SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Mast cell

173

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a specific form of wheat allergy typically induced by exercise after ingestion of wheat products. Wheat ω-5 gliadin is a major allergen associated with conventional WDEIA, and detection of serum immunoglobulin E (IgE) specific to recombinant ω-5 gliadin is a reliable method for its diagnosis. Recently, an increased incidence of a new subtype of WDEIA, which is likely to be sensitized via a percutaneous and/or rhinoconjunctival route to hydrolyzed wheat protein (HWP), has been observed. All of the patients with this new subtype had used the same brand of soap, which contained HWP. Approximately half of these patients developed contact allergy several months later and subsequently developed WDEIA. In each of these patients, contact allergy with soap exposure preceded food ingestion-induced reactions. Other patients directly developed generalized symptoms upon ingestion of wheat products. The predominant observed symptom of the new WDEIA subtype was angioedema of the eyelids; a number of patients developed anaphylaxis. This new subtype of WDEIA has little serum ω-5 gliadin-specific serum IgE.

Concepts: Immune system, Asthma, Hypersensitivity, Immunoglobulin E, Allergy, Mast cell, Wheat, Allergology

171

Recent studies have shown that zinc ion (Zn) can behave as an intracellular signaling molecule. We previously demonstrated that mast cells stimulated through the high-affinity IgE receptor (FcεRI) rapidly release intracellular Zn from the endoplasmic reticulum (ER), and we named this phenomenon the “Zn wave”. However, the molecules responsible for releasing Zn and the roles of the Zn wave were elusive. Here we identified the pore-forming α(1) subunit of the Cav1.3 (α(1D)) L-type calcium channel (LTCC) as the gatekeeper for the Zn wave. LTCC antagonists inhibited the Zn wave, and an agonist was sufficient to induce it. Notably, α(1D) was mainly localized to the ER rather than the plasma membrane in mast cells, and the Zn wave was impaired by α(1D) knockdown. We further found that the LTCC-mediated Zn wave positively controlled cytokine gene induction by enhancing the DNA-binding activity of NF-κB. Consistent with this finding, LTCC antagonists inhibited the cytokine-mediated delayed-type allergic reaction in mice without affecting the immediate-type allergic reaction. These findings indicated that the LTCC α(1D) subunit located on the ER membrane has a novel function as a gatekeeper for the Zn wave, which is involved in regulating NF-κB signaling and the delayed-type allergic reaction.

Concepts: Immune system, Signal transduction, Asthma, Cell membrane, Cell biology, Immunoglobulin E, Allergy, Mast cell

171

Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so-called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host’s IgE response.

Concepts: Immune system, White blood cell, Asthma, Hypersensitivity, Immunoglobulin E, Allergy, Mast cell, Atopy

170

Mast cell-derived mediators mediate several of the pathological features of asthma. Microbial infections induce asthma exacerbations in which the contribution of mast cells remains incomprehensible.

Concepts: Immune system, Bacteria, Asthma, Cell biology, Immunoglobulin E, Allergy, Mast cell, Leukotriene

168

Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of asthma. Bronchial provocation tests (BPTs) are objective tests for AHR that are clinically useful to aid in the diagnosis of asthma in both adults and children. BPTs can be either “direct” or “indirect,” referring to the mechanism by which a stimulus mediates bronchoconstriction. Direct BPTs refer to the administration of pharmacological agonist (e.g., methacholine or histamine) that act on specific receptors on the airway smooth muscle. Airway inflammation and/or airway remodeling may be key determinants of the response to direct stimuli. Indirect BPTs are those in which the stimulus causes the release of mediators of bronchoconstriction from inflammatory cells (e.g., exercise, allergen, mannitol). Airway sensitivity to indirect stimuli is dependent upon the presence of inflammation (e.g., mast cells, eosinophils), which responds to treatment with inhaled corticosteroids (ICS). Thus, there is a stronger relationship between indices of steroid-sensitive inflammation (e.g., sputum eosinophils, fraction of exhaled nitric oxide) and airway sensitivity to indirect compared to direct stimuli. Regular treatment with ICS does not result in the complete inhibition of responsiveness to direct stimuli. AHR to indirect stimuli identifies individuals that are highly likely to have a clinical improvement with ICS therapy in association with an inhibition of airway sensitivity following weeks to months of treatment with ICS. To comprehend the clinical utility of direct or indirect stimuli in either diagnosis of asthma or monitoring of therapeutic intervention requires an understanding of the underlying pathophysiology of AHR and mechanisms of action of both stimuli.

Concepts: Immune system, Inflammation, Asthma, Allergy, Mast cell, Histamine, Nitric oxide, Exhaled nitric oxide

151

Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.

Concepts: Immune system, DNA, Protein, Cancer, Mast cell, Symptom, Medical sign, Mastocytosis

139

Allergy immunotherapy targets the immunological cause of allergic rhinoconjunctivitis and allergic asthma and has the potential to alter the natural course of allergic disease.

Concepts: Immune system, Asthma, Immunology, Allergy, Mast cell, Pollen, Rhinitis, Allergen immunotherapy

112

Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.).

Concepts: Immune system, Protein, Amino acid, Cell biology, Mast cell, Histamine, Degranulation, Urticaria

105

The rates of childhood allergic conditions are changing, prompting the need for continued surveillance. Examination of healthcare provider-based diagnosis data is an important and lacking methodology needed to complement existing studies that rely on participant reporting.

Concepts: Immune system, Cohort study, Asthma, Allergy, Mast cell, Food allergy, Eczema, Rhinitis

32

Papain is commonly used in food, pharmaceutical, textile and cosmetic industries and is known to induce occupational allergic asthma. We have previously shown that the papain-like cysteine protease Der p 1 from house dust mite per se exhibits percutaneous sensitization potential. We aimed here to investigate the potential of papain itself in epicutaneous sensitization. The effects of papain on tight junction proteins were tested in-vitro in human primary keratinocytes. Using C57BL/6 WT and TLR4-deficient mice, we analyzed the sensitization potential of papain, its effects on the skin barrier and immune cell recruitment. Our results show, that papain affects the skin barrier by increasing transepidermal water loss, degrading tight junction proteins and inducing vasodilation. When topically applied, papain exhibited a high epicutaneous inflammatory potential by recruiting neutrophils, mast cells and CD3-positive cells and by induction of a TH2-biased antibody response. However, its high potency for specific sensitization via the skin was independent of its enzymatic function. The mechanism for specific sensitization was TLR4-independent and, in spite of its capacity to degrade epidermal tight junction proteins, does not rely on its enzymatic function. From our data we conclude that papain has all features to act as a strong allergen via the skin.Journal of Investigative Dermatology accepted article preview online, 23 February 2015. doi:10.1038/jid.2015.58.

Concepts: Immune system, Antibody, Enzyme, Asthma, Immunology, Allergy, Mast cell, House dust mite