Allergy and the skin.

Allergic skin disorders include urticaria, angioedema, contact dermatitis and atopic dermatitis, but the model fitting most closely the systemic concept of allergy is atopic dermatitis (AD), the pathogenesis of which is linked to a complex interaction between skin barrier dysfunction and environmental factors such as allergens and microbes. In particular, an important advance was the demonstration that the mutation of the skin barrier protein filaggrin is related strictly to allergen sensitization and to the development of asthma in subjects with AD. The altered skin barrier function, caused by several factors, results in the passage of allergens through the skin and to systemic responses. A pivotal role in such a response is exerted by Langerhans cells which, via their immunoglobulin E (IgE) receptor, capture the allergens and present them to T cells. When T helper type 2 (Th2) cells are activated, the production of a proinflammatory cytokines and chemokines pattern sustains the persistence of inflammation. Known AD-related cytokines are interleukin (IL)-5, IL-13 and tumour necrosis factor (TNF)-alpha, with emerging importance for IL-17, which seems to drive airway inflammation following cutaneous exposure to antigens, and IL-31, which is expressed primarily in skin-homing Th2 cells. Skin-homing is another crucial event in AD, mediated by the cutaneous lymphocyte-associated antigens (CLA) receptor, which characterizes T cell subpopulations with different roles in AD and asthma.

Early cytokine modulation after the rapid induction phase of sublingual immunotherapy with mite monomeric allergoids.

The influence of different treatment schedules of sublingual immunotherapy (SLIT) in activating IL-10-producing T-cells, crucial in inducing allergen-specific tolerance, is not completely understood. The present work was designed to evaluate allergen driven interleukin release by mononuclear cells in the early phase of SLIT, after application of different induction schemes. Twenty mite-allergic patients were enrolled, 10 (group A) treated with a traditional 98 day induction scheme and 10 (group B) with a 16 day scheme with monomeric allergoid vaccine. At the end of the induction phase, the cumulative doses taken by group A and group B patients were equivalent to 50.5 and 50.3 microg of mite group 1 allergens, respectively. The release of Th1-, Th2- and Treg-related interleukins was assessed in culture supernatants of 5 microg/ml Der-p1-stimulated mononuclear cells, isolated before and after the induction phases. No relevant treatment-related side effects were observed. Interleukin release was similar in the two groups at the enrolment. Non-stimulated and Der p 1 stimulated release of studied cytokines was similar in the two groups at enrolment. Der p 1 stimulation significantly increased IL-10 release (p<0.0002) after treatment in group B patients, and this effect was higher (p=0.05) compared to group A patients. Furthermore, at the end of SLIT induction TNF-alpha, IL-4 and IFN-gamma production were reduced in group B patients (p<0.05, p=0.062 and p=0.060, respectively). The rapid induction scheme of sublingual immunotherapy induces an early immune suppression more effectively than the slower one. The rapid induction scheme should be the preferential way to start sublingual immunotherapy, particularly when monomeric allergoids are utilized.

Immunotoxicity and sensitizing capacity of metal compounds depend on speciation.

Immunotoxicity of metal compounds is an issue of great importance due to the recent industrial application of metals with unknown toxicity on the immune system and the discovery of metal intermediary compounds not sufficiently studied yet. In this report we show results of our study on the immunotoxicity of the following metals: the Platinum group elements (Platinum, Palladium, Rhodium), Titanium and Arsenic. We applied functional and non functional assays and investigated both innate and adaptive immune systems, in particular, cell proliferation, cytokine production by PBMCs and O*2 production by neutrophils. We obtained the following results: only some Ti compounds (Titanocene, Ti ascorbate and Ti oxalate) show immunotoxicity. Trivalent As compounds (Sodium arsenite and tetraphenyl arsonium chloride) are more immunotoxic than the other investigated As compounds. Genotoxicity of Pt group compounds is in the following order: Pt > Rh > Pd. Immunotoxicity of Pt group compounds is in the following order: Pd > Pt > Rh. Lymphocytes and macrophages show a different reaction of neutrophils to metal toxicity. We can conclude that these studies show that metal immunotoxicity depends on speciation. In general speciation provides additional and often essential information in evaluating metal toxicity. However, there are many difficulties in applying speciation in investigating toxico-kinetic aspects to many metals, mainly due to the lack of information about the existence and significance of species and to the lack of analytical methods for measuring species in biological samples.

