The levels of IL-6 and soluble IL-33R are increased in the renal vein during surgery for clear cell renal cell carcinoma.

PURPOSE: The main aim was to map serum levels of IL-1/IL-6 family cytokines and relevant receptors from serum samples taken across treatment in patients with Renal Cell Carcinoma (RCC). Additionally, we explored the possible interactions between these measurements, immunohistochemistry and intratumoral blood flow. METHODS: We included 40 patients undergoing open surgery for renal tumors. Blood samples were collected before, during (taken simultaneously from a peripheral site and the renal vein (RV) before clamping) and after surgery. Samples were analyzed for IL-6, IL-27, IL-31, OSM, TNF-α, serum (s)-gp130, s-IL-6Rα, s-IL-33R, IL-1Rα and VEGF. All 35 RCC tumors were histologically subtyped as clear cell (CCRCC), papillary or chromophobe. Immunohistochemistry for the CCRCC group included expression of IL-6/IL-6R. Intratumoral blood flow was determined by calculating intratumoral contrast enhancement on preoperative computerized tomography (CT) imaging. RESULTS: In the CCRCC patients, the intraoperative RV concentration of IL-6 was significantly higher than in both the preoperative and postoperative samples (p = 0.005 and p = 0.032, respectively). Furthermore, the intraoperative ratio showed significantly higher levels of IL-6 in the RV than in the simultaneously drawn peripheral sample. Immunohistochemistry showed general expression of IL-6 (23/24) in both tumor cells and the vasculature (20/23). Moreover, s-IL-6R was expressed in tumor cells in 23/24 studied patients. Increased blood flow in the CCRCC tumors predicted increased IL-6 levels in the RV (p < 0.001). The other cytokines and receptors showed an overall stability across the measurements. However, the intraoperative ratios of IL-33R and gp130 showed significantly higher levels in the RV. CONCLUSION: Serum levels of IL-6 increased during surgery. Intraoperative IL-6 and s-IL-33R values were higher in the RV compared to the periphery, suggesting secretion from the tumor or tumor microenvironment itself. Supportive of this is an almost general expression of IL-6/s-IL-6R in tumor cells and IL-6 in vasculature in the tumor microenvironment. Other studied cytokines/receptors were remarkably stable across all measurements.

Patients with obstructive sleep apnea have suppressed levels of soluble cytokine receptors involved in neurodegenerative disease, but normal levels with airways therapy.

PURPOSE: Obstructive sleep apnea (OSA) results in systemic intermittent hypoxia. By one model, hypoxic stress signaling in OSA patients alters the levels of inflammatory soluble cytokines TNF and IL6, damages the blood brain barrier, and activates microglial targeting of neuronal cell death to increase the risk of neurodegenerative disorders and other diseases. However, it is not yet clear if OSA significantly alters the levels of the soluble isoforms of TNF receptors TNFR1 and TNFR2 and IL6 receptor (IL6R) and co-receptor gp130, which have the potential to modulate TNF and IL6 signaling. METHODS: Picogram per milliliter levels of the soluble isoforms of these four cytokine receptors were estimated in OSA patients, in OSA patients receiving airways therapy, and in healthy control subjects. Triplicate samples were examined using Bio-Plex fluorescent bead microfluidic technology. The statistical significance of cytokine data was estimated using the nonparametric Wilcoxon rank-sum test. The clustering of these high-dimensional data was visualized using t-distributed stochastic neighbor embedding (t-SNE). RESULTS: OSA patients had significant twofold to sevenfold reductions in the soluble serum isoforms of all four cytokine receptors, gp130, IL6R, TNFR1, and TNFR2, as compared with control individuals (p = 1.8 × 10-13 to 4 × 10-8). Relative to untreated OSA patients, airways therapy of OSA patients had significantly higher levels of gp130 (p = 2.8 × 10-13), IL6R (p = 1.1 × 10-9), TNFR1 (p = 2.5 × 10-10), and TNFR2 (p = 5.7 × 10-9), levels indistinguishable from controls (p = 0.29 to 0.95). The data for most airway-treated patients clustered with healthy controls, but the data for a few airway-treated patients clustered with apneic patients. CONCLUSIONS: Patients with OSA have aberrantly low levels of four soluble cytokine receptors associated with neurodegenerative disease, gp130, IL6R, TNFR1, and TNFR2. Most OSA patients receiving airways therapy have receptor levels indistinguishable from healthy controls, suggesting a chronic intermittent hypoxia may be one of the factors contributing to low receptor levels in untreated OSA patients.

