Human Eosinophils Express the High Affinity IgE Receptor,FcεRI,in Bullous Pemphigoid

Bullous pemphigoid (BP) is an autoimmune blistering disease mediated by autoantibodies targeting BP180 (type XVII collagen). Patient sera and tissues typically have IgG and IgE autoantibodies and elevated eosinophil numbers. Although the pathogenicity of the IgE autoantibodies is established in BP, their contribution to the disease process is not well understood. Our aims were two-fold: 1) To establish the clinical relationships between total and BP180-specific IgE, eosinophilia and other markers of disease activity; and 2) To determine if eosinophils from BP patients express the high affinity IgE receptor, FcεRI, as a potential mechanism of action for IgE in BP. Our analysis of 48 untreated BP patients revealed a correlation between BP180 IgG and both BP180 IgE and peripheral eosinophil count. Additionally, we established a correlation between total IgE concentration and both BP180 IgE levels and eosinophil count. When only sera from patients (n = 16) with total IgE≥400 IU/ml were analyzed, BP180 IgG levels correlated with disease severity, BP230 IgG, total circulating IgE and BP180 IgE. Finally, peripheral eosinophil count correlated more strongly with levels of BP180 IgE then with BP180 IgG. Next, eosinophil FcεRI expression was investigated in the blood and skin using several methods. Peripheral eosinophils from BP patients expressed mRNA for all three chains (α, β and γ) of the FcεRI. Surface expression of the FcεRIα was confirmed on both peripheral and tissue eosinophils from most BP patients by immunostaining. Furthermore, using a proximity ligation assay, interaction of the α- and β-chains of the FcεRI was observed in some biopsy specimens, suggesting tissue expression of the trimeric receptor form in some patients. These studies provide clinical support for the relevance of IgE in BP disease and provide one mechanism of action of these antibodies, via binding to the FcεRI on eosinophils.     

α-Antitrypsin Deficiency and Neonatal Hepatitis

Five out of 28 infants investigated in a regional survey of neonatal hepatitis were found to have genetically-determined deficiency of α₁-antitrypsin (ZZ phenotype). The clinical course and pathological changes varied considerably. All five infants had an acute hepatitis-like illness, and although this subsided cirrhosis later developed in three cases. The remaining two infants had minimal abnormalities of the liver function tests at 12 and 18 months of age, and one had increased hepatic fibrosis. Australia antigen was found in the serum of three infants, and Australia antigen or antibody in one or both parents of these and of one further case whose serum was negative. It is suggested that the association of neonatal hepatitis with α₁-antitrypsin deficiency may be commoner than previously realized and that Australia antigen acts as a trigger factor in these cases.     

Serum Inflammatory Cytokine Levels Correlate with Hand-Foot-Mouth Disease Severity: A Nested Serial Case-Control Study

Background

Hand-food-mouth disease (HFMD) cases can be fatal. These cases develop rapidly, and it is important to predict the severity of HFMD from mild to fatal and to identify risk factors for mild HFMD. The objective of this study was to correlate the levels of serum inflammatory cytokines with HFMD severity.

Methods

This study was designed as a nested serial case-control study. The data collected included general information, clinical symptoms and signs, laboratory findings and serum cytokine levels.

Results

The levels of IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with severe HFMD were significantly higher than in mild patients during the 2nd to 5th day after disease onset. The levels of IL-4, IL-6, IL-10 and IFN-γ increased from the 2nd day to the 4th day and later decreased. The levels of TNF-α were high on the first two days and subsequently decreased. The changes of IL-10, TNF-α and IFN-γ in the controls were similar for all cases. The levels of IL-4, IL-6 and IL-17 in the controls were not significantly different with the progression of HFMD.

Conclusions

Our findings indicate that the IL-4, IL-6, IL-10, TNF-α and IFN-γ levels correlate with HFMD severity.     

HIF-1α Inhibition Reduces Nasal Inflammation in a Murine Allergic Rhinitis Model

Background

Hypoxia-inducible factor 1α (HIF-1α) is an important regulator of immune and inflammatory responses. We hypothesized that nasal allergic inflammation is attenuated by HIF-1α inhibition and strengthened by HIF-1α stabilization.

