Search

There is increased serum CRH with decreased lesional skin CRHR-1 gene expression in psoriasis and atopic dermatitis, suggesting possible involvement in stress-induced worsening of symptoms.

Mast cells are important in the development of allergic and anaphylactic reactions, but also in acquired and innate immunity. There is also increasing evidence that mast cells participate in inflammatory diseases, where they can be activated by non-allergic triggers, such as neuropeptides and cytokines, often having synergistic effects as in the case of substance P (SP) and IL-33. Secretion of vasoactive mediators, cytokines and proteinases contribute to the development of coronary artery disease (CAD), as well as to diet-induced obesity and the metabolic syndrome. Mast cells may be able to orchestrate such different biological processes through their ability to release pro-inflammatory mediators selectively without the degranulation typical of allergic reactions. Recent evidence suggests that mitochondrial uncoupling protein 2 (UCP2) and mitochondrial translocation regulate mast cell degranulation, but not selective mediator release. Better understanding of these two processes and how mast cells exert both immunostimulatory and immunosuppressive actions could lead to the development of inhibitors of release of specific mediators with novel therapeutic applications. more...

Corticotropin-releasing hormone (CRH) is secreted under stress and regulates the hypothalamic-pituitary-adrenal axis. However, CRH is also secreted outside the brain where it exerts proinflammatory effects through activation of mast cells, which are increasingly implicated in immunity and inflammation. Substance P (SP) is also involved in inflammatory diseases. Human LAD2 leukemic mast cells express only CRHR-1 mRNA weakly. Treatment of LAD2 cells with SP (0.5-2 μM) for 6 hours significantly increases corticotropin-releasing hormone receptor-1 (CRHR-1) mRNA and protein expression. Addition of CRH (1 μM) to LAD2 cells, which are "primed" with SP for 48 hours and then washed, induces synthesis and release of IL-8, tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) 24 hours later. These effects are blocked by pretreatment with an NK-1 receptor antagonist. Treatment of LAD2 cells with CRH (1 μM) for 6 hours induces gene expression of NK-1 as compared with controls. However, repeated stimulation of mast cells with CRH (1 μM) leads to downregulation of CRHR-1 and upregulation in NK-1 gene expression. These results indicate that SP can stimulate mast cells and also increase expression of functional CRHR-1, whereas CRH induces NK-1 gene expression. These results may explain CRHR-1 and NK-1 expression in lesional skin of psoriatic patients. more...

Mast cells are well known for their involvement in allergic and anaphylactic reactions, but recent findings implicate them in a variety of inflammatory diseases affecting different organs, including the heart, joints, lungs, and skin. In these cases, mast cells appear to be activated by triggers other than aggregation of their IgE receptors (FcepsilonRI), such as anaphylatoxins, immunoglobulin-free light chains, superantigens, neuropeptides, and cytokines leading to selective release of mediators without degranulation. These findings could explain inflammatory diseases, such as asthma, atopic dermatitis, coronary inflammation, and inflammatory arthritis, all of which worsen by stress. It is proposed that the pathogenesis of these diseases involve mast cell activation by local release of corticotropin-releasing hormone (CRH) or related peptides. Combination of CRH receptor antagonists and mast cell inhibitors may present novel therapeutic interventions. more...

Background: Chronic urticaria is a prevalent condition associated with substantial disability. Its pathogenesis is not clearly understood and is divided into autoimmune and chronic idiopathic urticaria (CIU). We investigated if the non-specific phosphodiesterase inhibitor theophylline could provide additional benefit to the histamine-1 receptor (H-1R) antagonist cetirizine in CIU. Methods: This was a double-blind, placebo-controlled, parallel study. Patients were randomized to receive either cetirizine and theophylline (200 mg twice daily; group A, 67 subjects) or cetirizine and placebo for 6 months (group B, 67 subjects). Group A patients took theophylline for 6 more months. Response was assessed by visual analog scale (VAS) and treatment effectiveness score (TES). Blood theophylline levels were also determined at visit t = 1 and t = 7. Results: The study was completed by 54 of the 67 patients (80.6%) in group A and 51 of the 67 patients (76.1%) in group B. The physician VAS values for group A were lower after t = 3, while the patient VAS values were decreased after t = 2. The physician and patient TES values in group A were statistically higher (p < 0.05) at all time points except for t = 1. At least 1 month of theophylline addition was necessary to obtain statistically significant benefit over cetirizine, and reducing theophylline by 50% during phase 2 did not alter this benefit. Pruritus values were reduced, but not statistically significant. Conclusions: Addition of theophylline to conventional H-1R antagonists was well tolerated without any adverse effects and provided considerable additional benefit in the management of CIU. more...

