TRPM8 (CMR1) is a Ca2+‐permeable channel, which can be activated by low temperatures, menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is ...related to vanilloid receptor type‐1 (VR1, TRPV1). We tested whether substances which are structurally related to menthol, or which produce a cooling sensation, could activate TRPM8, and compared the responses of TRPM8 and VR1 to these ligands.
The effects of 70 odorants and menthol‐related substances on recombinant mouse TRPM8 (mTRPM8), expressed in HEK293 cells, were examined using a FLIPR® assay. In all, 10 substances (linalool, geraniol, hydroxycitronellal, WS‐3, WS‐23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists.
The EC50 values of the agonists defined their relative potencies: icilin (0.2±0.1 μM)>FrescolatML (3.3±1.5 μM) > WS‐3 (3.7±1.7 μM) >(−)menthol (4.1±1.3 μM) >frescolatMAG (4.8±1.1 μM) > cooling agent 10 (6±2.2 μM) >(+)menthol (14.4±1.3 μM) > PMD38 (31±1.1 μM) > WS‐23 (44±7.3 μM) > Coolact P (66±20 μM) > geraniol (5.9±1.6 mM) > linalool (6.7±2.0 mM) > eucalyptol (7.7±2.0 mM) > hydroxycitronellal (19.6±2.2 mM).
Known VR1 antagonists (BCTC, thio‐BCTC and capsazepine) were also able to block the response of TRPM8 to menthol (IC50: 0.8±1.0, 3.5±1.1 and 18±1.1 μM, respectively).
The Ca2+ response of hVR1‐transfected HEK293 cells to the endogenous VR1 agonist N‐arachidonoyl‐dopamine was potentiated by low pH. In contrast, menthol‐ and icilin‐activated TRPM8 currents were suppressed by low pH.
In conclusion, in the present study, we identified 10 new agonists and three antagonists of TRPM8. We found that, in contrast to VR1, TRPM8 is inhibited rather than potentiated by protons.
British Journal of Pharmacology (2004) 141, 737–745. doi:10.1038/sj.bjp.0705652
Excessive mast cell mediator release may lead to anaphylaxis in patients with mastocytosis. However, the incidence, clinical features and trigger factors have not yet been analyzed. To identify risk ...factors for anaphylaxis in mastocytosis, we determined cumulative incidence, severity, clinical characteristics, and trigger factors for anaphylaxis in 120 consecutive patients (53 male; 67 female, median age and range 24 years, 1 month to 73 years), and correlated these with disease severity of mastocytosis, skin involvement, basal total serum tryptase, and diaminooxidase concentrations. The cumulative incidence of anaphylaxis in patients with mastocytosis was higher in adults (49%; P < 0.01) compared with that in children (9%). Only children with extensive skin involvement had experienced anaphylaxis. In adults, anaphylaxis was correlated to the absence of urticaria pigmentosa lesions (P < 0.03). Reactions occurred more frequently in adults with systemic (56%) when compared with cutaneous mastocytosis (13%; P < 0.02). In adults, 48% of reactions were severe, and 38% resulted in unconsciousness. Major perceived trigger factors for adults were hymenoptera stings (19%), foods (16%), and medication (9%); however, in 26% of reactions, only a combination of different triggers preceded anaphylaxis. Trigger factors remained unidentified in 67% of reactions in children compared with 13% in adults. Patients with anaphylaxis had higher basal tryptase values (60.2 ± 55 ng/ml, P < 0.0001) in comparison with those without (21.2 ± 33 ng/ml), but not diaminooxidase levels. Adult patients and children with extensive skin disease with mastocytosis have an increased risk to develop severe anaphylaxis; thus, an emergency set of medication including epinephrine is recommended.
Gender differences in the development and prevalence of human diseases have long been recognized. Immense interest grows in the understanding of the role of sex hormones in the homeostasis of ...immunity. Asthma predominates in boys before puberty and this gender preference reverses after puberty and in adulthood, when adult women tend to have a more severe disease, often recalcitrant to treatment. Atopic eczema in preschool children shows insignificant gender difference or male preponderance in different studies, with more adult females suffering from atopic eczema. The limited data on the prevalence of immediate hypersensitivity to hymenoptera venom show controversial results. Discrepancy exists regarding the gender difference in food allergy, with females reporting significantly more allergic reactions in questionnaire studies. In general, adverse reactions to nonionic iodinated radiocontrast media are more commonly observed in females. The course of allergic diseases varies unpredictably during pregnancy, whereas hormone replacement therapy in postmenopausal women usually has a favorable influence on the course of asthma. Experiments in rodents confirm an effect of estrogens on mast cell activation and allergic sensitization, while progesterone is shown to suppress histamine release but potentiate IgE induction. Dehydroepiandrosterone may antagonize the production of Th2 cytokines but the effect of testosterone and the other androgens remains less defined. Actual data from human studies are lacking.
