Treatment of acute urticaria: A systematic review.

There are only a few clinical trials which address the treatment of acute urticaria (AU). Especially, the added value of systemic corticosteroids to antihistamines is unclear in treatment of severe AU. To review the existing evidence-based approaches for AU treatment. A systematic electronic search was done in PubMed and Web of Science to retrieve all studies on the treatment of patients with AU. A descriptive synthesis was conducted based on the PRISMA statement. Quality assessment was independently performed by both reviewers ('Cochrane risk-of-bias tool' for RCTs). Ten randomized controlled trials (RCTs) (n = 857 participants) were included. Four studies assessed corticosteroid effectiveness added to antihistamines and six studies compared the efficacy of H1 and/ or H2 -antihistamines. The addition of corticosteroid (prednisone) to an antihistamine (levo)cetirizine did not improve symptoms of AU compared to antihistamine alone in two out of three RCTs. The combination of diphenhydramine (50 mg, IV) and ranitidine (50 mg, IV) or cimetidine (300 mg, IV) was most efficient for relief of urticaria in two out of five studies. Most frequent adverse effects were sedation and drowsiness. Recent guidelines on urticaria treatment mainly focus on chronic urticaria rather than on AU. Moreover, only few, small RCTs provide evidence for the management of AU. Thus, the state-of-the-art management of this frequent condition remains unclear. The addition of corticosteroids to an antihistamine as treatment for AU needs to be further investigated. Well-designed, high-quality interventional trials are needed to establish evidence-based treatment guidelines for AU.

Autoreactive IgE: Pathogenic role and therapeutic target in autoimmune diseases.

Autoimmunity is the break of tolerance to self-antigens that leads to organ-specific or systemic diseases often characterized by the presence of pathogenic autoreactive antibodies (AAb) produced by plasmablast and/or plasma cells. AAb are prevalent in the general population and not systematically associated with clinical symptoms. In contrast, in some individuals, these AAb are pathogenic and drive the development of signs and symptoms of antibody-mediated autoimmune diseases (AbAID). AAb production, isotype profiles, and glycosylations are promoted by pro-inflammatory triggers linked to genetic, environmental, and hormonal parameters. Recent evidence supports a role for pathogenic AAb of the IgE isotype in a number of AbAID. Autoreactive IgE can drive the activation of mast cells, basophils, and other types of FcεRI-bearing cells and may play a role in promoting autoantibody production and other pro-inflammatory pathways. In this review, we discuss the current knowledge on the pathogenicity of autoreactive IgE in AbAID and their status as therapeutic targets. We also highlight unresolved issues including the need for assays that reproducibly quantify IgE AAbs, to validate their diagnostic and prognostic value, and to further study their pathophysiological contributions to AbAID.

Immunoglobulin E autoantibodies in atopic dermatitis associate with Type-2 comorbidities and the atopic march.

BACKGROUND: Autoreactive immunoglobulin E (IgE) antibodies to self-peptides within the epidermis have been identified in patients with atopic dermatitis (AD). Prevalence, concomitant diseases, patient characteristics, and risk factors of IgE autoantibody development remain elusive. We aimed to determine IgE autoantibodies in serum samples (n = 672) from well-characterized patients with AD and controls (1.2-88.9 years). METHODS: Atopic dermatitis patients were sub-grouped in AD with comorbid Type-2 diseases ("AD + Type 2"; asthma, allergic rhinitis, food allergy, n = 431) or "solely AD" (n = 115). Also, subjects without AD but with Type-2 diseases ("atopic controls," n = 52) and non-atopic "healthy controls" (n = 74) were included. Total proteins from primary human keratinocytes were used for the immunoassay to detect IgE autoantibodies. Values were compared to already known positive and negative serum samples. RESULTS: Immunoglobulin E autoantibodies were found in 15.0% (82/546) of all analyzed AD-patients. "AD + Type 2" showed a higher prevalence (16.4%) than "solely AD" (9.6%). "Atopic controls" (9.6%) were comparable with "solely AD" patients, while 2.7% of healthy controls showed IgE autoantibodies. Of those with high levels of IgE autoantibodies, 15 out of 16 were patients with "AD + Type 2". AD patients with IgE autoantibodies were younger than those without. Patients with IgE autoreactivity also displayed higher total serum IgE levels. Factors that affected IgE autoantibody development were as follows: birth between January and June, cesarean-section and diversity of domestic pets. CONCLUSIONS: Immunoglobulin E autoantibodies in AD seem to associate with the presence of atopic comorbidities and environmental factors. The potential value of IgE autoantibodies as a predictive biomarker for the course of AD, including the atopic march, needs further exploration.

A Novel Method for Total IgE Purification from Human Serum.