TLR9 polymorphism correlates with immune activation, CD4 decline and plasma IP10 levels in HIV patients.

BACKGROUND: The mechanism behind HIV mediated immune activation remains debated, although the role of virus replication in this process is increasingly evident. Toll like Receptor 9 (TLR9) has been implicated in HIV mediated immune activation via sensing of viral CpG DNA. Polymorphisms in the TLR9 gene and promoter region including TLR9 1635A/G and 1486C/T have been found to be associated with multiple infectious diseases and cancers. METHODS: In the current study, we looked at the correlation of TLR9 polymorphisms 1635A/G and 1486C/T with key hallmarks of HIV disease in a cohort of 50 HIV infected patients. We analyzed CD4 counts, T cell immune activation characterized by upregulation of CD38 and HLA-DR and upregulation of plasma biomarkers of inflammation like LPS, sCD14, IL-6 and IP10 in the HIV patient cohort and compared it to healthy controls. RESULTS: We found that TLR9 1635AA genotype was associated with lower CD4 counts and significantly higher immune activation in both CD4+ and CD8+ T cells. Analysis of HIV associated plasma biomarkers including LPS, sCD14, IL-6 and IP10 revealed a strong correlation between IP10 and immune activation. Interestingly, IP10 levels were also found to be higher in HIV patients with the 1635AA genotype. Furthermore, the TLR9 1486C/T polymorphism that is in linkage disequilibrium with 1635A/G was weakly associated with lower CD4 counts, higher CD8 immune activation and higher IP10 levels. CONCLUSIONS: As TLR9 stimulation is known to induce IP10 production by dendritic cells, our findings provide new insights into HIV mediated immune activation and CD4 loss. TLR9 stimulation by viral CpG DNA may be important to HIV immunopathogenesis and the TLR9 polymorphisms 1635A/G and 1486C/T may be associated with disease progression.

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

Interferon-Inducible Protein 10 and Disease Activity in Systemic Lupus Erythematosus and Lupus Nephritis: A Systematic Review and Meta-Analysis.

There is increasing evidence of a correlation between interferon-inducible protein 10 (IP-10) and disease activity of systemic lupus erythematosus (SLE) and lupus nephritis (LN). We conducted a comprehensive search on IP-10 using MEDLINE, Scopus, and Cochrane electronic databases from the beginning to the end of December 2017. All studies that compared serum and/or urine IP-10 between active SLE/LN patients and any control groups were identified and included in this systematic review and meta-analysis. The mean difference (MD) of IP-10 level among active SLE and LN patients, as well as the correlation of IP-10 with disease activity, were meta-analyzed using a random-effects model. From 23 eligible studies, 15 provided adequate data for meta-analysis. Serum IP-10 was significantly elevated in patients with active SLE compared to non-active SLE patients (MD 356.5 pg/mL, 95% CI 59.6 to 653.4, p = 0.019). On the other hand, the levels of serum IP-10 was not different between active LN and non-active LN. However, serum IP-10 was positively correlated with disease activity like SLE disease activity index (SLEDAI) (pooled r = 0.29, 95% CI 0.22 to 0.35, p < 0.001). Furthermore, urine IP-10 tended to be higher in patients with active LN compared to non-active LN patients but this did not reach statistical significance (MD 3.47 pg/mgCr × 100, 95% CI -0.18 to 7.12, p = 0.06). Nevertheless, urine IP-10 was positively correlated with renal SLEDAI (pooled r = 0.29, 95% CI 0.05 to 0.50, p = 0.019). In conclusion, serum and urine IP-10 levels may be useful in monitoring the disease activity of SLE and LN. Serum IP-10 was correlated with systemic disease whereas urine IP-10 was a useful biomarker for detecting active LN.

