Brain-derived neurotrophic factor is increased in atopic dermatitis and modulates eosinophil functions compared with that seen in nonatopic subjects

BACKGROUND: Recently, the pivotal role of brain-derived neurotrophic factor (BDNF) has been described in allergic asthma. However, the role of this neurotrophin in atopic dermatitis (AD) still remains unknown. OBJECTIVE: The aim of this study was to investigate the functional role of BDNF on eosinophils and to assess BDNF levels in patients with AD and nonatopic control subjects. Methods p75 Neurotrophin receptor and tyrosine kinase B receptor expression was demonstrated by using FACS analysis and immunohistochemistry. BDNF levels were assessed with ELISA and FACS analysis. Chemotactic activity (modified Boyden chamber assay), eosinophil cationic protein release (fluoroenzyme immunoassay), respiratory burst (lucigenin-dependent chemiluminescence), and apoptosis (Nicoletti protocol and Annexin-V method) assays were used to assess BDNF functional activity. RESULTS: BDNF levels were increased in serum, plasma, eosinophils, and supernatants of stimulated eosinophils from patients with AD compared with levels seen in nonatopic control subjects ( P < .05-.001). In addition, p75 neurotrophin receptor and tyrosine kinase B expression was higher on eosinophils from patients with AD compared with that seen on eosinophils from nonatopic control subjects ( P < .05-.001). Eosinophil apoptosis was inhibited by BDNF ( P < .05-.01) and chemotactic index was increased ( P < .001) in BDNF-stimulated eosinophils from patients with AD, whereas this effect was not shown in eosinophils from nonatopic control subjects. However, no response of BDNF through the release of eosinophil cationic protein or reactive oxygen species was found. CONCLUSION: This study provides the first evidence for a functional role of BDNF on eosinophils from patients with AD, probably mediated by an increased expression of BDNF receptors compared with that seen in nonatopic control subjects. In addition, higher intracellular, serum, and plasma BDNF levels, as well as the release of BDNF by eosinophils, underline the particular importance of BDNF in patients with AD, pointing to new pathophysiologic aspects of this chronic inflammatory skin disease.     

Effects of adjuvants on the immune response to allergens in a murine model of allergen inhalation: cholera toxin induces a Th1-like response to Bet v 1, the major birch pollen allergen

Based on the fact that type I allergies are frequently elicited by inhalant allergens, we have established a model of aerosol inhalation leading to allergic sensitization in BALB/c mice. Using this model we studied the effects of aluminium hydroxide (Al(OH)₃), known to enhance IgE antibody responses, compared with cholera toxin (CT), a potent mucosal adjuvant, on the immune response to birch pollen (BP) and its major allergen Bet v 1. Two groups of BALB/c mice were either systemically immunized with recombinant Bet v 1 in Al(OH)₃ and subsequently aerosol exposed to BP allergen, or aerosolized with BP and CT. IgE-mediated skin reactions were only elicited in the mice which had received Bet v1/Al(OH)₃. Allergen-specific serum IgE and IgG1 antibodies dominated in the Al(OH)₃ group, IgG2a antibody levels to BP and rBet v 1 were markedly higher in the sera of mice exposed to CT with the allergen. IgA antibodies were only detected in the bronchial lavage of the CT-treated group. Moreover, the latter group displayed consistently higher T cell proliferative responses to BP and interferon-gamma production in vitro. Thus, the systemic immunization with rBet v 1 in Al(OH)₃ before inhalation of the BP extract promoted a Th2-like immune response, while CT mixed with the aerosolized BP extract rather induced a Th1-like immune response. In an attempt to reverse these ongoing immune responses we could achieve a shift towards a Th0 response. Immunization with BP extract without adjuvant treatment led to undetectable antibody or cellular immune responses. We conclude from the present study that the induction of an immune response to BP allergen after aerosol inhalation can be directed towards a Th1- or a Th2-like response. Once established, the immune response can be modulated.     

Superantigen-induced T cell death by apoptosis: analysis on a single cell level and effect of IFN-gamma and IL-4 treatment

BACKGROUND: A role of bacterial superantigens in several chronic inflammatory diseases has previously been proposed. Many of these diseases are associated with an imbalance of the T helper cell subsets and their cytokine production. METHODS: Peripheral blood mononuclear cells from healthy donors were incubated with various concentrations of staphylococcal enterotoxin B (SEB) with or without IL-4 or IFN-gamma. After different time points cell activation, proliferation, Fas expression, cytokine release and cell death via apoptosis were detected. RESULTS: SEB treatment resulted in sequential T cell activation, proliferation, Fas expression, cytokine release, subsequently followed by cell death via apoptosis in a dose- and time-dependent manner. This biphasic effect occurred preferentially in SEB-responsive cells represented by the expression of Vbeta3 and Vbeta12 on T cells. A strong relationship between T cell activation and apoptosis was observed. The amplitude between these events increased with the dose of SEB. The highest rate of apoptotic T cells was observed at a dose of 1,000 ng/ml SEB. Addition of IFN-gamma to SEB-treated cells significantly reduced the rate of apoptotic cells, whereas IL-4 prevented apoptosis only in SEB-untreated cells. CONCLUSION: These results support the concept that the dose of superantigen exposure determines the rate of T cell proliferation and subsequent cell death. This T cell immune response is modulated by the presence and the type of cytokines.     

