D. Kalogeromitros

Differential release of mast cell mediators and the pathogenesis of inflammation.

Summary:  Mast cells are well known for their involvement in allergic and anaphylactic reactions, during which immunoglobulin E (IgE) receptor (FcɛRI) aggregation leads to exocytosis of the content of secretory granules (1000 nm), commonly known as degranulation, and secretion of multiple mediators. Recent findings implicate mast cells also in inflammatory diseases, such as multiple sclerosis, where mast cells appear to be intact by light microscopy. Mast cells can be activated by bacterial or viral antigens, cytokines, growth factors, and hormones, leading to differential release of distinct mediators without degranulation. This process appears to involve de novo synthesis of mediators, such as interleukin‐6 and vascular endothelial growth factor, with release through secretory vesicles (50 nm), similar to those in synaptic transmission. Moreover, the signal transduction steps necessary for this process appear to be largely distinct from those known in FcɛRI‐dependent degranulation. How these differential mast cell responses are controlled is still unresolved. No clinically available pharmacological agents can inhibit either degranulation or mast cell mediator release. Understanding this process could help develop mast cell inhibitors of selective mediator release with novel therapeutic applications.

IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1–10 μM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5–100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component.

Novel therapeutic targets for autism

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, diagnosed in early childhood when acquired skills are lost or the acquisition of new skills becomes delayed. ASDs are associated with varying degrees of dysfunctional communication and social skills, in addition to repetitive and stereotypic behaviors. The diagnosis has increased considerably to approximately one in 180 people, but it is not clear whether this is because of a higher prevalence of the disorder, improved awareness by clinicians or a combination of both. There are no defined mechanisms of pathogenesis or curative therapy presently available. Oxidative stress, overactivation of the hypothalamic-pituitary-adrenal axis and increased gut-blood-brain-barrier permeability might be involved. The scope of this article is to integrate these findings and present the opinion that non-allergic activation of gastrointestinal and brain mast cells could contribute to many of the pathologic findings and provide unique targets for ASD therapy. We make suggestions for new research directives and possible novel therapies from readily available molecules.

Influence of the menstrual cycle on skin-prick test reactions to histamine, morphine and allergen

The purpose of this study was to examine the possible influence of the phases of the menstrual cycle on dermal reactivity to skin‐prick testing. We studied 15 atopic, menstruating women with seasonal rhinoconjunctivitis and/or asthma, with known sensitivity to olive and parietaria (mean age 25.2 years) and 15 non‐atomic, healthy, female controls (mean age 24.7 years). Skin‐prick tests with histamine, morphine, and in the atopic group with parietaria/and/or olive, were repeated three times during the same menstrual cycle, corresponding to bleeding (day 1–4), midcycle (day 12–16) and the late progesterone phase (day 24–28). None of the patients had received oral antihistamines or exogenous hormones for at least 1 month prior to testing. Results indicate a significant increase in weal‐and‐flare size to histamine, morphine, and parietaria on days 12–16 of the cycle, corresponding to ovulation and peak oestrogen levels. This was observed in both atopic and non‐atopic women. Differences in skin reactivity to histamine and morphine between the groups were not significant. Therefore, in women, the phase of the menstrual cycle is another factor that may influence skin‐test results.

Progesterone Inhibits Mast Cell Secretion

Mast cells are involved in allergic reactions, where they secrete numerous vasoactive, inflammatory and nociceptive mediators in response to immunoglobulin E (IgE) and antigen. However, they have also been implicated in inflammatory conditions, such as painful bladder syndrome/interstitial cystitis (PBS/IC), irritable bowel syndrome (IBS) and migraines, all of which occur more often in women and are exacerbated during ovulation, but are suppressed during pregnancy. Mast cells express high affinity estrogen receptors and estradiol augments their secretion, while tamoxifen inhibits it. Here we report that progesterone (100 nM), but not the structurally related cholesterol, inhibits histamine secretion from purified rat peritoneal mast cells stimulated immunologically or by substance P (SP), an effect also documented by electron microscopy. These results suggest that mast cell secretion may be regulated by progesterone and may explain the reduced symptoms of certain inflammatory conditions during pregnancy.

Fish and shellfish allergy in children: review of a persistent food allergy.