Circulating levels of IL-1 family cytokines and receptors in Alzheimer's disease: new markers of disease progression?

BACKGROUND: Although the mechanisms underlying AD neurodegeneration are not fully understood, it is now recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration. A neuro-inflammatory network, based on the anomalous activation of microglial cells, includes the production of a number of inflammatory cytokines both locally and systemically. These may serve as diagnostic markers or therapeutic targets for AD neurodegeneration. METHODS: We have measured the levels of the inflammation-related cytokines and receptors of the IL-1 family in serum of subjects with AD, compared to mild cognitive impairment (MCI), subjective memory complaints (SMC), and normal healthy subjects (NHS). Using a custom-made multiplex ELISA array, we examined ten factors of the IL-1 family, the inflammation-related cytokines IL-1α, IL-1ß, IL-18, and IL-33, the natural inhibitors IL-1Ra and IL-18BP, and the soluble receptors sIL-1R1, sIL-1R2, sIL-1R3, and sIL-1R4. RESULTS: The inflammatory cytokines IL-1α and IL-1ß, their antagonist IL-1Ra, and their soluble receptor sIL-1R1 were increased in AD. The decoy IL-1 receptor sIL-1R2 was only increased in MCI. IL-33 and its soluble receptor sIL-1R4 were also significantly higher in AD. The soluble form of the accessory receptor for both IL-1 and IL-33 receptor complexes, sIL-1R3, was increased in SMC and even more in AD. Total IL-18 levels were unchanged, whereas the inhibitor IL-18BP was significantly reduced in MCI and SMC, and highly increased in AD. The levels of free IL-18 were significantly higher in MCI. CONCLUSIONS: AD is characterised by a significant alteration in the circulating levels of the cytokines and receptors of the IL-1 family. The elevation of sIL-1R4 in AD is in agreement with findings in other diseases and can be considered a marker of ongoing inflammation. Increased levels of IL-1Ra, sIL-1R1, sIL-1R4, and IL-18BP distinguished AD from MCI and SMC, and from other inflammatory diseases. Importantly, sIL-1R1, sIL-1R3, sIL-1R4, and IL-18BP negatively correlated with cognitive impairment. A significant elevation of circulating sIL-1R2 and free IL-18, not present in SMC, is characteristic of MCI and disappears in AD, making them additional interesting markers for evaluating progression from MCI to AD.

Relationship between serum cytokines receptors and matrix metalloproteinase 9 levels and coronary artery disease.

BACKGROUND: The prevalence of coronary artery disease (CAD) is increasing globally, supporting the need for the identification of novel biomarkers. Therefore in the present study, we have explored the association of SIL2A, SIL6R, STNFRI, STNFRII, and MMP9 in CAD patients. METHODS: Twenty one patients with angiographically defined CAD with more than 50% occlusion, at least, in one coronary artery and twenty healthy subjects (n=20) without the history of cardiovascular symptoms were enrolled. Demographic and biochemical analysis (e.g. Total Cholesterol (TC), Triglyceride (TG), and HDL-C) were measured in all the subjects. The level of cytokines receptor (SIL2A, SIL6R, SIL6R, STNFRI, STNFRII, and matrix metallopeptidase 9 (MMP9) were evaluated. RESULTS: Our results showed the higher level of MMP9 in patients group compared to the control subjects, while no significant differences were detected for other cytokines. In particular the level of MMP9 was significantly (P=.015) increased from 181.16 ng/mL (95%CI: 112.1-199.2) to 192.0 ng/mL (95%CI: 181.5-265.2). Moreover, the sensitivity and specificity of MMP9 were 95.45% and 45%, respectively, as detected by receiver operating characteristic (ROC) curves. CONCLUSION: We demonstrate the significant correlation of MMP-9 with CAD with sensitivity of 95.45%, suggesting its role as a biomarker in CAD patients. Further studies in larger population - preferably multicenter setting - are warranted to explore the functional role of this marker in coronary artery disease.