Objective

To elucidate the role of HIF-1α in a murine model of allergic rhinitis (AR).

Methods

Mice were pretreated with the HIF-1α inhibitor 2-methoxyestradiol (2ME2) or the HIF-1α inducer cobalt chloride (CoCl₂) in an established AR murine model using ovalbumin (OVA)-sensitized BALB/c mice. HIF-1α and vascular endothelial growth factor (VEGF) expression in nasal mucosa was measured and multiple parameters of allergic responses were evaluated.

Results

HIF-1α and VEGF levels were locally up-regulated in nasal mucosa during AR. Inflammatory responses to OVA challenge, including nasal symptoms, inflammatory cell infiltration, eosinophil recruitment, up-regulation of T-helper type 2 cytokines in nasal lavage fluid, and serum OVA-specific IgE levels were present in the OVA-challenged mice. 2ME2 effectively inhibited HIF-1α and VEGF expression and attenuated the inflammatory responses. Stabilization of HIF-1α by CoCl₂ facilitated nasal allergic inflammation. HIF-1α protein levels in nasal airways correlated with the severity of AR in mice.

Conclusions

HIF-1α is intimately involved in the pathogenesis of nasal allergies, and the inhibition of HIF-1α may be useful as a novel therapeutic approach for AR.     

Reduced Renal α-Klotho Expression in CKD Patients and Its Effect on Renal Phosphate Handling and Vitamin D Metabolism

Renal α-Klotho (α-KL) plays a fundamental role as a co-receptor for fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)₂ vitamin D₃ (1,25VitD₃). Disruption of FGF23-α-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal α-KL expression and a reciprocal rise in serum FGF23. It remains unclear, however, whether the rise in FGF23 is related to the loss of renal α-KL. We evaluated α-KL expression in renal biopsy samples and measured levels of several parameters of mineral metabolism, as well as soluble α-KL (sKL), in serum and urinary samples from CKD patients (n = 236). We found that although renal α-KL levels were significantly reduced and serum FGF23 levels were significantly elevated in early and intermediate CKD, serum phosphate levels remained within the normal range. Multiple regression analysis showed that the increases in FGF23 were significantly associated with reduced renal function and elevated serum phosphate, but were not associated with loss of renal α-KL. Moreover, despite falling renal α-KL levels, the increase in FGF23 enhanced urinary fractional excretion of phosphate and reduced serum 1,25VitD₃ levels in early and intermediate CKD, though not in advanced CKD. Serum sKL levels also fell significantly over the course of CKD, and renal α-KL was a significant independent determinant of sKL. These results demonstrate that FGF23 levels rise to compensate for renal failure-related phosphate retention in early and intermediate CKD. This enables FGF23-α-KL signaling and a neutral phosphate balance to be maintained despite the reduction in α-KL. In advanced CKD, however, renal α-KL declines further. This disrupts FGF23 signaling, and serum phosphate levels significantly increase, stimulating greater FGF23 secretion. Our results also suggest the serum sKL concentration may be a useful marker of renal α-KL expression levels.     

Obesity Increases Airway Hyperresponsiveness via the TNF-α Pathway and Treating Obesity Induces Recovery

Obesity is a known risk factor for allergic asthma. It has been recognized as a key player in the pathogenesis of several inflammatory disorders via activation of macrophages, which is also vital to the development of allergic asthma. We investigated the mechanism of obesity-related asthma and whether treating obesity through exercise or diet ameliorates the severity of asthma in the obesity-related asthma model. We generated diet-induced obesity (DIO) in C57BL/6 mice by high-fat-feeding and ovalbumin-induced asthma (lean-OVA or DIO-OVA). The DIO-OVA mice were then treated with tumor necrosis factor (TNF)-α neutralizing antibody as a TNF-α blockade or a Cl₂MDP-containing liposome to induce an alveolar macrophage deficiency. To treat obesity, the DIO-OVA mice were under dietary restrictions or exercised. The pathophysiological and immunological responses were analyzed. Airway hyperresponsiveness (AHR), serum IgE and TNF-α levels in the lung tissue increased in the DIO-OVA mice compared to the lean-OVA mice. Both the TNF-α blockade and depletion of alveolar macrophages in the DIO-OVA mice decreased AHR compared to the DIO-OVA mice. Treating obesity by exercise or through dietary means also reduced pulmonary TNF-α levels and AHR in the DIO-OVA mice. These results suggest that restoring normal body weight is an appropriate strategy for reducing TNF-α levels, and controlling inflammation may help improve asthma severity and control in obesity-related asthma.     

