Ulrike Raap

Selective Nasal Allergen Provocation Induces Substance P–Mediated Bronchial Hyperresponsiveness

Although the concept of global airway allergy has become widely accepted during recent years, nasobronchial interaction and its mechanisms remain incompletely understood. The experimental study of the effect of nasal allergen deposition on lower airway pathology is hampered by the difficulty of avoiding lower airway penetration of the allergens. In ovalbumin-sensitized mice with experimental airway allergy, nasal allergen provocations were performed after complete anatomical separation of upper and lower airways by means of a tracheotomy. A canula was inserted in the trachea, and the trachea was ligated, thus inhibiting any passage of allergens from upper to lower airways. Mice showed bronchial hyperresponsiveness to methacholine as early as 4 hours after nasal allergen provocation in the absence of recruitment of inflammatory cells. An increased substance P (SP) concentration in the bronchial lumen was found, as well as an increased number of SP-positive pulmonary nerves. Treatment with a neurokinin (NK) 1 receptor antagonist abolished the allergen-induced bronchial hyperresponsiveness. Moreover, endobronchial administration of SP caused NK1 receptor-dependent bronchial hyperresponsiveness in mice with airway allergy. Nasal allergen provocation rapidly induces bronchial hyperresponsiveness via pulmonary up-regulation of SP and activation of NK1 receptors.

Management of Childhood Urticaria: Current Knowledge and Practical Recommendations

Urticaria, defined by the presence of wheals and/or angio-edema, is a common condition in children, prompting parents to consult physicians. For its successful management, paediatric-specific features must be taken into account, regarding the identification of eliciting triggers and pharmacological therapy. This review systematically discusses the current best-available evidence on spontaneous acute and chronic urticaria as well as physical and other urticaria types in children. Potential underlying causes, namely infections, food and drug hypersensitivity, autoreactivity and autoimmune or other conditions, and eliciting stimuli are considered, with practical recommendations for specific diagnostic approaches. Second-generation antihistamines are the mainstay of pharmacological treatment aimed at relief of symptoms, which require dose adjustment for pae-diatric use. Other therapeutic interventions are also discussed. In addition, unmet needs are highlighted, aiming to promote research into the paediatric population, ultimately aiming at the effective management of childhood urticaria.

H1-antihistamine-refractory chronic spontaneous urticaria: It's worse than we thought – first results of the multicenter real-life AWARE study

Most data on chronic spontaneous urticaria (CSU) originate from highly selected patient populations treated at specialized centres. Little is known about CSU patient characteristics and the burden of CSU in routine clinical practice. AWARE (A World‐wide Antihistamine‐Refractory chronic urticaria patient Evaluation) is an ongoing global study designed to assess chronic urticaria in the real‐life setting.

European EADV network on assessment of severity and burden of Pruritus (PruNet): first meeting on outcome tools

Chronic pruritus is a frequently occurring symptom of various dermatoses that causes a high burden and impaired quality of life. An effective anti pruritic therapy is important for the patient, but its effectiveness is difficult to evaluate. Diverse methods and interpretations of pruritic metrics are utilized in clinical trials and the daily clinical practice in different countries, resulting in difficulties comparing collected data.

Human basophil chemotaxis and activation are regulated via the histamine H4 receptor.

IgE‐mediated cross‐linking of FcεRI results in the release of mediators stored in basophil granules, such as histamine and proteases, and in the de novo synthesis of sulfidoleukotrienes.

Histamine and T helper cytokine–driven epithelial barrier dysfunction in allergic rhinitis

Background: Allergic rhinitis (AR) is characterized by mucosal inflammation, driven by activated immune cells. Mast cells and TH2 cells might decrease epithelial barrier integrity in AR, maintaining a leaky epithelial barrier. Objective: We sought to investigate the role of histamine and TH2 cells in driving epithelial barrier dysfunction in AR. Methods: Air‐liquid interface cultures of primary nasal epithelial cells were used to measure transepithelial electrical resistance, paracellular flux of fluorescein isothiocyanate‐dextran 4 kDa, and mRNA expression of tight junctions. Nasal secretions were collected from healthy control subjects, AR patients, and idiopathic rhinitis patients and were tested in vitro. In addition, the effect of activated TH1 and TH2 cells, mast cells, and neurons was tested in vitro. The effect of IL‐4, IL‐13, IFN‐&ggr;, and TNF‐&agr; on mucosal permeability was tested in vivo. Results: Histamine as well as nasal secretions of AR but not idiopathic rhinitis patients rapidly decreased epithelial barrier integrity in vitro. Pretreatment with histamine receptor‐1 antagonist, azelastine prevented the early effect of nasal secretions of AR patients on epithelial integrity. Supernatant of activated TH1 and TH2 cells impaired epithelial integrity, while treatment with anti‐TNF‐&agr; or anti‐IL‐4R&agr; monoclonal antibodies restored the TH1‐ and TH2‐induced epithelial barrier dysfunction, respectively. IL‐4, IFN‐&ggr;, and TNF‐&agr; enhanced mucosal permeability in mice. Antagonizing IL‐4 prevented mucosal barrier disruption and tight junction downregulation in a mouse model of house dust mite allergic airway inflammation. Conclusions: Our data indicate a key role for allergic inflammatory mediators in modulating nasal epithelial barrier integrity in the pathophysiology in AR.