Infliximab and etanercept have distinct actions but similar effects on cytokine profiles in rheumatoid arthritis.

OBJECTIVE: Pro-inflammatory cytokines, especially TNFα, play a central role in the pathogenesis of rheumatoid arthritis (RA). The available TNF inhibitors are only slightly different from one another in terms of clinical efficacy, at least at the group level, but their structures and modes of action are not identical. Infliximab (IFX) and etanercept (ETN) differ in their ability to induce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and in their ability to bind TNFß. The purpose of our study was to elucidate the different cytokine pathways through which these two drugs enact their clinical efficacy. METHODS: Serum from 44 RA patients treated with IFX and 24 patients treated with ETN was studied. All patients had been given these biologics at identical dosages and intervals for one year. The concentrations of 11 inflammatory cytokines and their receptors (IL-1ß, IL-2, IL-6, IL-6R, IL-8, IL-10, IL-12, TNFα, TNFß, IFNγ, and GM-CSF) were measured at weeks 0, 22, and 54 using a high-sensitivity electro-chemiluminescence assay. Cytokine profiles were analyzed along with clinical efficacy. RESULTS: IL-6 was significantly decreased in the ETN+MTX and IFX+MTX groups, although not in the ETN-only group; this change was consistent with changes in disease activity. IFNγ was gradually increased only in the non-remission subgroup of the IFX group, and not at all in the ETN group. TNFß increased after starting IFX regardless of clinical efficacy. CONCLUSION: IL-6 inhibition is a pathway affected by both IFX and ETN. In addition, IFNγ increase is a distinctive feature of the inefficacy of IFX.

Circulating levels of inflammatory cytokines and cytokine receptors in patients with ankylosing spondylitis: a cross-sectional comparative study.

OBJECTIVES: Insight into the most important inflammatory pathways in ankylosing spondylitis (AS) could be of importance in risk stratification and the development of treatment strategies. Therefore, we aimed to compare circulating levels of inflammatory biomarkers between AS patients and controls, and explore associations between these biomarkers and clinical measures of disease activity. METHOD: In a cross-sectional study, 143 AS patients were compared with 124 population controls. Blood samples were analysed by immunoassays for interleukin (IL)-6, IL-17a, IL-23, soluble tumour necrosis factor receptor 1 (sTNF-R1) and 2 (sTNF-R2), and osteoprotegerin (OPG). Disease activity was measured by the AS Disease Activity Score (ASDAS) and the Bath AS Disease Activity Index (BASDAI). RESULTS: Analysis of covariance (ANCOVA) demonstrated elevated plasma levels of sTNF-R1 [geometrical mean 0.94 (95% CI 0.88-1.00) vs. 0.83 (95% CI 0.78-0.89) ng/mL, p < 0.01] and OPG (2.3, 95% CI 2.1-2.4 vs. 2.0, 95% CI 1.9-2.2 ng/mL, p = 0.02) and, although not significant, of IL-23 (122, 95% CI 108-139 vs. 106, 95% CI 93-120 pg/mL, p = 0.07) in AS patients vs. CONTROLS: More AS patients had a high level of sTNF-R2 than controls (22 vs. 1, p < 0.01). No differences between the groups were seen for IL-6 and IL-17a. In patients, no significant associations were seen between inflammatory markers and disease activity measures after adjusting for personal characteristics. CONCLUSION: Significantly higher plasma levels of sTNF-R1, sTNF-R2, and OPG and numerically but non-significantly higher levels of IL-23 were found in AS patients compared to controls, indicating that these cytokines and cytokine receptors are important inflammatory pathways. Clinical measures of disease activity were not significantly correlated with circulating inflammatory markers.

T helper 17 cells and related cytokines after allergen inhalation challenge in allergic asthmatics.

