17A in Renal Ischemia-Reperfusion Injury in Mice

Renal ischemia-reperfusion (I/R) injury, as a common and clinically important problem, starts with direct damage caused by chemokines and inflammatory cytokines, which is aggravated by specific and nonspecific immune reactions. Recently, IL-17A has been considered to be in a uniquely powerful position between adaptive and innate immunity. The present study investigated the role of IL-17A in renal I/R injury in mice. We measured the time-course of changes in plasma and renal IL-17A levels using a murine model of renal I/R injury. Then, the protective effect of monoclonal anti-IL-17A antibody, given intravenously at 30 min before or after renal I/R operation, on renal I/R injury was investigated. In addition, the levels of plasma and renal pro- and anti-inflammatory cytokines and chemokines were assessed. IL-17A was significantly increased in plasma and kidneys after renal I/R injury in mice. Furthermore, intravenous administration of neutralizing monoclonal anti-IL-17A antibody attenuated renal I/R injury by evaluating renal function and histopathology. In addition, administration of anti-IL-17A antibody substantially reduced the plasma and renal levels of many pro-inflammatory mediators (TNF-α, IL-6, high-mobility group box 1 (HMGB1), IL-1β, IL-17A, macrophage inflammatory protein-1α (MIP-1α), and monocyte chemoattractant protein-1 (MCP-1), as well as increased the plasma and renal levels of anti-inflammatory cytokines IL-10 and transforming growth factor β (TGF-β). The above data suggest that IL-17A has a detrimental effect on renal I/R injury via facilitating the production of pro-inflammatory cytokines and chemokines as well as hampering the production of anti-inflammatory cytokines.

Interleukin-17A is not expressed by CD207+ cells in Langerhans cell histiocytosis lesions

Interleukin-17 (IL-17A) is a pro-inflammatory cytokine that has recently been implicated in pathogenesis of Langerhans Cell Histiocytosis (LCH), a potentially fatal disease characterized by lesions including CD207+ (langerin +) histiocytes. However, in this study we were unable to identify IL-17A gene expression in Langerhans cell lesions, and plasma levels of IL-17A did not correlate with disease activity. Therefore, this study does not support a central role for IL-17A in LCH pathogenesis.