Dimenhydrinate is a widely used H1 antihistamine that has rarely been responsible for causing fixed drug eruption. We report a case of fixed drug eruption associated with dimenhydrinate in a non-prescription motion sickness medicine confirmed by a positive oral challenge test, which is still the gold standard for establishing the offending agent in FDE. Patch testing in non-affected skin was negative. Physician awareness to such an adverse event of this widely used drug is mandatory. Key words: Dimenhydrinate, fixed drug eruption, oral challenge, patch test. INTRODUCTION Fixed drug eruption (FDE) is a common type of cutaneous adverse drug reaction, triggered by a large number of drugs 1 . In general, antibiotics, anti-inflammatory analge-sics and hypnotics are the most frequent culprit drugs. In addition to phenolphthalein, phenazone, barbiturates, feprazone, sulfonamides, trimethoprim, tetracyclines and naproxen have been reported as the most frequent causes of FDE 1 . Fixed drug eruptions from dimenhydrinate have been reported rarely more...

Background Acute generalized exanthematous pustulosis (AGEP) is a rare and severe cutaneous reaction usually triggered by drugs. Other causative factors such as viral infections are rarely involved. In this study, we report a case of AGEP caused by a spider bite. Case Summary A 56-year-old woman was referred to the allergy unit after a spider bite at the left popliteal fossa, while gardening, 5 days earlier. The offending spider was captured and identified by an entomologist as belonging to the Loxosceles rufescens species. No acute reaction was observed; however, after 24 hours, due to the occurrence of typical dermonecrotic skin lesions associated with erythema and edema, Cefuroxime and Clindamycin were administered intramuscularly after medical advice was given. Almost 72 hours after the spider bite, an erythematous and partly edematous eruption appeared locally in the gluteus area bilaterally, which progressively expanded to the trunk, arms and femors. Within 24 hours dozens of small, pinhead sized, non- follicular pustules were present, mainly in the folds. The patient complained of a burning sensation of the skin in addition to pruritus; and simultaneously had a fever of 38-39 °C as the eruption expanded. Discussion A spider bite may represent a possible causative factor of AGEP. A spider's venom contains sphingomyelinase that stimulates the release of IL8 and GM-CSF, which are involved in AGEP pathogenesis. Whether or not the con-current use of antibiotics has an effect in AGEP appearance when combined with a spider's venom, cannot be excluded. more...

Since aspirin was introduced over a century ago, many new anti-inflammatory agents have been marketed. NSAIDs are currently the most commonly prescribed agents in Western medicine (1). Their widespread use has resulted in a number of well-documented adverse reactions. These most frequently involve the gastro-intestinal tract, causing discomfort, nausea and diarrhoea or, occasionally, bleeding and ulceration (2). Cutaneous reactions mainly include urticaria, angioedema, fixed drug eruption, pruritus, photosensitivity and, in severe cases, Stevens-Johnson syndrome and toxic epidermal necrolysis (3). Lornoxicam (chlortenoxicam) is a new selective cyclooxygenase-2 (COX-2) inhibitor of the oxicam class, with analgesic, anti-inflammatory and antipyretic properties (4). Lornoxicam has a tolerability profile characteristic of an NSAID. No pseudolymphomatous reaction has been reported before. CASE REPORT more...