BACKGROUND: T helper (Th)17 cells may play a role in allergic asthma. This study assessed the effect of allergen inhalation challenge on circulating Th17 cells and related cytokines in allergic asthmatics. METHODS: Peripheral blood mononuclear cells were collected from 16 atopic asthmatics before and 24 h after allergen challenge, as well as from 10 atopic nonasthmatics and 10 normal controls. Cells were stained for Th17 cytokines and their receptors (IL-17A, IL-17F, IL-21, IL-22, IL-17R, and IL-23R) using flow cytometry. Cytokine concentrations from cell culture supernatants were quantified using a multiplex assay for IL-17A, IL-17F, IL-21, IL-22, and IL-23. RESULTS: At baseline, asthmatics had a higher percentage of circulating Th17 cells (1.2 ± 0.5%) compared to normal controls (0.9 ± 0.66%, p < 0.001) but not compared to atopic nonasthmatics (1.13 ± 0.5%). There was a significant increase in Th17 cells in asthmatics after allergen challenge to 1.55 ± 0.4% (p < 0.05) and a trend toward significance in IL-17R expression from 3.4 ± 4.3 to 6.86 ± 6.84% after allergen challenge (p = 0.06). There was also a significant reduction in IL-21-positive cells following allergen challenge from 3.46 ± 1.85 to 2.33 ± 1.37% (p < 0.001). There were no significant differences in IL-17F, IL-22 and IL-23R expression. The concentration of IL-17A in culture supernatant was significantly higher in asthmatics compared to normal controls and IL-17A significantly increased 24 h after allergen challenge. CONCLUSIONS: The increase of Th17 cells and IL-17A in atopic asthma after allergen inhalation challenge suggests a possible role for Th17 in allergen-induced airway responses.

In situ expression and serum level of thymic stromal lymphopoietin in oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease of oral mucosa in which the CD8(+) T cell-mediated cytotoxicity is regarded as a major mechanism of pathogenesis. The main objective of this study is to investigate in situ expression and secretion of thymic stromal lymphopoietin (TSLP) in specimens and sera from patients with oral lichen planus. METHODS: Thirty-six patients with OLP and 35 donors enrolled in specimen and serum collection. Immunohistochemical method and immunofluorescence double-staining method were used to detect the expression of thymic stromal lymphopoietin and its receptor (TSLPR) together with CD8 in OLP specimens. Enzyme-linked immunosorbent assay (ELISA) was used to detect TSLP secretion. RESULTS: More TSLP- or TSLPR-positive cells showed in OLP specimens than in normal controls, and TSLP-positive cells were mainly in the epithelium, while TSLPR-positive cells mainly in the lamina propria. Furthermore, the number of TSLP-positive cells in the stratum basal was associated with the amount of mononuclear cells infiltrating in the lamina propria of OLP specimens. Among infiltrating mononuclear cells in the lamina propria, some CD8-positive cells also expressed TSLPR. The TSLP serum level of patients with OLP was significantly higher than of healthy donors, but there was no statistically difference between two clinical subtypes of OLP. CONCLUSIONS: Our findings provided the first evidence that TSLP may enroll in the pathology of OLP and the TSLP-TSLPR interaction may play an important role in it.

Expression analysis and specific blockade of the receptor for human thymic stromal lymphopoietin (TSLP) by novel antibodies to the human TSLPRα receptor chain.

Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7)-like cytokine with a pivotal role in development and maintenance of atopic diseases such as allergic asthma and atopic dermatitis. Moreover, recent studies show an involvement of TSLP in the progression of various cancers. TSLP signaling is mediated by the TSLP receptor (TSLPR), a heterodimeric type I cytokine receptor. It consists of the IL-7 receptor alpha chain (IL-7Rα), which is shared with the IL-7 receptor, and the TSLPRα chain as a specific subunit. Blocking signal release by TSLP without affecting IL-7 function is a potentially interesting option for the treatment of atopic diseases or certain tumors. By employing the extracellular domain of human TSLPRα chain (hTSLPRα(ex)) as an antigen, we generated a set of monoclonal antibodies. Several binders to native and/or denatured receptor protein were identified and characterized by cytometry and Western blot analysis. A screen based on a STAT3-driven reporter gene assay in murine pro-B cells expressing a functional hTSLPR yielded two hybridoma clones with specific antagonistic properties towards hTSLP, but not IL-7. Kinetic studies measuring blockade of hTSLP-dependent STAT phosphorylation in a TSLP-responsive cell line revealed an inhibitory constant in the nanomolar range.