The allergenic content of the atmosphere varies according to climate, geography and vegetation. Data on the presence and prevalence of allergenic airborne pollens, obtained from both aerobiological ...studies and allergological investigations, make it possible to design pollen calendars with the approximate flowering period of the plants in the sampling area. In this way, even though pollen production and dispersal from year to year depend on the patterns of preseason weather and on the conditions prevailing at the time of anthesis, it is usually possible to forecast the chances of encountering high atmospheric allergenic pollen concentrations in different areas. Aerobiological and allergological studies show that the pollen map of Europe is changing also as a result of cultural factors (for example, importation of plants such as birch and cypress for urban parklands), greater international travel (e.g. colonization by ragweed in France, northern Italy, Austria, Hungary etc.) and climate change. In this regard, the higher frequency of weather extremes, like thunderstorms, and increasing episodes of long range transport of allergenic pollen represent new challenges for researchers. Furthermore, in the last few years, experimental data on pollen and subpollen-particles structure, the pathogenetic role of pollen and the interaction between pollen and air pollutants, gave new insights into the mechanisms of respiratory allergic diseases.
The immune system is regulated to protect the host from exaggerated stimulatory signals establishing a state of tolerance in healthy individuals. The disequilibrium in immune regulatory vs effector ...mechanisms results in allergic or autoimmune disorders in genetically predisposed subjects under certain environmental conditions. As demonstrated in allergen‐specific immunotherapy and in the healthy immune response to high‐dose allergen exposure models in humans, T regulatory cells are essential in the suppression of Th2‐mediated inflammation, maintenance of immune tolerance, induction of the two suppressive cytokines interleukin‐10 and transforming growth factor‐β, inhibition of allergen‐specific IgE, and enhancement of IgG4 and IgA. Also, suppression of dendritic cells, mast cells, and eosinophils contributes to the construction of peripheral tolerance to allergens. This review focuses on mechanisms of peripheral tolerance to allergens with special emphasis on recent developments in the area of immune regulation.
Outdoor particulate matter (PM10) is associated with detrimental health effects. However, individual PM10 exposure occurs mostly indoors. We therefore compared the toxic effects of classroom, ...outdoor, and residential PM10. Indoor and outdoor PM10 was collected from six schools in Munich during teaching hours and in six homes. Particles were analyzed by scanning electron microscopy and X‐ray spectroscopy (EDX). Toxicity was evaluated in human primary keratinocytes, lung epithelial cells and after metabolic activation by several human cytochromes P450. We found that PM10 concentrations during teaching hours were 5.6‐times higher than outdoors (117 ± 48 μg/m3 vs. 21 ± 15 μg/m3, P < 0.001). Compared to outdoors, indoor PM contained more silicate (36% of particle number), organic (29%, probably originating from human skin), and Ca‐carbonate particles (12%, probably originating from paper). Outdoor PM contained more Ca‐sulfate particles (38%). Indoor PM at 6 μg/cm2 (10 μg/ml) caused toxicity in keratinocytes and in cells expressing CYP2B6 and CYP3A4. Toxicity by CYP2B6 was abolished with the reactive oxygen species scavenger N‐acetylcysteine. We concluded that outdoor PM10 and indoor PM10 from homes were devoid of toxicity. Indoor PM10 was elevated, chemically different and toxicologically more active than outdoor PM10. Whether the effects translate into a significant health risk needs to be determined. Until then, we suggest better ventilation as a sensible option.
Practical Implications
Indoor air PM10 on an equal weight base is toxicologically more active than outdoor PM10. In addition, indoor PM10 concentrations are about six times higher than outdoor air. Thus, ventilation of classrooms with outdoor air will improve air quality and is likely to provide a health benefit. It is also easier than cleaning PM10 from indoor air, which has proven to be tedious.
Summary
Background
Data on molecular allergy diagnostics in adults with grass pollen allergy with regard to conjunctival and nasal provocation test outcome and specific immunotherapy are lacking to ...date.
Objective
To assess whether molecular allergy diagnostics for grass pollen allergens could help with predicting provocation test outcomes and serve as a basis for future component‐resolved specific immunotherapy.
Methods
Sera of 101 adults with grass pollen allergy was analysed for IgE against timothy grass pollen (Phleum pratense), rPhl p 1, rPhl p 2, nPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11 and rPhl p12 and correlated with the individuals' outcome in the nasal and conjunctival provocation tests and investigated in regard to a potential component‐resolved specific immunotherapy.