The increased consumption of fish and shellfish has resulted in more frequent reports of adverse reactions to seafood, emphasizing the need for more specific diagnosis and treatment of this condition and exploring reasons for the persistence of this allergy. This review discusses interesting and new findings in the area of fish and shellfish allergy. New allergens and important potential cross‐reacting allergens have been identified within the fish family and between shellfish, arachnids, and insects. The diagnostic approach may require prick to‐prick tests using crude extracts of both raw and cooked forms of seafood for screening seafood sensitization before a food challenge or where food challenge is not feasible. Allergen‐specific immunotherapy can be important; mutated less allergenic seafood proteins have been developed for this purpose. The persistence of allergy because of seafood proteins’ resistance after rigorous treatment like cooking and extreme pH is well documented. Additionally, IgE antibodies from individuals with persistent allergy may be directed against different epitopes than those in patients with transient allergy. For a topic as important as this one, new areas of technological developments will likely have a significant impact, to provide more accurate methods of diagnosing useful information to patients about the likely course of their seafood allergy over the course of their childhood and beyond.

Impact of stress and mast cells on brain metastases

Metastases continue to be the chief cause of morbidity and mortality for many tumors, including brain metastases of lung and mammary adenocarcinoma. Stress appears to increase metastases, but the mechanism is not understood. Recent evidence suggests that local inflammation is conducive for cancer growth and a unique immune cell, the mast cell, accumulates in the stroma surrounding tumors and is critically located at the blood-brain-barrier (BBB). Mast cells express receptors for and can be stimulated by corticotropin-releasing hormone (CRH), secreted under stress, to release mediators such as histamine, IL-8, tryptase and vascular endothelial growth factor (VEGF), which disrupt the BBB permitting metastases. Stress and mast cells could serve as new targets for drug development to prevent brain metastases, especially since CRH receptor antagonists and brain mast cell inhibitors have recently been developed.

Frontal fibrosing alopecia: treatment with oral dutasteride and topical pimecrolimus

© 2008 The Authors JEADV 2009, 23, 570–620 Journal compilation

Clinical features and natural history of acquired cold urticaria in a tertiary referral hospital: a 10-year prospective study.

Background  Acquired cold urticaria (ACU) represents a heterogeneous group of disorders that share a common clinical feature: the development of urticaria or angioedema after cold exposure. We present epidemiological and clinical data of subjects with ACU, natural progression and we examine possible parameters that could correlate with disease severity.

Patch tests in children: a review of 14 years experience

Studies in children with dermatitis vary widely in observed reactivity to patch tests (1-9), the mean ranging around 40% (6, 8). From I980-I993, we patch tested approximately 5900 patients of all ages with suspected contact dermatitis. Of these, 232 were children under the age of 16 years (>6 months); 87 boys and I45 girls. All children were patch tested with a modified European standard series (Trolab, Hermal, Germany), and with additional series as indicated, according to ICDRG guidelines, standard adult concentrations of test substances being used in all cases. Of the 232 children patch tested, 101 (43.5%) were positive to at least 1 allergen. The 2 recent studies from the Italian (5) and Portuguese contact dermatitis groups (3) also used adult concentrations, and report frequencies of positive patch tests of 35.5% and 52%, respectively, in children under 14 years. The hands were involved in 38% of the 101 reactive children, the face and the feet in 16% each, and the body in 6%. Multiple skin sites were involved in 24%. The age and sex distributions are shown in Table I. 53% of the girls and 39% of the boys were reactive. Increased reactions in girls versus boys became evident over the age of 10 years, which could be explained by the higher incidence of nickel sensitivity among girls (Table 2). Metals were the most common allergens and nickel sensitivity predominated (Table 2). This finding is consistent with other reports (6-8), though Levy et al. (4) and Camarasa et al. (9) have reported more positive tests to mercury than to nickel in children. The 2nd most common category of allergens was fragrances and preservatives and here there was no sex predominance, in agreement with Rademaker & Forsyth (8). As compared to other studies, relatively few of the children in our study reacted to medicaments and antiseptics (3-5), which may be explained by differences in formulations of topical products from country to country and in the frequency with which they are applied to the skin. We also examined the association of atopic dermatitis and contact dermatitis in children. The % of atopic children who reacted was 28%, versus 50% of non-atopic