Soluble TNF and IL-6 receptors: indicators of vascular health in women without cardiovascular disease.

Cytokine receptor subunits are released from cells in a regulated manner and circulate in soluble forms at concentrations that are orders of magnitude greater than the concentrations of the cytokines themselves. The purpose of this study was to determine if the circulating concentrations of soluble receptor subunits for interleukin-1 beta (IL-1ß), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) might serve as early indicators of vascular dysfunction independent of the traditional cardiovascular disease (CVD) risk factors in women. Healthy women, aged 20-50 years (n = 36), were assessed for circulating concentrations of the cytokines IL-1ß, IL-6 and TNFα and the soluble cytokine receptor subunits interleukin-1 receptor type I (sIL-1RI), sIL-1RII, sIL-6Rα, glycoprotein 130 (s-gp130), soluble TNF receptor type 1 (sTNFR1), and sTNFR2, along with traditional CVD risk factors. Cytokine receptor subunit expression on mononuclear cells and the release of these subunits in vitro were also determined. Brachial artery flow-mediated dilation (FMD), carotid intima-media thickness (cIMT) and carotid-femoral pulse wave velocity (cfPWV) were assessed by ultrasonography and Doppler probes. Circulating sIL-6Rα correlated negatively with FMD (r = -0.56, p = 0.007) independent of age and other CVD risk factors. Circulating sTNFR1 correlated positively with cfPWV (r = 0.60, p = 0.002). TNFR1 receptor expression on monocytes correlated positively with cIMT (r = 0.51, p = 0.004). Plasma concentrations of IL-1ß, IL-6 and TNFα were not significantly associated with FMD, cIMT or cfPWV. These data suggest that the receptors for IL-6 and TNFα, rather than the cytokines themselves, may be better indicators of early vascular changes that are associated with CVD.

Profiling the expression of interleukin (IL)-28 and IL-28 receptor α in systemic lupus erythematosus patients.

BACKGROUND: Interleukin (IL)-28 is an interferon-λ-family member involved in immunity against viral infection and tumour. We here determined the expression profiles of IL-28 and IL-28 receptor α (IL-28RA) in patients with systemic lupus erythematosus (SLE) to evaluate the possibility that IL-28 is linked to the pathogenesis of SLE. MATERIALS AND METHODS: The serum IL-28 protein levels were determined by ELISA, and the IL-28 and IL-28RA transcript levels in peripheral blood mononuclear cells (PBMCs) and peripheral blood T cells were determined by RT-PCR. The levels in patients with SLE with the active disease activity were statistically compared with those in normal controls. RESULTS: IL-28 protein in sera and IL-28 transcripts in PBMCs and unactivated T cells were detectable only in some individuals, and IL-28 transcripts in T cells were induced by cell activation with anti-CD2, anti-CD3 and anti-CD28 antibodies. However, compared with normal controls, patients with SLE more frequently had detectable IL-28 protein in serum and had the higher IL-28 transcript levels in activated CD4(+) T cells, but not activated CD8(+) T cells. Two IL-28RA transcripts isoforms were detected in PBMCs and T cells, and their levels in patients with SLE were comparable with those in normal controls. CONCLUSIONS: The expression of IL-28, a T-cell autocrine factor, is dysregulated in patients with SLE, supporting the possibility that IL-28 may contribute to some of the SLE pathogenesis.

Inflammatory cytokines in maternal circulation and placenta of chromosomally abnormal first trimester miscarriages.