Eotaxin-1 in exhaled breath condensate of stable and unstable asthma patients.

Background

Airway eosinophilia is considered a central event in the pathogenesis of asthma. Eotaxin plays a key role in selective eosinophil accumulation in the airways and, subsequently, their activation and degranulation. The study was undertaken to evaluate eotaxin-1 levels in the exhaled breath condensate (EBC) of asthmatics with different degrees of asthma severity and to establish the possible correlation of these measurements with other recognized parameters of airway inflammation.

Methods

EBC was collected from 46 patients with allergic asthma (14 with steroid-naïve asthma, 16 with ICS-treated, stable asthma, 16 with ICS-treated unstable asthma) and 12 healthy volunteers. Concentrations of eotaxin-1 were measured by ELISA.

Results

In the three groups of asthmatics, eotaxin-1 concentrations in EBC were significantly higher compared with healthy volunteers (steroid-naïve asthma: 9.70 pg/ml ± 1.70, stable ICS-treated asthma: 10.45 ± 2.00, unstable ICS-treated asthma: 17.97 ± 3.60, healthy volunteers: 6.24 ± 0.70). Eotaxin-1 levels were significantly higher in patients with unstable asthma than in the two groups with stable disease. We observed statistically significant correlations between the concentrations of eotaxin-1 in EBC and exhaled nitric oxide (F_ENO) or serum eosinophil cationic protein (ECP) in the three studied groups of asthmatics. We also discovered a significantly positive correlation between eotaxin-1 in EBC and blood eosinophil count in the groups of patients with unstable asthma and steroid-naïve asthma.

Conclusions

Measurements of eotaxin-1 in the EBC of asthma patients may provide another useful diagnostic tool for detecting and monitoring airway inflammation and disease severity.     

Secreted Heat Shock Protein 90α Induces Colorectal Cancer Cell Invasion through CD91/LRP-1 and NF-κB-mediated Integrin αV Expression

HCT-8 colon cancer cells secreted heat shock protein 90α (HSP90α) and had increased invasiveness upon serum starvation. The concentrated conditioned medium of serum-starved HCT-8 cells was able to stimulate the migration and invasion of non-serum-starved cells, which could be prevented by treatment with an anti-HSP90α antibody. Recombinant HSP90α (rHSP90α) also enhanced HCT-8 cell migration and invasion, suggesting a stimulatory role of secreted HSP90α in cancer malignancy. HSP90α binding to CD91α and Neu was evidenced by the proximity ligation assay, and rHSP90α-induced HCT-8 cell invasion could be suppressed by the addition of anti-CD91α or anti-Neu antibodies. Via CD91α and Neu, rHSP90α selectively induced integrin α_V expression, and knockdown of integrin α_V efficiently blocked rHSP90α-induced HCT-8 cell invasion. rHSP90α induced the activities of ERK, PI3K/Akt, and NF-κB p65, but only NF-κB activation was involved in HSP90α-induced integrin α_V expression. Additionally, we investigated the serum levels of HSP90α and the expression status of tumor integrin α_V mRNA in colorectal cancer patients. Serum HSP90α levels of colorectal cancer patients were significantly higher than those of normal volunteers (p < 0.001). Patients with higher serum HSP90α levels significantly exhibited elevated levels of integrin α_V mRNA in tumor tissues as compared with adjacent non-tumor tissues (p < 0.001). Furthermore, tumor integrin α_V overexpression was significantly correlated with TNM (Tumor, Node, Metastasis) staging (p = 0.001).     