Background Mast cells are involved in allergy and inflammation by the secretion of multiple mediators, including histamine, cytokines, and platelet-activating factor (PAF), in response to different triggers, including emotional stress. PAF has been associated with allergic inflammation, but there are no clinically available PAF inhibitors. Objective To investigate whether PAF could stimulate human mast cell mediator release and whether rupatadine (RUP), a dual histamine-1 and PAF receptor antagonist, could inhibit the effect of PAF on human mast cells. Methods Laboratory of allergic diseases 2 cultured mast cells were stimulated with PAF (0.001, 0.01, and 0.1 μmol/L) and substance P (1 μmol/L) with or without pretreatment with RUP (2.5 and 25 μmol/L), which was added 10 minutes before stimulation. Release of β-hexosaminidase was measured in supernatant fluid by spectrophotoscopy, and histamine, interleukin-8, and tumor necrosis factor were measured by enzyme-linked immunosorbent assay. Results PAF stimulated a statistically significant release of histamine, interleukin-8, and tumor necrosis factor (0.001–0.1 μmol/L) that was comparable to that stimulated by substance P. Pretreatment with RUP (25 μmol/L) for 10 minutes inhibited this effect. In contrast, pretreatment of laboratory of allergic diseases 2 cells with diphenhydramine (25 μmol/L) did not inhibit mediator release, suggesting that the effect of RUP was not due to its antihistaminic effect. Conclusion PAF stimulates human mast cell release of proinflammatory mediators that is inhibited by RUP. This action endows RUP with additional properties in treating allergic inflammation. more...

Tacrolimus is a macrolide immunosuppressant that has been demonstrated to inhibit T-lymphocyte activation without the side-effects of corticosteroids. The safety profile of tacrolimus makes it a promising therapeutic option for dermatitis. To evaluate and compare the therapeutic ability of tacrolimus 0.1% ointment and mometasone furoate 0.1% ointment in patients with chronic hand eczema and positive patch tests. Thirty adults with chronic hand eczema and positive patch test reaction to relevant contact allergens were treated with tacrolimus 0.1% ointment or mometasone furoate 0.1% ointment in a single-centre, randomized comparative study. The scores of the evaluated clinical parameters (erythema, infiltration, vesiculation, desquamation, presence of cracks and itching) did not differ between Groups A and B at any of the four time points (p>0.05).On the other hand, in both groups, a significant difference was detected in all parameters between baseline and Day 90 recorded values. Tacrolimus is a promising alternative therapy for contact dermatitis patients as it is effective from the first month of treatment, well tolerated and offers similar therapeutic results to topical corticosteroid therapy. more...

He could fit in the palms of both hands, seemed to look at you beseechingly while you rushed to thread a vein and snake a tube down a tiny nostril of this 24 week preemie. Already exposed to the prenatal stress that culminated in premature delivery, he has been further exposed to the stress associated with the separation from his mother and multiple medical interventions. Like other premature babies, he is more vulnerable to invasive infections from bacteria and viruses; moreover, the delayed development of his gut-blood-brain barriers could expose him to potential neurotoxins. Such infants are up to 4 times more likely to develop autism. If their mothers had allergies, mastocytosis or an autoimmune disease, this risk almost doubles. Autism Spectrum Disorders (ASD) are pervasive developmental disorders that include Autistic Disorder and Asperger’s Disorder, although Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) is frequently included (Johnson & Myers, 2007). ASD are characterized by variable deficits in social skills, stereotypic behaviors, and a wide range of behavioral and learning problems. ASD manifest during early childhood and at least 30% present with sudden clinical regression of development around 3 years of age (Matson J.L. & Kozlowski A.M., 2010; Zappella, 2010). Over the last 20 years, there has been an impressive rise in ASD with current prevalence estimates of 1/100 children (Fombonne, 2009; Kogan et al., 2009). In the majority of cases, the cause of ASD is unknown (Levy et al., 2009). Some autism susceptibility genes have been identified (Weiss et al., 2009), but gene interactions with environmental factors are increasingly suspected (Deth et al., 2008; Herbert, 2010). Recent reviews have focused mostly on genomic screens that suggest there are multiple gene interactions in autism; however no gene abnormality alone can explain the apparent increase in ASD prevalence (Durkin et al., 2010; Herbert, 2010; Miles, 2011). Increasing evidence suggests that there are different ASD endophenotypes, even within the ASD spectrum (Palmieri & Persico, 2010). more...