Role of nerve growth factor in a mouse model of allergic airway inflammation and asthma

The role of nerve growth factor (NGF), a potent mediator acting in the development and differentitation of both neuronal and immune cells, was examined in a mouse model of allergic asthma. NGF-positive cells were detected in the inflammatory infiltrate of the lung and enhanced levels of NGF were detected in serum and broncho-alveolar lavage fluids. Mononuclear cells in inflamed airway mucosa as well as broncho-alveolar macrophages were identified as one source of NGF production. Splenic mononuclear cells from allergen-sensitized mice produced NGF in response to allergen. They responded to exogenously added NGF with a dose-dependent increase in IL-4 and IL-5 production and augmented IgE and IgG₁ synthesis. In contrast, IFN-γ and IgG_2a levels remained unaffected. The effects were NGF specific, since they could be blocked by an anti-NGF-antibody. Nasal application of anti-NGF to allergen-sensitized mice significantly reduced IL-4 and prevented development of airway hyperreactivity. These results show that allergic airway inflammation is accompanied by enhanced local NGF production that acts as an amplifier for Th2 effector functions and plays an important role in the development of airway hyperreactivity. Therefore it is suggested that NGF may serve as a link between the immune and nerve system.     

MR-guided facet joint injection therapy using an open 1.0-T MRI system: an outcome study

Objectives

To evaluate the accuracy, safety and efficacy of magnetic resonance imaging (MRI)-guided facet joint injection therapy using a 1.0-T open MRI.

Methods

One hundred and sixty-six facet joint blocks in 45 patients with lower back pain were performed under MR fluoroscopic guidance using a proton-density-weighted turbo-spin-echo sequence. An in-room monitor, wireless MR-mouse for operator-controlled multiplanar navigation, a flexible surface coil and MR-compatible 20-G needle were used. Clinical outcome was evaluated by questionnaire before intervention and after 1 week, 3, 6 and 12 months using a numerical visual analogue scale (VAS).

Results

All facet joint blocks were considered technically successful with distribution of the injectant within and/or around the targeted facet joint. No major complications occurred. The final outcome analysis included 38 patients. An immediate effect was reported by 63 % of the patients. A positive mid-/long-term effect was seen in 13 patients (34 %) after 6 months and in 9 patients (24 %) after 12 months. Mean VAS was reduced from 7.1?±?1.7 (baseline) to 3.5?±?2.2, 4.1?±?3.0, 3.8?±?2.9 and 4.6?±?2.9 at 1 week, 3, 6 and 12 months (P?<?0.01).

Conclusions

MR-guided facet joint injection therapy of the lumbosacral spine is accurate, safe and efficient in the symptomatic treatment of lower back pain.

Key Points

? MR-guided facet joint infiltration provides an alternative to CT and conventional fluoroscopy. ? Clinical outcomes are comparable with conventional fluoroscopy and CT-guided facet joint interventions. ? Ionising radiation can be avoided for both patient and physician. ? MR-guided facet joint injection provides safe and effective treatment of back pain.     

Outline and arrangement of enamel rods in human deciduous and permanent enamel. 3D-reconstructions obtained from CLSM and SEM images based on serial ground sections

Human enamel rods were made visible continuously from the dentino-enamel junction (DEJ) up to the enamel surface. From 12 teeth (1st and 2nd dentition) enamel blocks from the cervical third were prepared with perpendicular planes, embedded in resin, and ground down in steps of 15 microm parallel to the enamel surface. Enamel rods were made visible by acid etching (35% H3PO4, 45 s), sputtered and examined in the scanning electron microscope (SEM). Prior to this, the enamel blocks were viewed under the CLSM and optical sections at distances of 2 microm were obtained, starting in the same plane as the grinding surface. The outlines of the rods were digitized and reconstructed three dimensionally. For the first time, the path of single and grouped enamel rods on their way through the entire enamel layer was depicted. 3D images obtained from confocal laser scanning microscopy (CLSM) data were similar to those gained from SEM images. Single rods did not maintain their same outline throughout their path; arcade outlines predominated close to the DEJ, while keyhole outlines prevailed at the enamel surface. Within a group of rods, neighborhood relations changed, and neighbor rods influenced their outlines mutually, including the variable extent of the tail. The interdependence between the plasticity of the rods and the ameloblasts' forms should be topics of further research.     