Respiratory allergy in agriculture.

Allergic respiratory diseases in farmers may be caused by exposures to many organic substances. Potentially inhalable particulate material of biologic origin are referred to collectively as organic dust, whose composition includes also molds and other microorganisms. Organic dust may evoke immuno-allergic reactions and cause rhinitis, asthma and extrinsic allergic alveolitis. The agricultural work environment represents a risk factor for these diseases, whose occupational origins are often overlooked by clinicians. Prevalence studies of respiratory allergic diseases among agricultural workers are advocated for the development of prevention strategies.

Eosinophil recruiting chemokines are down-regulated in peripheral blood mononuclear cells of allergic patients treated with deflazacort or desloratadine.

Chemokines are cytokines with chemotactic properties on leukocyte subsets whose modulation plays a key role in allergic inflammatory processes. To better understand the possible anti-inflammatory effects of histamine-1 receptor antagonists in allergic asthma, we studied the mRNA expression of a set of chemokines known to be involved in the eosinophils-basophils activation as well as recruitment and T-cell signaling events, before and after corticosteroid or antihistamine treatment in PBMCs from allergic-asthmatic patients ex vivo. Twelve patients were enrolled, all of whom were allergic to Parietaria judaica and suffering for mild persistent asthma: six were treated with desloratadine (10 mg/day), and six with deflazacort (12 mg/day). Before and after the treatment, PBMC samples were collected from each patient and analyzed for the expression of encoding mRNAs for several chemokines, I-309 (CCL1), MCP-1 (CCL2), MIP1-alpha (CCL3), MIP1-beta (CCL4), RANTES (CCL5), IL-8 (CXCL8), IP-10 (CXCL10), Lymphotactin (XCL1). Clinical and functional improvements were seen after 3 weeks of therapy; this was associated with a reduced expression in the mRNA levels for the chemokines RANTES, MIP1-alpha and MIP1-beta with either the corticosteroid or the antihistamine, compared to the pre-treatment levels. Chemokine downregulation was statistically significant in both groups of patients. These findings suggest that certain antihistamines may act as down-modulators of allergic inflammation, possibly through a negative regulation of the chemokines involved in activation and attraction of eosinophils. Our results suggest that clinical trials with long follow-ups may be useful in evaluating histamine-1 receptor antagonists as add-on therapy to steroids in the treatment of asthma.

Cobalt nano-particles modulate cytokine in vitro release by human mononuclear cells mimicking autoimmune disease.

The use of particles from micro to nanoscale provides benefits to diverse scientific fields, but because a large percentage of their atoms lie on the surface, nanomaterials could be highly reactive and pose potential risks to humans. Due to their wide range of application, Cobalt nano-particles are of great interest both in industry and in life-science. To date, there are few studies on Co nano-particle toxicology. In this respect, this study aims at evaluating in vitro the potential interference of Co nano-particles on the production of several cytokines (IL-2, IL-4, IL-6, IL-10, IFNgamma and TNFalpha) by PBMCs, comparing their effects to those of Co micro-particles and Co solution (CoCl2). Cells were cultured in Opticell flasks with escalating concentrations (10-5, 10-6 and 10-7 M), of Co nano and micro-particles and CoCl2 or without metal. Cytokines were quantified in the supernatants using a human Th1/Th2 cytokine cytometric bead array. Co micro-particles showed a greater inhibitory effect compared to other Co forms. Its inhibitory activity was detected at all concentrations and towards all cytokines, whereas Co solutions selectively inhibited IL-2, IL-10 and TNF-alpha at maximal concentration. Co nano-particles induced an increase of TNF-alpha and IFN-gamma release and an inhibition of IL-10 and IL-2: a cytokine pattern similar to that detected in the experimental and clinical autoimmunity. On the basis of the obtained data, immune endpoints should be sought in the next series of studies both in vitro and in vivo in subjects exposed to cobalt nano-particles.

Neurobehavioral functions, serum prolactin and plasma renin activity of manganese-exposed workers.