The impact of abnormal placental karyotype on the inflammatory response within the villous tissue and peripheral circulation of women with miscarriage was evaluated. Villous (n = 38) and venous blood samples (n = 26) were obtained from women with missed miscarriage. Tissue chromosome analysis indicated 23 abnormal and 15 normal karyotypes. Concentration of tumour necrosis factor alpha (TNFα), TNF-R1 and TNF-R2, and interleukin (IL)-10 were measured using flowcytometric bead array in fresh villous homogenate, cultured villous extracts, culture medium, maternal whole blood, and plasma. Plasma TNFα/IL-10 ratios were significantly (P < 0.05) lower in miscarriages with abnormal karyotype. In the abnormal karyotype group, there were significantly higher levels of TNFα (P < 0.01), IL-10 (P < 0.01), TNF-R1 (P < 0.001), and TNF-R2 (P < 0.001) in the villous extracts and culture-conditioned medium compared to normal karyotype group. In miscarriage with abnormal karyotype, there is an exacerbated placental inflammatory response, in contrast to miscarriage of normal karyotype where maternal systemic response is increased.

Plasma concentrations of soluble cytokine receptors in euthymic bipolar patients with and without subsyndromal symptoms.

BACKGROUND: Current evidence suggests that high concentrations of pro-inflammatory markers are associated with bipolar disorder characterized by severe impairment during inter-episodic periods, reduced treatment response and persistent subsyndromal symptoms. We tested whether persistent subsyndromal symptoms in euthymic bipolar patients were associated with markers of an ongoing chronic pro-inflammatory process. METHODS: Forty-five euthymic bipolar patients (22 with subsyndromal symptoms (BD+) and 23 without subsyndromal symptoms (BD-) and 23 well controls (WC) were recruited for assessment of soluble tumor necrosis factor receptor-1 (sTNF-R1), soluble interleukin-6 receptor (sIL-6R) and soluble interleukin-2 receptor (sIL-2R) concentrations. Soluble cytokine receptor concentrations were assessed using enzyme-linked immunosorbent assay. RESULTS: In comparison to WC, sTNF-R1 concentration was higher in both BD- and BD+ (age and sex adjusted standardized ß, respectively: ß = 0.34, p = 0.012 and ß = 0.41, p = 0.003). Similarly, compared to WC, sIL-6R concentration was higher in both BD- and BD+ (age and sex adjusted standardized ß, respectively: ß = 0.44, p = 0.001 and ß = 0.37, p = 0.008). There was no difference between BD- and BD+ in the concentration of either sTNF-R1 or sIL-6R; plasma concentration of sIL-2R was not analyzed as 75% percent of the samples were non-detectable. CONCLUSIONS: Although bipolar patients present with a pro-inflammatory shift compared to well controls, subsyndromal symptoms are not associated with additive increasing effects. Longitudinal studies with larger samples are required to clarify the relationship between illness course and inflammatory markers in bipolar disorder.

Identification of inflammatory biomarkers for pediatric malarial anemia severity using novel statistical methods.

Areas where Plasmodium falciparum transmission is holoendemic are characterized by high rates of pediatric severe malarial anemia (SMA) and associated mortality. Although the etiology of SMA is complex and multifactorial, perturbations in inflammatory mediator production play an important role in the pathogenic process. As such, the current study focused on identification of inflammatory biomarkers in children with malarial anemia. Febrile children (3 to 30 months of age) presenting at Siaya District Hospital in western Kenya underwent a complete clinical and hematological evaluation. Children with falciparum malaria and no additional identifiable anemia-promoting coinfections were stratified into three groups: uncomplicated malaria (hemoglobin [Hb] levels of ≥11.0 g/dl; n = 31), non-SMA (Hb levels of 6.0 to 10.9 g/dl; n = 37), and SMA (Hb levels of <6.0 g/dl; n = 80). A Luminex hu25-plex array was used to determine potential biomarkers (i.e., interleukin 1ß [IL-1ß], IL-1 receptor antagonist [IL-1Ra], IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, tumor necrosis factor alpha [TNF-α], alpha interferon [IFN-α], IFN-γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], macrophage inflammatory protein 1 alpha [MIP-1α], MIP-1ß, IFN-inducible protein of 10 kDa [IP-10], monokine induced by IFN-γ [MIG], eotaxin, RANTES, and monocyte chemoattractant protein 1 [MCP-1]) in samples obtained prior to any treatment interventions. To determine the strongest biomarkers of anemia, a parsimonious set of predictor variables for Hb was generated by least-angle regression (LAR) analysis, controlling for the confounding effects of age, gender, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and sickle cell trait, followed by multiple linear regression analyses. IL-12p70 and IFN-γ emerged as positive predictors of Hb, while IL-2R, IL-13, and eotaxin were negatively associated with Hb. The results presented here demonstrate that the IL-12p70/IFN-γ pathway represents a set of biomarkers that predicts elevated Hb levels in children with falciparum malaria, while activation of the IL-13/eotaxin pathway favors more profound anemia.