Effects of intranasal TNFα on granulocyte recruitment and activity in healthy subjects and patients with allergic rhinitis

Background

TNFα may contribute to the pathophysiology of airway inflammation. For example, we have recently shown that nasal administration of TNFα produces late phase co-appearance of granulocyte and plasma exudation markers on the mucosal surface. The objective of the present study was to examine indices of granulocyte presence and activity in response to intranasal TNFα challenge.

Methods

Healthy subjects and patients with allergic rhinitis (examined out of season) were subjected to nasal challenge with TNFα (10 μg) in a sham-controlled and crossover design. Nasal lavages were carried out prior to and 24 hours post challenge. Nasal biopsies were obtained post challenge. Nasal lavage fluid levels of myeloperoxidase (MPO) and eosinophil cationic protein (ECP) were analyzed as indices of neutrophil and eosinophil activity. Moreover, IL-8 and α₂-macroglobulin were analyzed as markers of pro-inflammatory cytokine production and plasma exudation. Nasal biopsy numbers of neutrophils and eosinophils were monitored.

Results

Nasal lavage fluid levels of MPO recorded 24 hours post TNFα challenge were increased in healthy subjects (p = 0.0081) and in patients with allergic rhinitis (p = 0.0081) (c.f. sham challenge). Similarly, α₂-macroglobulin was increased in healthy subjects (p = 0.014) and in patients with allergic rhinitis (p = 0.0034). Lavage fluid levels of ECP and IL-8 were not affected by TNFα challenge. TNFα increased the numbers of subepithelial neutrophils (p = 0.0021), but not the numbers of eosinophils.

Conclusion

TNFα produces a nasal inflammatory response in humans that is characterised by late phase (i.e., 24 hours post challenge) neutrophil activity and plasma exudation.     

Thyroid Hormones Regulate Selenoprotein Expression and Selenium Status in Mice

Impaired expression of selenium-containing proteins leads to perturbed thyroid hormone (TH) levels, indicating the central importance of selenium for TH homeostasis. Moreover, critically ill patients with declining serum selenium develop a syndrome of low circulating TH and a central downregulation of the hypothalamus-pituitary-thyroid axis. This prompted us to test the reciprocal effect, i.e., if TH status would also regulate selenoprotein expression and selenium levels. To investigate the TH dependency of selenium metabolism, we analyzed mice expressing a mutant TH receptor α1 (TRα1+m) that confers a receptor-mediated hypothyroidism. Serum selenium was reduced in these animals, which was a direct consequence of the mutant TRα1 and not related to their metabolic alterations. Accordingly, hyperthyroidism, genetically caused by the inactivation of TRβ or by oral TH treatment of adult mice, increased serum selenium levels in TRα1+m and controls, thus demonstrating a novel and specific role for TRα1 in selenium metabolism. Furthermore, TH affected the mRNA levels for several enzymes involved in selenoprotein biosynthesis as well as serum selenoprotein P concentrations and the expression of other antioxidative selenoproteins. Taken together, our results show that TH positively affects the serum selenium status and regulates the expression of several selenoproteins. This demonstrates that selenium and TH metabolism are interconnected through a feed-forward regulation, which can in part explain the rapid parallel downregulation of both systems in critical illness.     

Preventing Olanzapine-Induced Weight Gain Using Betahistine: A Study in a Rat Model with Chronic Olanzapine Treatment

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H₁ receptors (H₁R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H₁R agonist and H₃R antagonist) and olanzapine (O+B) reduced (−45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (−51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H₁R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP₁ and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H₁R, pAMPKα, BAT UCP₁ and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment.     

The influence of cathelicidin LL37 in human anti-neutrophils cytoplasmic antibody (ANCA)-associated vasculitis

Introduction

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterised by the autoinflammation and necrosis of blood vessel walls. The renal involvement is commonly characterised by a pauci-immune crescentic glomerulonephritis (PiCGN) with a very rapid decline in renal function. Cathelicidin LL37, an endogenous antimicrobial peptide, has recently been implicated in the pathogenesis of autoimmune diseases. To assess whether serum LL37 reflects renal crescentic formation, we measured the serum levels of LL37 in AAV patients with and without crescentic glomerulonephritis (crescentic GN) as compared to healthy controls (HCs). We also analysed the correlation of the serum levels of LL37 and interferon-α (IFN-α) with the clinical characteristics of the patients.