Objective of this study was to assess effects of manganese (Mn) exposure on 56 workers employed in a Mn welding workshop of a machine building factory in Taiyuan (Shanxi Province, P.R. China) for a mean period of 16.1 years. The mean air Mn level in the workshop was 138.4 microg/m3. Neurobehavioral Core Test Battery (NCTB), including the Profile fo Mood States, (POMS), was performed. Blood pressure (BP) increase following immediate stand-up (BP-IS), serum prolactin (PRL) and plasma renin activity (PRA) in supine position were also determine. Most of the NCTB scores of the Mn-exposed workers were lower than those of controls, while the POMS scores were higher, indicating a Mn-induced impairment of neurophysiological functions and a deflection of mood towards negative emotion states. PRL values of the Mn-exposed workers were higher than those of the controls. BP-IS of Mn-exposed workers was significantly lower than that of the controls. PRA of the same workers was augmented more that 200%. In the Mn-exposed workers, the higher PRL values are possibly due to a reduced inhibitory effect on pituitary lactotrope cells by the tubero-infundibular dopamine system; the decreased BP-IS was referred to imbalance between the sympathetic and parasympathetic activities, whereas the higher basal PRA was thought to depend on neuroendocrine changes (including increased central sympathetic tone) and/or on a direct effect of Mn on renal juxta-glomerular cells. On the whole, this study demonstrates that occupational Mn exposure is responsible for neurobehavioral changes coexisting with alterations of neuroendocrine and humoral systems.

Occupational asthma due to low molecular weight agents.

Occupational asthma is defined as variable airflow obstruction and airways hyperresponsiveness caused by exposure to agents present in the workplace. Low molecular weight agents such as isocyanates, aldehydes, anhydrides, colophony, dyes, persulphate, amines, acrylates and metals are steadily increasing as causative agents of occupational asthma. Isocyanates, aldehydes and anhydrides my cause sensitisation through an IgE mediated response in some workers. These agents act as haptens which combine with a carrier protein to form a complete antigen. Assays for the detection of specific IgE are standardized for very few agents and have a good specificity, but poor sensitivity. The diagnosis of occupational asthma relies not only on a suggestive hystory showing that asthma is caused or exacerbated specifically by work exposure, but in most cases needs to be confirmed by objective means. Combined monitoring of lung function parameters, such as peak expiratory flow rate at the work site and non specific bronchial hyperresponsiveness during and away from exposure, is necessary. The "gold standard" for confirming a diagnosis in an individual worker still remains the specific bronchoprovocation test, which has now reached a high degree of sensitivity, specificity and reproducibility for agents such a s isocyanates. In occupation asthma due to low molecular weight agents there are no individual risk factors which could predict the susceptibility to develop the disease. The primary prevention is based on appropriate interventions tn the workplace. The strict medical surveillance of workers may allow the early diagnosis and removal from further exposure in order to prevent morbidity and disability.

Immune effects of nickel.

Data on nickel immunomodulation are contradictory. The most consistent immune effects are suppression of immune responses. It has been shown that T-lymphocytes and NK cells are more susceptible to nickel toxicity than are B lymphocytes or macrophages. Data reported about cytokine production in human and nickel reactive T-cell clones are also conflicting. Some authors studied showed a higher synthesis of IL4, IL5 and IL13 but not of IFN gamma and TNFalpha in Ni allergic subjects. We found that the addiction on NiSo4 to the PBMC cultures of non sensitised subjects induces a reduction of release of IL5, IFN gamma and TNFalpha. Our studies demonstrate a clear difference in the NK cell activity between nickel-tolerant and intolerant individuals. In particular NK cell activity in reduced in sensitised patients respect to the normal subjects and the addition of Ni has immunotoxic potential. Researches are in progress in an Attempt to correlate the present data with other immune parameters and to measure the effects of a Ni Free diet on the immune system of subjects with Ni intolerance. The comprehension of the mechanisms inducing these changes requires further studies in the uptake and intracellular distribution and binding of the metal.

"In vitro" comparative immune effects of different titanium compounds.

Exposure to Ti compounds is today an occupational and environmental health hazard. Object of this study was to determine "in vitro" effects of different Ti salts on cultured human peripheral blood mononuclear cells (PBMC) proliferation and cytokine release. 10(-4) and 10(-7) M Ti compounds did not modify spontaneous PBMC proliferation. Ti dioxide (a biocompatible material and sunscreen component) did not exert effects on phytoemagglutinin (PHA) stimulated PBMC proliferation and on PHA stimulated IFN-gamma and TNF-alpha release from PBMC. On the other hand, 10(-4) M Ti oxalate (with wide industrial applications) and Ti ascorbate (used mainly in agriculture) inhibited about 70% the PHA stimulate PBMC proliferation; both these Ti compounds at 10(-4) and 10(-7) M concentrations significantly inhibited TNF-alpha release, while only Ti oxalate inhibited that of IFN-gamma. Titanocene (used in chemotherapy) did no exert effects on PBMC proliferation but markedly inhibited IFN-gamma and TNF-alpha release. On the whole, this study demonstrates that Ti dioxide is not immunotoxic; Ti oxalate shows marked immunotoxicity; titanocene exerts selective toxicity on cytokine release but not on PBMC proliferation, while Ti ascorbate affects TNF-alpha release from PBMC but not iFN-gamma release. In conclusion, the data show that immunotoxicity fo Ti depends on speciation.