For Ab purification, high-affinity chromatography is commonly used. This technique results in high-purity Abs, but it requires highly specific knowledge and equipment. Commercial kits for purification of IgE are not available. Therefore, we established a (to our knowledge) novel method for the purification of total IgE from human serum. Sera from 19 allergic and nonallergic patients were included. After depletion of polyclonal IgG, total serum IgE was captured using anti-human IgE Abs coupled to beads, eluted from the beads, and incubated with protein G-coupled beads to increase the final purity. Purity analysis and Ab detection were performed by Western blot. Total serum IgE and purified IgE concentrations were analyzed using ELISA. To determine their functionality, primary human mast cells were sensitized with purified IgE and activated with anti-IgE or a relevant allergen. CD63+ expression and histamine release were used as readout parameters. Concentrations of purified total IgE corresponded with the levels of total serum IgE. Minor fractions of IgE remained attached to the beads, confirming an effective elution of IgE Abs. Only minimal amounts of IgG were found in the purified IgE fractions, confirming a high purity of IgE. Mast cells sensitized with purified IgE and subsequent activation with anti-IgE Ab or a relevant allergen showed increased expression of CD63+ and increased histamine release. This (to our knowledge) novel method represents a highly effective and widely accessible approach for purification of human serum IgE, which can improve the use of IgE-based in vivo and in vitro models and contribute to allergy research.

The effect of resistance exercise on the immune cell function in humans: A systematic review.

BACKGROUND: Resistance exercise is beneficial for the immune system, including decreased susceptibility to infections and improved effectiveness of vaccinations. This review aims to provide a systematic analysis of the literature regarding the impact of resistance exercise on immune cells in the blood circulation. MATERIALS AND METHODS: The protocol of this review followed the PRISMA guidelines and registered in PROSPERO (ID: CRD42020157834). PubMed and Web-of-Science were systematically searched for relevant articles. Outcomes were divided into two categories: 1) inflammatory gene expression or secretion of inflammation-related cytokines and 2) other aspects such as cell migration, proliferation, apoptosis, phagocytosis, and redox status. RESULTS: Thirty intervention studies were included in this review, of which 11 articles were randomized controlled trials and six non-randomized controlled trials. Although only resistance exercise interventions were included, there was a high heterogeneity regarding specific exercise modalities. The most frequently studied outcome measures were the gene and protein expression levels in peripheral blood mononuclear cells (PBMC). This review reveals that already one acute exercise bout activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in PBMC. Although resistance exercise induces an acute cytosolic oxidative stress response, the antioxidant enzyme expression is improved after resistance training period. Natural killer cell activity increases in older but decreases in younger adults immediately after a resistance exercise bout. Moreover, resistance exercise improves neutrophil phagocytic activity. Finally, effects on lymphocyte proliferation remain unclear. CONCLUSIONS: The results of this systematic review demonstrate that resistance exercise has beneficial effects on several aspects of immune cell function both in young and older individuals. Acute changes in immune cell function occur already after a single bout of resistance exercise. However, regular resistance training during several weeks seems necessary to obtain beneficial adaptations that can be related to better immunity and reduced inflammation. The effects documented in this review confirm the beneficial effects of resistance exercise in young as well as older persons on the immune cell function.

T-cell subsets in the skin and their role in inflammatory skin disorders.

T lymphocytes (T cells) are major players of the adaptive immune response. Naive T cells are primed in the presence of cytokines, leading to polarization into distinct T-cell subsets with specific functions. These subsets are classified based on their T-cell receptor profile, expression of transcription factors, surface cytokine and chemokine receptors, and their cytokine production, which together determine their specific function. This review provides an overview of the various T-cell subsets and their function in several inflammatory skin disorders ranging from allergic inflammation to skin tumors. Moreover, we highlight similarities of T-cell responses across different skin disorders, demonstrating the presence of similar and opposing functions for the different T-cell subsets. Finally, we discuss the effects of currently available and promising therapeutic approaches to harness T cells in inflammatory skin diseases for which efficacy next to unwanted side effects provide new insights into the pathophysiology of skin disorders.

Autoreactive T cells and their role in atopic dermatitis.

Atopic dermatitis (AD) is an itchy, non-contagious relapsing and chronic inflammatory skin disease that usually develops in early childhood. This pathology is associated with food allergy, allergic asthma, allergic rhinitis and anaphylaxis which may persist in adulthood. The underlying mechanisms of AD (endotypes) are just beginning to be discovered and show a complex interaction of various pathways including skin barrier function and immune deviation. Immune reactions to self-proteins (autoantigens) of the skin have been identified in patients with inflammatory skin diseases, such as chronic spontaneous urticaria, connective tissue disease, pemphigus vulgaris and bullous pemphigoid. IgE antibodies and T cells directed against epitopes of the skin were observed in adult patients with severe and chronic AD as well. This was associated with disease severity and suggests a progression from allergic inflammation to severe autoimmune processes against the skin. IgE-mediated autoimmunity and self-reactive T cells might accelerate the ongoing skin inflammation or might contribute to the relapsing course of the disease. However, to date, the exact mechanisms of IgE-mediated autoimmunity and self-reactive T cells in the pathophysiology of AD are still unclear. The aim of this review is to evaluate the development of (autoreactive) T cells and their response to (auto)antigens, as well as the role of the peripheral tolerance in autoimmunity in the pathophysiology of AD, including the unmet needs and gaps.