Methods

The study population consisted of 85 AAV patients and 51 HCs. In 40 ANCA-positive patients, a parallel analysis was performed, including the assessment of LL37 and IFN-α levels in the serum and renal biopsies. Of those studied, 15 AAV patients had biopsy-proven crescentic GN, and 25 AAV patients lacked crescent formation. The serum levels of cathelicidin LL37 and IFN-α were both measured by ELISA, and the clinical and serological parameters were assessed according to routine procedures. Immunofluorescence staining was performed on frozen sections of kidney needle biopsies from AAV patients with crescentic GN.

Results

The serum levels of LL37 and IFN-α were significantly increased in AAV patients with crescentic GN compared to AAV patients without crescentic formation and HCs, and patients with high LL37 and IFN-α levels were more likely to be in the crescentic GN group. The LL37 levels were positively correlated with the IFN-α levels, and both LL37 and IFN-α levels showed a positive correlation with serum creatinine and no correlation with complement C3. The renal tissue of crescentic GN patients showed expression of LL37 and IFN-α at the Bowman’s capsule and extracellular sites, suggesting the active release of LL37 and IFN-α.

Conclusions

Significantly higher levels of LL-37 and IFN-α were observed in AAV patients, particularly those with crescentic formation, and LL37 and IFN-α were expressed in the renal tissue of patients with crescentic GN. These data suggest that serum levels of LL37 and IFN-α may reflect both local renal inflammation and systemic inflammation.     

Outbreak of trichinosis near Paris.

A localised outbreak of trichinosis occurred in January 1976 in the southern suburbs of Paris. A total fo 125 cases was recorded including 30 children. The prominent symptoms were oedema of the face or eyelids, fever, and myalgia; diarrhoea was unusual and constipation common. An increased blood eosinophil count and raised serum concentrations of muscular enzymes strongly indicated trichinosis. This diagnosis was confirmed later immunologically. The parasite was found in only three out of 32 muscle biopsy specimens but this investigation was made relatively early in the disease. No deaths occurred. In all cases clinical recovery was fast and serum antibody titres were maximum during the first month and decreased slowly. The disease was milder and the recovery faster in children than adults. Epidemiological study suggested that horse meat was responsible for the infection, though no meat could be examined.     

CULTIVATION OF MAMMALIAN CELLS IN DEFINED MEDIA WITH PROTEIN AND NONPROTEIN SUPPLEMENTS

An improved chemically defined basal medium (CMRL-1415) has been used to advantage in studying the effects on trypsinized, newly explanted mouse embryo cells of certain glycoproteins from plasma and serum, certain nonprotein macromolecules, and various combinations of these, in stationary cultures. When protein and nonprotein fractions were separated from fetal calf serum, the entire growth activity was found to be associated with the protein. When 100 mg % of dialyzed, freeze-dried, supernatant solution of Cohn's fraction V (method 6) from human plasma was used as a supplement for CMRL-1415, there was considerable improvement in the cultures; and seromucoid prepared from calf serum had a similar effect. Supernatant V was further fractionated by gel filtration to give a threefold concentration of growth activity in a single, highly purified α₁-acid glycoprotein (orosomucoid). Starch gel electrophoresis of horse serum that was used to supplement the basal medium revealed a decrease of both α₁-acid glycoprotein and α₂-macroglobulin during the cultivation of mouse embryo cells. When horse serum was fractionated on DEAE-cellulose columns, the only fraction that showed growth activity was a slow α₂-globulin. When the α₂-macroglobulin of Schultze was prepared from horse serum by salt precipitation, it was equally effective. When the α₂-macroglobulin from horse serum was tested (at 100 mg %) in combination with α₁-acid glycoprotein from Supernatant V, seromucoid from calf serum, or unfractionated Supernatant V, the growth response was greatly in excess of that produced by any of these supplements tested separately. The α₂-macroglobulin from horse serum could be replaced by certain nonprotein macromolecules (e.g., dextran or Ficoll). Thus, dextran (mol. wt. 100,000 to 200,000) had no visible effect on the cells when used alone at 0.1 or 1%. But when these levels of dextran were used in combination with low molecular weight glycoproteins (e.g., unfractionated Supernatant V at 100 mg %), the cultures remained active and healthy for unusually long periods.     