Mast cells are crucial for the development of allergic and anaphylactic reactions, but they are also involved in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases through activation by non-allergic triggers such as neuropeptides and cytokines. This review discusses how mast cells contribute to the inflammatory processes associated with coronary artery disease and obesity. Animal models indicate that mast cells, through the secretion of various vasoactive mediators, cytokines and proteinases, contribute to coronary plaque progression and destabilization, as well as to diet-induced obesity and diabetes. Understanding how mast cells participate in these inflammatory processes could help in the development of unique inhibitors with novel therapeutic applications for these diseases, which constitute the greatest current threat to global human health and welfare. more...

Many children with Autism Spectrum Disorders (ASD) have either family and/or personal history of “allergic symptomatology”, often in the absence of positive skin or RAST tests. These symptoms may suggest mast cell activation by non-allergic triggers. Moreover, children with mastocytosis or mast cell activation syndrome (MCAS), a spectrum of rare diseases characterized by increased number of activated mast cells in many organs, appear to have ASD at a rate tenfold higher (1/10 children) than that of the general population (1/100 children). Mast cell activation by allergic, infectious, environmental and stress-related triggers, especially perinatally, would release pro-inflammatory and neurotoxic molecules. We speculate these could disrupt the gut–blood–brain barriers, thus contributing to brain inflammation and ASD pathogenesis. Increased mast cell responsiveness may define at least a subgroup of ASD subjects, who could benefit from inhibition of mast cell activation. more...

Autism spectrum disorders (ASD) are a group of pervasive neurodevelopmental disorders diagnosed in early childhood. They are associated with a set of "core symptoms" that include disabilities in social interaction skills, verbal and non-verbal communication, as well as repetitive and stereotypic behaviors. There is no definite pathogenetic mechanism or diagnostic tests. Many children with ASD also have "allergic-like" symptoms, but test negative implying mast cell activation by non-allergic triggers. We measured by Milliplex arrays serum levels of 3 neuropeptides that could stimulate mast cells in children with autistic disorder (n = 19; 16 males and 3 females; mean age 3.0 ± 0.4 years) and healthy, unrelated controls (n = 16; 13 males and 3 females; mean age 3 ± 1.2 years). Only neurotensin (NT) was significantly increased from 60.5 ± 6.0 pg/ml in controls to 105.6 ± 12.4 pg/ml in autistic disorder (p = 0.004). There was no statistically significant difference in the serum levels of β-endorphin or substance P (SP). NT could stimulate immune cells, especially mast cells, and/or have direct effects on brain inflammation and ASD. more...

Purpose: To evaluate allergy skin testing as a diagnostic tool of adverse reactions to fluorescein and whether allergy and previous sodium fluorescein angiography (SFA) act as predisposing factors. Methods: Patients with adequate indication for fluorescein angiography and normal skin responsiveness were subjected to allergy skin-prick and intradermal tests for fluorescein, followed by SFA. During SFA, adverse reactions were monitored and classified as mild, moderate or severe. Previous SFAs and adverse reactions as well as the presence of atopy were also registered. Results: One thousand and thirty-seven patients were enrolled in the study and 1284 SFAs were executed. Forty-four patients (4.3%) developed 55 adverse reactions; among them 50 (3.8%) were mild, three (0.2%) moderate and two (0.16%) severe. None of the reactors produced positive skin tests to fluorescein. Patients with atopy and previous SFAs were not more susceptible to adverse reactions. Conclusion: The vast majority of adverse reactions to fluorescein are mild and not attributed to immunological mechanisms. Allergy skin tests cannot predict non-immunological reactions but their utility remains substantial in predicting anaphylaxis during SFAs and must be performed in patients reporting risk factors in their past medical history. more...