IgE autoantibodies and autoreactive T cells and their role in children and adults with atopic dermatitis.

The pathophysiology of atopic dermatitis (AD) is highly complex and understanding of disease endotypes may improve disease management. Immunoglobulins E (IgE) against human skin epitopes (IgE autoantibodies) are thought to play a role in disease progression and prolongation. These antibodies have been described in patients with severe and chronic AD, suggesting a progression from allergic inflammation to severe autoimmune processes against the skin. This review provides a summary of the current knowledge and gaps on IgE autoreactivity and self-reactive T cells in children and adults with AD based on a systematic search. Currently, the clinical relevance and the pathomechanism of IgE autoantibodies in AD needs to be further investigated. Additionally, it is unknown whether the presence of IgE autoantibodies in patients with AD is an epiphenomenon or a disease endotype. However, increased knowledge on the clinical relevance and the pathophysiologic role of IgE autoantibodies and self-reactive T cells in AD can have consequences for diagnosis and treatment. Responses to the current available treatments can be used for better understanding of the pathways and may shed new lights on the treatment options for patients with AD and autoreactivity against skin epitopes. To conclude, IgE autoantibodies and self-reactive T cells can contribute to the pathophysiology of AD based on the body of evidence in literature. However, many questions remain open. Future studies on autoreactivity in AD should especially focus on the clinical relevance, the contribution to the disease progression and chronicity on cellular level, the onset and therapeutic strategies.

Immunology of COVID-19: Mechanisms, clinical outcome, diagnostics, and perspectives-A report of the European Academy of Allergy and Clinical Immunology (EAACI).

With the worldwide spread of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulting in declaration of a pandemic by the World Health Organization (WHO) on March 11, 2020, the SARS-CoV-2-induced coronavirus disease-19 (COVID-19) has become one of the main challenges of our times. The high infection rate and the severe disease course led to major safety and social restriction measures worldwide. There is an urgent need of unbiased expert knowledge guiding the development of efficient treatment and prevention strategies. This report summarizes current immunological data on mechanisms associated with the SARS-CoV-2 infection and COVID-19 development and progression to the most severe forms. We characterize the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the severe multiorgan disease. The similarities of the human immune response to SARS-CoV-2 and the SARS-CoV and MERS-CoV are underlined. We also summarize known and potential SARS-CoV-2 receptors on epithelial barriers, immune cells, endothelium and clinically involved organs such as lung, gut, kidney, cardiovascular, and neuronal system. Finally, we discuss the known and potential mechanisms underlying the involvement of comorbidities, gender, and age in development of COVID-19. Consequently, we highlight the knowledge gaps and urgent research requirements to provide a quick roadmap for ongoing and needed COVID-19 studies.

Nasal epithelial barrier dysfunction increases sensitization and mast cell degranulation in the absence of allergic inflammation.

BACKGROUND: Increased epithelial permeability has been reported in allergic rhinitis, with histamine and type-2 inflammation being responsible for tight junction dysfunction. The impact of an epithelial barrier defect on allergic sensitization and mast cell (MC) degranulation remains speculative. METHODS: Transepithelial passage of allergens was evaluated on primary human nasal epithelial cell cultures. Active sensitization was attempted by repeated intranasal ovalbumin (OVA) applications in Naïve mice. In a passive sensitization model, mice were injected with IgE to Dermatophagoides pteronyssinus (rDer p)2 and then exposed intranasally to the allergen. Chitosan was used to disrupt nasal epithelial integrity in vitro and in vivo. RESULTS: Chitosan strongly reduced transepithelial electrical resistance and facilitated transepithelial allergen passage in cultured primary nasal epithelial cells. In vivo, intranasal chitosan affected occludin expression and facilitated allergen passage. After epithelial barrier disruption, intranasal OVA application induced higher OVA-specific IgG1 and total IgE in serum, and increased eosinophilia and interleukin-5 in bronchoalveolar lavage (BAL) compared to sham-OVA mice. Chitosan exposure, prior to rDer p2 allergen challenge in passively sensitized mice, resulted in increased ß-hexosaminidase levels in serum and BAL compared to sham-rDer p2 mice. Intranasal treatment with the synthetic glucocorticoid fluticasone propionate prevented chitosan-induced barrier dysfunction, allergic sensitization, and MC degranulation. CONCLUSION: Epithelial barrier dysfunction facilitates transepithelial allergen passage, allergic sensitization, and allergen-induced MC degranulation even in the absence of inflammatory environment. These results emphasize the crucial role of an intact epithelial barrier in prevention of allergy.