IFNα Serum Levels Are Associated with Endothelial Progenitor Cells Imbalance and Disease Features in Rheumatoid Arthritis Patients

Introduction

IFNα has been largely implicated in the ethiopathogenesis of autoimmune diseases but only recently it has been linked to endothelial damage and accelerated atherosclerosis in autoimmunity. In addition, proinflammatory conditions are supposed to be implicated in the cardiovascular status of these patients. Since a role for IFNα in endothelial damage and impaired Endothelial Progenitor Cell (EPC) number and function has been reported in other diseases, we aimed to evaluate the potential associations of IFNα serum levels on EPC populations and cytokine profiles in Rheumatoid Arthritis (RA) patients.

Methods

pre-EPC, EPC and mature EPC (mEPC) populations were quantified by flow cytometry analyzing their differential CD34, CD133 and VEGFR2 expression in blood samples from 120 RA patients, 52 healthy controls (HC), and 83 systemic lupus erythematosus (SLE) patients as disease control. Cytokine serum levels were measured by immunoassays and clinical and immunological data, including cardiovascular (CV) events and CV risk factors, were retrospectively obtained by reviewing clinical records.

Results

Long-standing, but not recent onset RA patients displayed a significant depletion of all endothelial progenitor populations, unless high IFNα levels were present. In fact, the IFN^high RA patient group (n = 40, 33%), showed increased EPC levels, comparable to SLE patients. In addition, high IFNα serum levels were associated with higher disease activity (DAS28), presence of autoantibodies, higher levels of IL-1β, IL-6, IL-10 and MIP-1α, lower amounts of TGF-β, and increased mEPC/EPC ratio, thus suggesting higher rates of endothelial damage and an endothelial repair failure. Finally, the relationship between high IFNα levels and occurrence of CV events observed in RA patients seems to support this hypothesis.

Conclusions

IFNα serum marker could be used to identify a group of RA patients with increased disease activity, EPC imbalance, enhanced proinflammatory profile and higher cardiovascular risk, probably due, at least in part, to an impaired endothelial repair.     

Protection of TGF-β1 against Neuroinflammation and Neurodegeneration in Aβ1–42-Induced Alzheimer’s Disease Model Rats

Neuroinflammation has been reported to be associated with Alzheimer’s disease (AD) pathogenesis. Neuroinflammation is generally considered as an outcome of glial activation; however, we recently demonstrated that T helper (Th)17 cells, a subpopulation of proinflammatory CD4+ T cells, are also involved in AD pathogenesis. Transforming growth factor (TGF)-β1, a cytokine that can be expressed in the brain, can be immunosuppressive, but its effects on lymphocyte-mediated neuroinflammation in AD pathogenesis have not been well addressed. In the current study we administered TGF-β1 via intracerebroventricle (ICV) and intranasal (IN) routes in AD model rats to investigate its antiinflammatory and neuroprotective effects. The AD rat model was prepared by bilateral hippocampal injection of amyloid-β (Aβ)_1–42. TGF-β1 was administered via ICV one hour prior to Aβ_1–42 injection or via both nares seven days after Aβ_1–42 injection. ICV administration of TGF-β1 before Aβ_1–42 injection remarkably ameliorated Aβ_1–42-induced neurodegeneration and prevented Aβ_1–42-induced increases in glia-derived proinflammatory mediators (TNF-α, IL-1β and iNOS), as well as T cell-derived proinflammatory cytokines (IFN-γ, IL-2, IL-17 and IL-22), in the hypothalamus, serum or cerebrospinal fluid (CSF) in a concentration-dependent manner. TGF-β1 pretreatment also prevented Aβ_1–42-induced decreases in the neurotrophic factors, IGF-1, GDNF and BDNF, and in the antiinflammatory cytokine, IL-10. Similarly, IN administration of TGF-β1 after Aβ_1–42 injection reduced neurodegeneration, elevation of proinflammatory mediators and cytokines, and reduction of neurotrophic and antiinflammatory factors, in the hypothalamus, serum or CSF. These findings suggest that TGF-β1 suppresses glial and T cell-mediated neuroinflammation and thereby alleviates AD-related neurodegeneration. The effectiveness of IN administered TGF-β1 in reducing Aβ_1–42 neurotoxicity suggests a possible therapeutic approach in patients with AD.     