Sodium fluorescein (SF) is widely used to assess chorioretinal disorders. Adverse reactions are well documented but the underlying mechanism is still uncertain. The aim of this study was the evaluation of skin testing to predict SF reaction, the identification of possible predisposing factors, and the objective record of the reported reactions. All patients with adequate indication for SF angiography (SFA) during an 18-month period were evaluated as follows: (a) detailed personal history of atopy, diabetes, previous SFA, and/or diagnostic procedures with radiocontrast media (RCM) and possible side effect; (b) skin testing with SF 10% diluted preparations; (c) SFA with 5 mL of SF, objective record of any reaction. Two hundred twenty-four patients (108 men and 116 women) with a mean age of 65.2 years (SD, 12.86; range, 16-92 years) underwent SFA. The overall rate of adverse reactions was 3.6% (8/224), which consists of 5 (2.2%) individuals with transient mild nausea; 2 (0.9%) subjects with face and upper trunk flushing that appeared in one case after 60 minutes and in the other case 24 hours later and both resolved without treatment, and I subject with transient bilateral frontal headache and dizziness. None of the 224 patients had positive skin or intradermal testings. One hundred thirty-six of 224 (60.7%) patients stated no previous SFA and 74.1% had not performed RCM injection. None of the recorded variables correlated with increased risk of reaction. SFA is a safe procedure with minor adverse effects. Although in vivo testing can not identify reactors it may help to exclude an underlying IgE-mediated mechanism in susceptible individuals. more...

Beekeepers are at increased risk for honeybee (Hb) venom allergy and they represent a unique population for Hymenoptera venom studies. The aim of this was to prospectively examine the pattern of Hb venom sensitization over a 5-year period in new beekeepers and define possible predisposing factors. Thirty-five beekeepers were tested every 6 months for 5 years with in vivo and in vitro methods to detect the possible development of sensitization to Hb and common wasp (Cw) venom. Inclusion criteria included the lack of previous beekeeping activity and absence of sensitization or reported reaction to Hymenoptera stings. Subjects with both in vivo and in vitro tests that were definitely positive or with one definitely positive and the other doubtful were considered sensitized. Ten of 35 new beekeepers (28.6%) and 3 of 36 controls (8.3%) developed sensitivity to Hb venom during the 5-year period. The risk ratio in incidence studies was calculated at 3.43 (SE of log risk ratio = 0.61; 95% CI of risk ratio = 1.03-11.42). All sensitized beekeepers were detected within the first 18 months of occupational exposure; 8 of 10 (80%) beekeepers were detected during the initial 12 months and the 2 remaining beekeepers were detected between 12 and 18 months. One of 35 (2.9%) beekeepers and 1 of 36 controls (2.8%) were sensitized to Cw venom. The number of stings per year and atopy had no effect on sensitization rate. Although predisposing factors to sensitization or anaphylaxis could not be identified, beekeepers developed sensitization to bee venom in more...

Background: Gadolinium chelates are relatively safe contrast media used in MRI. Immediate severe adverse effects are exceptionally rare and mostly concern mild anaphylactoid reactions. We report a case of anaphylaxis to gadobenate dimeglumine (Gd-BOPTA, Multihance®), a gadolinium-based contrast agent. Methods: A 32-year-old female patient with a personal history of multiple sclerosis, while undergoing an MRI scan, developed bronchospasm and acute urticaria with diffuse giant pruritic plaques in the first minute of Gd-BOPTA infusion. The procedure was cancelled and acute treatment of the reaction took place. The patient reported 2 additional MRI scans with definite use of unknown contrast media in the past 2 years without any adverse effect. Blood samples were obtained 2 and 48 h after the reaction for measurement of serum tryptase concentration (Pharmacia Diagnostics, Uppsala, Sweden). Skin prick tests and intradermal tests were performed using 1:1,000, 1:100 and 1:10 dilution of the offending agent and alternative gadolinium-based agents [gadodiamide (Omniscan®) and gadoteric acid (Dotarem®)]. A group of 10 nonatopic individuals who underwent the same skin testing comprised the control group. Results: Tryptase concentration was highly elevated 2 h after the reaction (21 µg/l) compared with that at 48 h (3 µg/l). Skin prick tests in our patient were all negative, while intradermal testing with 0.03 ml of 1:100 and 1:10 preparations of Multihance showed a definite positive wheal-and-flare reaction. Skin tests to the alternative agents showed no response. In the control group, all performed tests were negative. Conclusion: We report the first case of an allergic reaction to gadobenate dimeglumine. Besides, skin testing seems to be a precious diagnostic tool which, if positive, strongly suggests a mast cell-mediated underlying mechanism. more...