Asthma worsened by benzoate contained in some antiasthmatic drugs.

Here, we report our experience on benzoate hypersensitivity. Drug and food additives are known to induce pseudo-allergic reactions such as urticaria, eczema, asthma and rhinitis. These reactions are often under-diagnosed, above all in allergic patients treated with additive containing drugs. On the contrary, attention to the additives present in some drug formulations and foods may often permit more correct diagnosis.

Ischaemia-reperfusion is an event triggered by immune complexes and complement.

BACKGROUND: Reperfusion injury is a common clinical problem that lacks effective therapy. Two decades of research implicating oxygen free radicals and neutrophils has not led to a single successful clinical trial. METHODS: The aim was to review new clinical and preclinical data pertaining to the alleviation of reperfusion injury. A review of the literature was undertaken by searching the MEDLINE database for the period 1966-2003 without language restrictions. RESULTS AND CONCLUSION: Evidence now points to complement and immune complexes as critical players in mediating reperfusion injury. Ischaemia is postulated to induce a phenotypical cellular change through the surface expression of a neoantigen. Preformed circulating natural IgM antibodies are then trapped and complement is activated. Final events leading to reperfusion injury include formation of the membrane attack complex and mast cell degranulation.

Simple renal cysts in hypertensive patients: relation between cyst growing and anti-hypertensive therapy.

The study investigates relationship between simple renal cyst enlargement studied by ultrasonography and anti-hypertensive treatment. To this purpose we enrolled 42 patients with newly diagnosed hypertension affected by simple renal cysts. Fourteen were randomly assigned to treatment with ACE-Inhibitors (group 1), twelve to diuretics (group 2) and sixteen to Ca-Antagonists (group 3). Patient performed a basal ultrasonography to evaluate basal cyst dimension before starting anti-hypertensive treatment. Following 12 months of the anti-hypertensive regimen, a new echograph was performed to evaluate changes in cyst size. A control group consisting of 15 patients with normal blood pressure and simple renal cysts was enrolled (group 0). An enlargement of cysts was detected in all patients. However, the enlargement observed in patients treated by Ca-Antagonists was significantly greater than that observed in the other groups (p<0.05). Our study supports the hypothesis that Ca-Antagonists may favor cyst enlargement by enhancing cyclic AMP production. In fact, cAMP and cAMP agonists stimulate fluid secretion by lining cells of the cyst wall, inducing cyst enlargement.

[Inflammation, bronchial hyperreactivity, and progression of asthma: a 5-year follow-up in grass sensitized farmers]. / Infiammazione, iperreattività bronchiale e progressione dell'asma: follow-up di 5 anni in contadini con asma allergico a graminacee.

We studied in a group of 53 asthmatic farmers the influence of various treatment regimens on progression of disease, during five years follow-up. Specific immuno-therapy (SIT) and steroid treated patients showed significantly lower ECP levels and higher methacholine PD20 FEV1 than untreated patients, during all years of the study. During the first two years, spring ECP increase was higher in SIT treated patients than in steroid ones, however no significant differences were found during the following years. Bronchial hyperreactivity showed same course, except for a significant higher PD20 FEV1 in steroid and SIT treated asthmatics, in respect to the steroid or SIT alone. We may conclude that ECP and bronchial reactivity are useful for asthma monitoring and SIT and inhalant steroids have additional effects on asthma.

Probiotics and food-allergic diseases.

The definition of probiotics is always evolving, since it includes natural live micro-organisms, cellular subfractions, as well as genetically engineered derivatives or proteins. The scope of probiotic administration is beneficial change of the intestinal microflora, and improvement of non immune or immune resistance in the intestinal tract. Very few controlled human studies have been reported, but many in vitro and experimental animal studies point to their safety and potentially useful applications. We shall review the published reports and discuss mainly the prospective uses in the field of allergic diseases, with reference to the implication of the natural (innate) immune system as regulator of the development of abnormal responses to ingested food antigens.