Thyroid Hormone Upregulates Zinc-α2-glycoprotein Production in the Liver but Not in Adipose Tissue

Overproduction of zinc-α₂-glycoprotein by adipose tissue is crucial in accounting for the lipolysis occurring in cancer cachexia of certain malignant tumors. The main aim of this study was to explore whether thyroid hormone could enhance zinc-α₂-glycoprotein production in adipose tissue. In addition, the regulation of zinc-α₂-glycoprotein by thyroid hormone in the liver was investigated. We performed in vitro (HepG2 cells and primary human adipocytes) and in vivo (C57BL6/mice) experiments addressed to examine the effect of thyroid hormone on zinc-α₂-glycoprotein production (mRNA and protein levels) in liver and visceral adipose tissue. We also measured the zinc-α₂-glycoprotein serum levels in a cohort of patients before and after controlling their hyperthyroidism. Our results showed that thyroid hormone up-regulates zinc-α₂-glycoprotein production in HepG2 cells in a dose-dependent manner. In addition, the zinc-α₂-glycoprotein proximal promoter contains functional thyroid hormone receptor binding sites that respond to thyroid hormone treatment in luciferase reporter gene assays in HepG2 cells. Furthermore, zinc-α₂-glycoprotein induced lipolysis in HepG2 in a dose-dependent manner. Our in vivo experiments in mice confirmed the up-regulation of zinc-α₂-glycoprotein induced by thyroid hormone in the liver, thus leading to a significant increase in zinc-α₂-glycoprotein circulating levels. However, thyroid hormone did not regulate zinc-α₂-glycoprotein production in either human or mouse adipocytes. Finally, in patients with hyperthyroidism a significant reduction of zinc-α₂-glycoprotein serum levels was detected after treatment but was unrelated to body weight changes. We conclude that thyroid hormone up-regulates the production of zinc-α₂-glycoprotein in the liver but not in the adipose tissue. The neutral effect of thyroid hormones on zinc-α₂-glycoprotein expression in adipose tissue could be the reason why zinc-α₂-glycoprotein is not related to weight loss in hyperthyroidism.     

Cytokine and chemokine levels in patients with severe Fever with thrombocytopenia syndrome virus

Background

Severe fever with thrombocytopenia syndrome virus (SFTSV), which can cause hemorrhagic fever–like illness, is a newly discovered bunyavirus in China. The pathogenesis of SFTSV infection is poorly understood. However, it has been suggested that immune mechanisms, including cytokines and chemokines, play an important role in disease pathogenesis. In the present study, we investigated host cytokine and chemokine profiles in serum samples of patients with SFTSV infection from Northeast China and explored a possible correlation between cytokine levels and disease severity.

Methods and Principal Findings

Acute phase serum samples from 40 patients, diagnosed with SFTSV infection were included. Patients were divided into two groups – severe or non-severe – based on disease severity. Levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, interleukin-6, interferon (IFN)-γ, IFN- γ-induced protein (IP)-10 and RANTES were measured in the serum samples with commercial ELISAs. Statistical analysis showed that increases in TNF-α, IP-10 and IFN-γ were associated with disease severity.

Conclusions

We suggest that a cytokine-mediated inflammatory response, characterized by cytokine and chemokine production imbalance, might be in part responsible for the disease progression of patients with SFTSV infection.     

TNF-α Acts as an Immunoregulator in the Mouse Brain by Reducing the Incidence of Severe Disease Following Japanese Encephalitis Virus Infection

Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.