Pruritus and urticaria

ZusammenfassungDie Urtikaria repräsentiert eine der häufigsten dermatologischen Erkrankungen, die durch das transiente Auftreten von juckenden Urtikae charakterisiert wird. Die Empfindung des Pruritus wird von Patienten mit chronischer Urtikaria als kribbelnd, brennend oder stechend angegeben. Da die Pruritusattacken und das Auftreten von Urtikae nicht vorhersehbar sind, beeinflusst die Urtikaria die Lebensqualität der Patienten stark. In diesem Überblick fokussieren wir uns auf die klinischen Charakteristika, therapeutischen Optionen sowie neue pathophysiologische Mechanismen wie das T-Zell-Zytokin IL-31 beim Pruritus von Patienten mit chronischer Urtikaria.AbstractUrticaria is a frequent dermatological skin disease characterized by the occurrence of transient pruritic wheals. The sensation of pruritus has been described to be stinging, tickling and burning in patients with chronic urticaria. Because of the unpredictable attacks of pruritus and swelling, urticaria strongly affects the quality of life in patients. In this review we focus on clinical characteristics, therapeutic options and new pathophysiological mechanisms including the novel T-cell cytokine IL-31 in pruritus of patients with chronic urticaria.

Human mast cells and basophils-How are they similar how are they different?

Mast cells and basophils are key contributors to allergies and other inflammatory diseases since they are the most prominent source of histamine as well as numerous additional inflammatory mediators which drive inflammatory responses. However, a closer understanding of their precise roles in allergies and other pathological conditions has been marred by the considerable heterogeneity that these cells display, not only between mast cells and basophils themselves but also across different tissue locations and species. While both cell types share the ability to rapidly degranulate and release histamine following high‐affinity IgE receptor cross‐linking, they differ markedly in their ability to either react to other stimuli, generate inflammatory eicosanoids or release immunomodulating cytokines and chemokines. Furthermore, these cells display considerable pharmacological heterogeneity which has stifled attempts to develop more effective anti‐allergic therapies. Mast cell‐ and basophil‐specific transcriptional profiling, at rest and after activation by innate and adaptive stimuli, may help to unravel the degree to which these cells differ and facilitate a clearer understanding of their biological functions and how these could be targeted by new therapies.

Increased Activity and Apoptosis of Eosinophils in Blister Fluids, Skin and Peripheral Blood of Patients with Bullous Pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease that is more common in elderly individuals. The aim of this study was to determine the functional activity of eosinophils in patients with BP compared with healthy donors. Blood, skin and blister-derived eosinophils were strongly activated in patients with BP, seen by increased surface expression of CD69 compared with controls. CD11b was also increased in BP blood eosinophils, which may explain the striking accumulation of eosinophils in BP (1×106 per ml blister fluid). Furthermore, CCL26 was expressed by activated eosinophils in BP skin and in blister fluid. BP eosinophils also released IL-6, IL-8 and IL-1α in BP blister fluids. Apoptosis in cultivated BP eosinophils was increased and accompanied by enhanced surface externalization of CD95. Caspase 3 positive eosinophils in lesional BP skin and blister fluid also showed the initiation of apoptosis. These results reveal novel pathophysiological aspects of BP, with a strong activation pattern and increased apoptosis of eosinophils in the peripheral blood, skin and blister fluids.

[New and rarley used treatment options for refractory hand eczema: local UVA-1 phototherapy, retinoids, calcineurin inhibitors].

ZusammenfassungDas Handekzem (HE) gehört zu den häufigsten Hauterkrankungen. Das klinische Bild des HE ist unterschiedlich und variiert aufgrund seiner Ätiologie, Schwere und Morphologie. Das HE wird oftmals durch einen chronisch rezidivierenden Verlauf charakterisiert, hat eine relativ schlechte Prognose und eine hohe Auswirkung auf die Lebensqualität. Obwohl es verschiedene Therapieoptionen gibt, ist die Behandlung von Patienten mit chronischem HE oftmals unbefriedigend. In diesem Beitrag diskutieren wir neue und seltener angewandte Therapieoptionen wie die lokale UVA-1-Phototherapie, die Therapie mit Retinoiden (insbesondere mit dem neuen RXR- und RAR-Retinoid Alitretinoin) und Calcineurininhibitoren (Ciclosporin systemisch, Tacrolimus lokal).AbstractHand eczema (HE) is one of the most frequent skin diseases. HE has a wide spectrum, with variable etiology, severity, and morphology. It often displays a chronically relapsing course with a poor prognosis, and has a high impact on the quality of life. Although different treatment options exist, the management of patients with chronic HE is often unsatisfactory. We highlight new and rarely used approaches to treat chronic HE uncluding local UVA-1-phototherapy, retinoids including the new oral retinoid alitretinoin, and calcineurin inhibitors.Hand eczema (HE) is one of the most frequent skin diseases. HE has a wide spectrum, with variable etiology, severity, and morphology. It often displays a chronically relapsing course with a poor prognosis, and has a high impact on the quality of life. Although different treatment options exist, the management of patients with chronic HE is often unsatisfactory. We highlight new and rarely used approaches to treat chronic HE uncluding local UVA-1-phototherapy, retinoids including the new oral retinoid alitretinoin, and calcineurin inhibitors.