Steroid and antihistamines modulate RANTES release in cultured peripheral blood mononuclear cells of atopic patients.

RANTES plays a crucial role in cell recruitment in allergic inflammation. We investigated the pharmacological modulation of RANTES release in cultured peripheral blood mononuclear cells obtained from allergic patients with active asthma. Chemokine production was assessed before and after 15 day treatment with histamine-1 receptor antagonists (antihistamines) (Loratadine or Cetirizine) and a steroid (Deflazacort), both in unstimulated and PHA-stimulated cell cultures. Results were compared with those obtained from placebo-treated patients. During the treatment period, patients recorded morning and evening peak expiratory flow (PEF) by the mini-Wright procedure. PEF absolute values and diurnal variability significantly improved respect to the pre-treatment in steroid-treated patients, in comparison to the placebo and antihistamine-treated groups (p<0.001 and 0.01, respectively). PEF diurnal variability in the antihistamine-treated group were lower than placebo-treated group without statistical significance (p=0.06). No differences could be found in RANTES levels in supernatants of all cultures between the two antihistamines. RANTES release significantly decreased in supernatants of all cell cultures from steroid (p<0.01) and antihistamine (p=0.03 and 0.04) groups after treatments, compared to the basal values; whereas it increased slightly in controls. Co-variance analysis on RANTES levels, adjusting for pre-treatment values, showed a significant reduction of RANTES release by PHA-stimulated PBMCs from steroid (p=0.003) and anti-histamine (p=0.03) groups, with respect to the placebo group. The same statistical tool applied between the steroid and the antihistamine groups showed, after therapy, the lowest levels of RANTES to be associated with steroid treatment (p=0.005). The study shows that the steroid is the most effective drug in modulating RANTES release from PBMCs. However, antihistamines, which are able to reduce cell recruitment due to chemokine release, avoiding important side effects, may be useful in long term therapy in controlling and preventing allergic inflammation.

Seasonal variability of non-specific bronchial responsiveness in asthmatic patients with allergy to house dust mites.

The aim of the study was to assess the seasonal variability of non-specific bronchial responsiveness to methacholine in allergic asthma. One hundred sixty-five patients (83 male and 82 female) entered the study: 86 subjects (group A) with allergy exclusively to mites and 79 (group B) with concomitant allergy to pollens, e.g., "Graminae" and "Parietaria." Inclusion criteria were the absence of sensitization to other allergens, no smoking habit, withdrawal from steroids, bronchodilators, sodium cromoglycate, and antihistamines for at least four weeks before enrollment, FEV1 > 70% of the predicted value, and absence of other respiratory diseases and of upper and lower respiratory tract infections for at least one month before the methacholine challenge. None of the patients had been previously treated with specific immunotherapy. Subjects of each group (A and B) underwent methacholine challenge at first visit and were divided into four subgroups according to the period when the challenge was performed. Subgroups A1 and B1 performed the challenge in December, January, and February; subgroups A2 and B2 in March, April, and May; subgroups A3 and B3 in June, July, and August; subgroups A4 and B4 in September, October, and November. PD20 values were expressed as the natural logs of the cumulative dose of methacholine causing at least a 20% fall in FEV1. Statistical analysis was carried out using multiple group analysis and Student's t-test. Results showed that the highest non-specific bronchial responsiveness was observed in autumn (ln PC20 = 4.54 +/- 1.51) in patients allergic to mites only (group A), and in summer (ln PC20 = 4.72 +/- 2.11) in those of group B. Multiple group analysis showed statistical significant differences between subgroups within each group (group A, p = 0.039; group B, p < 0.001). In patients allergic exclusively to house dust mites (group A), multiple comparisons and Student's t-test showed statistically significant differences between non-specific bronchial responsiveness (NSBR) assessed in autumn and those of other seasons (winter, p = 0.002; spring, p < 0.001; summer, p = 0.082). These results confirm that the level of allergen exposure may influence NSBR. Mite-allergic patients showed an increase of NSBR in autumn, possibly as a consequence of higher indoor mite concentration. However, mite- and grass-allergic patients had wider variations of NSBR, possibly reflecting changes in seasonal pollen concentration.