Occupational-related allergic sensitization has been reported in fishery workers. The aim of this study was to investigate the prevalence, work-related symptoms, and possible risk factors in this occupationally exposed population in Greece. Sixty-four fish and seafood processing workers were compared with 60 controls regarding sensitization to seafood allergens. All participants underwent skin-prick tests (SPTs) with cod, sardines, shrimp, spiny lobster, crabs, salmon, mussels, and trout plus negative and positive control. The level of specific IgE (radioallergosorbent test) was evaluated in subjects with positive SPTs. Sensitization criteria were both SPTs and the corresponding positive radioallergosorbent test. Atopic status was tested with SPTs to seven common inhalant allergens. Potential risk factors for IgE sensitization were investigated using logistic regression analysis. Twenty-three of 64 workers (35.9%) were sensitive to at least one of the seafood allergens tested, and the prevalence in the control group was 10% (6/60; odds ratio, 5.049; 95% CI, 1.884-13.533). The prevalence of sensitization in allergen species tested in the fishery workers group was shrimp, 12.5%; spiny lobster, 10.9%; mussels, 7.8%; crabs 3.1%; cod, 3.1%; sardines, 1.6%; salmon, 1.6%; and trout, 1.6%. Presence of atopy (p = 0.02), intensity (p = 0.03), and duration of exposure (p = 0.03) was found as potential risk factors for IgE sensitization. Four of 64 (6.25%) workers reported work-related symptoms. Occupational exposure to fish and seafood significantly increases the likelihood of sensitization in seafood allergens and atopy, duration, and intensity of exposure may represent potential risk factors in seafood processing workers. more...

Chronic urticaria is a prevalent condition associated with substantial disability. Its pathogenesis is not clearly understood and is divided into autoimmune and chronic idiopathic urticaria (CIU). We investigated if the non-specific phosphodiesterase inhibitor theophylline could provide additional benefit to the histamine-1 receptor (H-1R) antagonist cetirizine in CIU.This was a double-blind, placebo-controlled, parallel study. Patients were randomized to receive either cetirizine and theophylline (200 mg twice daily; group A, 67 subjects) or cetirizine and placebo for 6 months (group B, 67 subjects). Group A patients took theophylline for 6 more months. Response was assessed by visual analog scale (VAS) and treatment effectiveness score (TES). Blood theophylline levels were also determined at visit t=1 and t=7.The study was completed by 54 of the 67 patients (80.6%) in group A and 51 of the 67 patients (76.1%) in group B. The physician VAS values for group A were lower after t=3, while the patient VAS values were decreased after t=2. The physician and patient TES values in group A were statistically higher (p0.05) at all time points except for t=1. At least 1 month of theophylline addition was necessary to obtain statistically significant benefit over cetirizine, and reducing theophylline by 50% during phase 2 did not alter this benefit. Pruritus values were reduced, but not statistically significant.Addition of theophylline to conventional H-1R antagonists was well tolerated without any adverse effects and provided considerable additional benefit in the management of CIU. more...

Penicillin often is excluded as a treatment option based on patients' self-reported history of an adverse reaction to penicillin. The objective of this prospective study was to determine the likelihood of true penicillin allergy in patients with vague and convincing histories of penicillin allergy and to evaluate the diagnostic value added by appropriate skin testing. Six hundred thirty-eight patients with prior beta-lactam intake had a current indication for penicillin therapy and were referred for testing with the major (benzylpenicilloyl polylysine) and minor (minor determinant mixture) penicillin determinants from the inpatient and outpatient service of Athens University Dermatological hospital from January 2000 to December 2002. The prevalence of positive skin tests in the total group and in those patients with vague and convincing histories of penicillin allergy was determined. Positive skin tests were observed in 19/638 (3%) of the total group, 5 out of 542 (0.9%) patients without any history of penicillin allergy, 14 out of 96 (14.6%) patients with vague history (confidence interval [CI] 95% = 5.95-59.92), and 13 out of 18 (72.2%) patients with a convincing history of type I hypersensitivity reaction (chi2 = 286.3: odds ratio = 281.3: CI 95% = 62.19-1440.8). Patients with a vague history of penicillin allergy are 18 times more likely to have a positive penicillin skin test, and a convincing reaction history increases the likelihood by 281-fold compared with patients without a history of penicillin allergy. However, the fact that 5 of 18 (27.8%) patients with a convincing history were negative when skin tested points out that skin testing is helpful if the need for penicillin administration is compelling. more...