Results
An increasing number of sensitizations to timothy grass allergens was correlated to a positive reaction in the conjunctival (4.9 vs. 3.6, P = 0.003) and nasal provocation tests (4.5 vs. 2.2, P = 0.0175). In molecular sensitization profiles, a substantial heterogeneity was detected, with none of the patients exactly matching the allergen composition of a previously published component‐resolved specific immunotherapy containing Phl p 1, Phl p 2, Phl p 5a/b and Phl p 6. The results indicate that in 95% of the patients, a proportion of 50% of timothy‐IgE would be targeted with such a specific immunotherapy, while in 50% and 10% of patients, 80% and 90% of timothy‐IgE would be targeted, respectively.
Conclusion and Clinical Relevance
Molecular allergy diagnostics is a prerequisite for future component‐resolved specific immunotherapy due to the high heterogeneity of sensitization profiles. However, of current clinical relevance is the observed correlation between the number of sensitizations and provocation test outcome.
To cite this article: Cecchi L, D'Amato G, Ayres JG, Galan C, Forastiere F, Forsberg B, Gerritsen J, Nunes C, Behrendt H, Akdis C, Dahl R, Annesi-Maesano I. Projections of the effects of climate ...change on allergic asthma: the contribution of aerobiology. Allergy 2010; 65: 1073-1081. Climate change is unequivocal and represents a possible threat for patients affected by allergic conditions. It has already had an impact on living organisms, including plants and fungi with current scenarios projecting further effects by the end of the century. Over the last three decades, studies have shown changes in production, dispersion and allergen content of pollen and spores, which may be region- and species-specific. In addition, these changes may have been influenced by urban air pollutants interacting directly with pollen. Data suggest an increasing effect of aeroallergens on allergic patients over this period, which may also imply a greater likelihood of the development of an allergic respiratory disease in sensitized subjects and exacerbation of symptomatic patients. There are a number of limitations that make predictions uncertain, and further and specifically designed studies are needed to clarify current effects and future scenarios. We recommend: More stress on pollen/spore exposure in the diagnosis and treatment guidelines of respiratory and allergic diseases; collection of aerobiological data in a structured way at the European level; creation, promotion and support of multidisciplinary research teams in this area; lobbying the European Union and other funders to finance this research.
Summary
The increase of allergies in East Germany – reaching West German prevalence shortly after the reunification – is considered a model for the allergy epidemic in the western world. Whether such ...a pattern was observed in all comparison studies and for all allergic manifestations is not known because a complete overview is missing. Hints about possible causal factors for the allergy epidemic could be gained by identifying known risk factors, which explain the observed pattern of allergy development in Germany. Again, an overview about these efforts is missing. We identified 14 cross‐sectional studies conducted after 1989 and calculated prevalence ratios (West/East) for asthma, hayfever, eczema and allergic sensitization. Additionally, a tabular overview about the explanatory power of risk factors hypothesized in the nineties and covering outdoor exposure, indoor factors, early childhood influences, nutrition as well as awareness is given. At the time of the German reunification, the prevalence ratio West/East was largest for hayfever and sensitization to birch pollen, less pronounced for the other phenotypes and even less than one for atopic eczema. Hayfever and sensitization to birch pollen also showed the steepest increase in East Germany afterwards. Single‐room heating with fossil fuels and living as only child in a family were identified as explaining up to 23.5% of the excess trend in East compared to the trend in West. Hayfever as most typical atopic disease showed the difference in allergy pattern between East and West Germany clearest. Risk factors identified for these phenotypes are completely different (single child) or even act in the opposite direction (single‐room heating) from classical risk factors for airway diseases. This might be the most important lesson from the West/East German experience. It already stimulated many other studies focussing on protective factors such as microbial stimulation.
Summary
Background
Flow cytometric basophil activation tests (BAT) have been developed as cellular tests for in vitro diagnosis of IgE‐mediated reactions. Different markers and techniques have been ...used after stimulation with various allergens.
Objective
It was the aim of the present study to compare an established BAT (Flow‐CAST®) with a newly developed basophil activation protocol using CD63 and CCR3 (Flow2 CAST®) in patients with type‐I allergy to antibiotics.
Materials and methods
Twenty‐four patients with a history of type‐I allergy to antibiotics were examined. A careful allergy history was taken, and skin tests and determination of specific IgE antibodies were performed. Two different BAT using CD63 expression but different protocols were carried out after stimulation with different concentrations of antibiotics. Fifteen healthy subjects without a history of antibiotic allergy were studied as controls.
Results
The Flow2 CAST® showed a higher sensitivity than the Flow‐CAST® (55% vs. 53%) with regard to patients' history. Specificity was 80% both for the Flow2 CAST® and for the Flow‐CAST® with regard to controls with negative history and negative RAST.
Conclusion
These results show the value of two different BAT as cellular tests in the in vitro diagnosis of patients with antibiotic allergy with equal specificity and a slightly higher sensitivity for the Flow2 CAST®.
Cite this as: B. Eberlein, I. León Suárez, U. Darsow, F. Ruëff, H. Behrendt and J. Ring, Clinical & Experimental Allergy, 2010 (40) 411–418.
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