Inflammation-related proteins in the blood of extremely low gestational age newborns. The contribution of inflammation to the appearance of developmental regulation.

BACKGROUND: We wanted to assess to what extent concentrations of circulating proteins appear to be developmentally regulated, and to what extent such regulation is influenced by intra-uterine inflammation. METHODS: We measured 22 proteins in blood obtained on postnatal days 1, 7, and 14 from 818 children born before the 28th week of gestation for whom we also had information about placenta morphology. RESULTS: Within the narrow gestational age range of this sample, some protein concentrations increase in blood with increasing gestational age. More commonly, the concentrations of inflammation-related proteins decrease with increasing gestational age. We observed this inverse pattern both in children whose placenta was and was not inflamed. CONCLUSIONS/INFERENCES: Regardless of whether or not the placenta is inflamed, the concentrations of inflammation-related proteins in early blood specimens appear to be developmentally regulated with the most common pattern being a decrease with increasing gestational age.

Markers of dengue disease severity.

Infection with one of the four serotypes of dengue virus (DENV) causes a wide spectrum of clinical disease ranging from asymptomatic infection, undifferentiated fever, dengue fever (DF) to dengue hemorrhagic fever (DHF). DHF occurs in a minority of patients and is characterized by bleeding and plasma leakage which may lead to shock. There are currently no reliable clinical or laboratory indicators that accurately predict the development of DHF. Human studies have shown that high viral load and intense activation of the immune system are associated with DHF. Recently, endothelial cells and factors regulating vascular permeability have been demonstrated to play a role. In the absence of animal models that closely mimic DHF, human studies are essential in identifying predictors of severe illness. Well planned prospective studies with samples collected at different time points of the illness in well characterized patients are crucial for this effort. Ideally, clinical and laboratory predictive tools should be suitable for resource poor countries where dengue is endemic.

Detection of immunological biomarkers correlated with asthma control and quality of life measurements in sera from chronic asthmatic patients.

BACKGROUND: Clinical outcomes of patients with asthma are highly variable. Immunological biomarkers associated with asthma control have not been elucidated. OBJECTIVE: To identify the association between clinical control of asthma and serum immunological profiles of asthmatics and compare these profiles with those of healthy controls by using a multiplex assay. METHODS: Sera were obtained from 28 nonsmokers 18 to 55 years of age with moderate and severe persistent asthma. Patients were classified as having well-controlled (WC, n = 14) or poorly controlled (PC, n = 14) asthma based on their responses to the Asthma Control Questionnaire and Asthma Quality of Life Questionnaire. Sera from nonasthmatic control individuals (NAC, n = 14) were used for comparison. Levels of 50 analytes, including cytokines, chemokines, angiogenic, and growth factors, were determined, using a multiplex assay. RESULTS: Twelve of the 29 cytokines levels were significantly higher in patients with asthma than in NACs, but only interferon gamma levels were significantly lower in patients with asthma than in the NAC group. Among these, interleukin (IL)-3 and IL-18 levels were significantly higher in the PC group than the WC group. Five of the 12 tested chemokine levels were significantly higher in patients with asthma than in NACs. Five of six growth factor levels were significantly higher in patients with asthma than in NACs, and 3 were higher in PC than WC. Interleukin-18, fibroblast growth factor, hepatocyte growth factor, and stem cell growth factor-beta were positively correlated with poor asthma control and negatively with quality of life scores. CONCLUSIONS: Increased serum levels of fibroblast growth factor, hepatocyte growth factor, and stem cell growth factor-beta might be useful biomarkers of asthma control status and targets of future asthma therapy.