Atopic dermatitis (AD) is a chronic highly pruritic inflammatory skin disease, which has increased considerably in industrialized countries.1 AD is characterized by allergic inflammation in the skin,2 and has a strong association with other atopic disorders such as asthma and allergic rhinitis.1 Thymic stromal lymphopoietin (TSLP) is a cytokine closely related to IL-7,3 mostly produced by epithelial cells and keratinocytes in response to infection, trauma and inflammation. TSLP mediates Th2 responses through activation of dendritic cells, and has emerged as an important regulator of allergic inflammation. TSLP also activates mast cells to release several cytokines, such as IL-5, IL-6 and IL-13, but only in the presence of IL-1 and TNF.4 One paper reported increased TSLP protein expression in lesional skin of AD patients.3 We investigated gene expression of TSLP in lesional skin biopsies and serum levels of AD patients (n=9, mean age ± 1 SD=41.33 ± 21.40; three males, six females) compared to controls (n=9, mean age ± 1 SD=42.8 ± 18.1; three males, six females). All 10 mm punch skin biopsies were obtained (abdomen, arm, back, hand, and neck; there was no apparent correlation between any of these sites and TSLP levels) from patients who had mild, localized, chronic AD, and from controls (back). No subject had received any anti-inflammatory medication for 15 days prior to the biopsy. Contact dermatitis, asteatotic eczema or other types of dermatitis were excluded. The Medical Ethics Committee of University of Athens Medical School approved this protocol. All participants gave their written informed consent according to the Declaration of Helsinki Principles. Patients were free of other major medical conditions except allergic rhinitis as noted. All biopsies were placed in RNAlater (Ambion Inc., Austin, TX) and stored at −20 °C. Total RNA from skin biopsies was extracted by TRIzol isolation method (Invitrogen, Carlsbad, CA). cDNA was synthesized using iScript cDNA Synthesis Kit (Bio-Rad, Hercules, CA). Quantitative PCR was performed using Taqman probes (Applied Biosystems, Foster City, CA) on a 7300 Real Time PCR System (Applied Biosystems). For qPCR, the cDNA was reverse-transcribed from 300 ng RNA from each sample. Relative mRNA levels were normalized to the GAPDH endogenous control. Data were analyzed with the non-parametric Mann-Whitney U test, since values did not conform to a normal distribution. Serum measurements are reported in pg/ml. Relative TSLP gene expression was significantly increased in the lesional AD skin samples (median=4.93; range=2.27–23.99) as compared to controls (median=0.84; range=0.49–1.85) (Fig. 1a, p more...

Background The legume food family is large and includes peanut and soybean, two of the most frequent causes of food allergy. Literature on type I hypersensitivity to lentils, also a legume, is scarce. Objective To describe a child with repeated anaphylactic reactions related to lentils. Methods Skin prick tests with both commercial and cooked extracts and serum-specific IgE measured by CAP-RIA were used to identify specific IgE antibodies to various legumes. Results An 8-year-old girl suffered four episodes of anaphylaxis related to lentils from age 3 to 7 years. The first three involved ingestion of cooked lentils and each time smaller amounts induced symptoms. The fourth episode occurred with inhalation exposure to cooking lentil soup. Subsequently, she presented with contact uticaria from raw chickpeas and an anaphylactic reaction after ingestion of cooked chickpeas. Prick tests showed strongly positive reactions to lentil and chickpea and weaker positive reactions to peanut, pea, soybean, and white bean. CAP-RIA was class 6 to lentil; class 5 to peanut, pea, and soybean; class 4 to white bean, and class 0 to green bean. Conclusion Severe type I hypersensitivity to lentils occurred in this patient and was associated with clinically relevant hypersensitivity to chickpeas. Prick tests and CAP-RIA demonstrated multiple positive reactions to other legumes. more...