Studies on the dynamics of transmission of onchocerciasis in a Sudan-savanna area of North Cameroon IV. The different exposure to Simulium bites and transmission of boys and girls and men and women, and the resulting manifestations of onchocerciasis

The sojourn times of the human population were monitored over one year at 12 sites in the vicinity of three villages in the Cameroon Sudan-savanna, where the Onchocerca volvulus transmission potentials had been measured one year previously. Boys stayed longer outside the villages, and were exposed 2.1 to 2.7 times more than girls to transmission of onchocerciasis, whereas the exposure of men was similar or only moderately higher than the exposure of women. In boys, the onset of infections and ocular lesions was earlier and the average microfilarial density at the buttock (2.2, 9.4 and 79.3 mff snip-1) was much higher than in girls (0.1, 5.8 and 42.2 mff snip-1 at the three villages respectively). These differences were maintained in the adult population, where the average microfilarial density was 52.3, 80.4 and 183.1 mff snip-1 in men and 15.6, 49.6 and 114.7 mff snip-1 in women. Ocular lesions due to onchocerciasis were found in 5, 13 and 55% of the male population in the three villages, as compared with 2, 3 and 8% of the female population. There was a close relationship between the degree of exposure to the transmission of disease and the resulting microfilarial load in the skin which was not different for the two sexes, and a similar trend was seen for the occurrence of ocular lesions due to onchocerciasis. The influence of an early and heavy infection on the evolution of disease manifestations is discussed.     

Neurotrophins in allergic disease of skin and lung: modulators of immunological and neuronal plasticity

Autoimmune diseases present clinically with many differences in disease pattern and are characterized by dysregulation of the immune response to inflammation, pain, disease, and stiffness. Cells of the innate immune system, such as dendritic cells (DCs), have been shown to stimulate production of autoantibodies and self-recognized T cells that induce autoimmune disease. DCs are considered amongst the most important of the antigen-presenting cells because of their highly efficient ability to present antigenic peptides in the presence of MHC class II molecules that activates naïve lymphocytes. They also secrete cytokines and express costimulatory cell-surface molecules that facilitate lymphocyte activation. These cells are responsive to regulation by the hypothalamic-pituitary-adrenal (HPA) axis, largely through the actions of the glucocorticoids. In addition to their long-recognized usefulness in pharmacotherapy of autoimmune diseases, glucocorticoids secreted the adrenal glands play an important physiologic anti-inflammatory role in regulating innate immunity. Interruption of this negative feedback loop by genetic, surgical, or pharmacological means leads to enhanced susceptibility to autoimmune/inflammatory disease. Evidence for the regulatory role of the HPA axis in autoimmune/inflammatory disease and its implications for treatment will be discussed.     

Infectious enteritis after intestinal transplantation: incidence, timing, and outcome

BACKGROUND: The study reviews the incidence, timing, and outcome of infectious enteritis (IE) after intestinal transplantation (ITx). METHODS: A retrospective review of all patients who underwent ITx at a single institution between 1991 and 2003 was undertaken using database and medical records. Standard statistical analyses were performed. RESULTS: Of 33 ITx recipients, 13 (39%) developed 20 culture- or biopsy-proven episodes of IE. Recipient demographics included the following: 10 males, median age 34 (10-585) months, 11 liver + intestine grafts, and two isolated intestine grafts. Infections were diagnosed a median of 76 days (32-1,800 days) after ITx. There were 14 viral (one cytomegalovirus, eight rotavirus, four adenovirus, one Epstein-Barr virus), three bacterial (Clostridium difficile), and three protozoal (one Giardia lamblia, two Cryptosporidium) infections. The bacterial infections tended to present earlier than the viral infections, and the most frequent presenting symptom was diarrhea. Complete resolution was achieved in 17 (94%) incidences with the appropriate antimicrobial or conservative therapy. It was interesting that there were seven rejection episodes documented by biopsy at the approximate time of diagnosis of IE. There were two graft losses: one because of adenoviral enteritis and one because of rejection after rotavirus enteritis. Three-year patient survival is 74% with no deaths directly attributable to IE. CONCLUSIONS: IE can occur in 39% of recipients after ITx. Viral agents are the cause in two thirds of the cases. With supportive care and appropriate treatment, resolution is possible in the majority of cases. Differentiating rejection and infection on histopathology can be difficult and relies on cultures and immunostaining.