Background Mast cells derive from hematopoietic cell precursors and participate in tissue allergic, immune, and inflammatory processes. They secrete many mediators, including preformed TNF, in response to allergic, neuropeptide, and environmental triggers. However, regulation of mast cell degranulation is not well understood. Objective We investigated the role of mitochondrial dynamics in degranulation of human cultured mast cells. Methods Human umbilical cord blood–derived mast cells (hCBMCs) and Laboratory of Allergic Diseases 2 (LAD2) mast cells were examined by confocal and differential interference contrast microscopy during activation by IgE/antigen and substance P (SP). Mast cells in control and atopic dermatitis (AD) skin were evaluated by transmission electron microscopy. LAD2 cells were pretreated with mitochondrial division inhibitor, a dynamin-related protein 1 (Drp1) inhibitor, and small interfering RNA for Drp1, which is necessary for mitochondrial fission and translocation. Calcineurin and Drp1 gene expression was analyzed in stimulated LAD2 cells and AD skin biopsies. Results Stimulation of hCBMCs with IgE/antigen or LAD2 cells with SP leads to rapid (30 minutes) secretion of preformed TNF. Degranulation is accompanied by mitochondrial translocation from a perinuclear location to exocytosis sites. Extracellular calcium depletion prevents these effects, indicating calcium requirement. The calcium-dependent calcineurin and Drp1 are activated 30 minutes after SP stimulation. Reduction of Drp1 activity by mitochondrial division inhibitor and decrease of Drp1 expression using small interfering RNA inhibit mitochondrial translocation, degranulation, and TNF secretion. Mitochondrial translocation is also evident by transmission electron microscopy in skin mast cells from AD biopsies, in which gene expression of calcineurin, Drp1, and SP is higher than in normal skin. Conclusion Human mast cell degranulation requires mitochondrial dynamics, also implicated in AD. more...

Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33 and neurotensin. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved. Preliminary evidence suggests that mitochondrial function and dynamics control mast cell degranulation, but not selective release. Recent findings also indicate that mast cells have immunomodulatory properties. Understanding selective release of mediators could explain how mast cells participate in numerous diverse biologic processes, and how they exert both immunostimulatory and immunosuppressive actions. Unraveling selective mast cell secretion could also help develop unique mast cell inhibitors with novel therapeutic applications. This article is part of a Special Issue entitled: Mast cells in inflammation. more...

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by varying degrees of dysfunctional communication and social interactions, repetitive and stereotypic behaviors, as well as learning and sensory deficits. Despite the impressive rise in the prevalence of autism during the last two decades, there are few if any clues for its pathogenesis, early detection or treatment. Increasing evidence indicates high brain expression of pro-inflammatory cytokines and the presence of circulating antibodies against brain proteins. A number of papers, mostly based on parental reporting on their children's health problems, suggest that ASD children may present with “allergic-like” problems in the absence of elevated serum IgE and chronic urticaria. These findings suggest non-allergic mast cell activation, probably in response to environmental and stress triggers that could contribute to inflammation. In utero inflammation can lead to preterm labor and has itself been strongly associated with adverse neurodevelopmental outcomes. Premature babies have about four times higher risk of developing ASD and are also more vulnerable to infections, while delayed development of their gut–blood–brain barriers makes exposure to potential neurotoxins likely. Perinatal mast cell activation by infectious, stress-related, environmental or allergic triggers can lead to release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in a subgroup of ASD patients. This article is part of a Special Issue entitled: Mast cells in inflammation. more...

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by difficulties in communication, cognitive and learning deficits, as well as stereotypic behaviors. For the majority of cases there are no reliable biomarkers or distinct pathogenesis. However, increasing evidence indicates ASD may be associated with some immune dysregulation, and may have a neuroimmune component. We recently showed that the peptide neurotensin (NT) is increased in autistic children. We now show that NT induces release of extracellular mitochondrial DNA (mtDNA) that could act as "autoimmune" trigger. We further show that serum from young autistic patients contains mtDNA (n = 20; cytochrome B, p = 0.0002 and 7S, p = 0.006), and anti-mitochondrial antibody Type 2 (n = 14; p = 0.001) as compared to normally developing, unrelated controls (n = 12). Extracellular blood mtDNA and other components may characterize an autistic endophenotype and may contribute to its pathogenesis by activating autoimmune responses. more...