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-γ, and TNF-α 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-α or anti-IL-4Rα monoclonal antibodies restored the TH1- and TH2-induced epithelial barrier dysfunction, respectively. IL-4, IFN-γ, and TNF-α 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.

The role of innate lymphoid cells in airway inflammation: evolving paradigms.

PURPOSE OF REVIEW: Innate lymphoid cells (ILCs) act as early orchestrators of the immune response, tissue repair, and maintenance of barrier homeostasis. This review summarizes recent findings of the role of ILCs in airway disease and highlights ongoing developments in clinical applications and treatment options. RECENT FINDINGS: On the basis of the transcription factors required for their development and cytokine profiles, ILCs have been classified into three subsets that resemble those of T-helper subtypes. ILCs produce multiple cytokines in response to signals from activated cells in their local environment. Recent studies in both humans and mice showed that ILCs are located at barrier surfaces and play critical roles in inflammatory diseases of the upper and lower airways. SUMMARY: The discovery of ILCs and their characterization in homeostatic and diseased conditions, have brought new insights into innate and adaptive immune responses at mucosal barrier surfaces. The recent progress in understanding the role of ILCs in airway inflammation directs translation of fundamental studies into clinical applications. This knowledge can be useful for future clinical practice.

Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.

BACKGROUND: The therapeutic action of capsaicin treatment in patients with idiopathic rhinitis (IR) is based on ablation of the transient receptor potential cation channel subfamily V, receptor 1 (TRPV1)-substance P nociceptive signaling pathway. However, the functional consequences of capsaicin treatment on nasal nerve activation and the association between the reduction in nasal hyperreactivity (NHR) and response to capsaicin treatment remain unknown. OBJECTIVE: We sought to study the effects of capsaicin nasal spray on the afferent innervation of the nasal mucosa by monitoring trigeminal nerve activity in patients with IR and healthy control (HC) subjects. METHODS: A double-blind, placebo-controlled randomized trial with capsaicin nasal spray was performed involving 33 patients with IR and 12 HC subjects. Before and at 4, 12, and 26 weeks after treatment, nasal mucosal potentials (NMPs) were measured while exposing the nasal mucosa of patients with IR and HC subjects to aerosols with increasing doses of the chemical irritants allyl isothiocyanate (AITC; also known as mustard oil) or capsaicin. The threshold for each compound was determined for each subject. The results of the NMP measurements were evaluated in parallel with the therapeutic response, visual analog scale scores for nasal symptoms, self-reported NHR, and mRNA expression of PGP9.5; TRPV1; transient receptor potential cation channel subfamily A, receptor 1 (TRPA1); TRPV4; transient receptor potential cation channel subfamily M, member 8 (TRPM8); and nerve growth factor (NGF) in nasal biopsy specimens. RESULTS: AITC turned out to be the best stimulus because the coughing induced by capsaicin interfered with measurements. At baseline, the threshold for evoking changes in NMPs based on AITC was significantly lower for patients with IR compared with HC subjects (P = .0423). Capsaicin treatment of IR patients increased the threshold for the response to AITC at 4 and 12 weeks compared with placebo (P = .0406 and P = .0325, respectively), which returned to baseline by week 26 (P = .0611). This increase correlated with changes in visual analog scale major symptom (P = .0004) and total symptom (P = .0018) scores. IR patients with self-reported NHR at baseline showed a trend to being better responders to capsaicin treatment compared with patients with IR but without NHR (P = .10). CONCLUSION: The lower threshold for AITC based on NMPs in patients with IR compared with HC subjects and the increased threshold for AITC after capsaicin treatment in patients with IR demonstrate the crucial role of TRPA1 and TRPV1 in IR pathophysiology. The strong correlation between the increase in AITC threshold in patients with IR and symptom reduction after capsaicin treatment demonstrates the clinical relevance of these findings.

Impaired barrier function in patients with house dust mite-induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression.

BACKGROUND: Tight junction (TJ) defects have recently been associated with asthma and chronic rhinosinusitis. The expression, function, and regulation of nasal epithelial TJs remain unknown in patients with allergic rhinitis (AR). OBJECTIVE: We investigated the expression, function, and regulation of TJs in the nasal epithelium of patients with house dust mite (HDM)-induced AR and in an HDM-induced murine model of allergic airway disease. METHODS: Air-liquid interface cultures of primary nasal epithelial cells of control subjects and patients with HDM-induced AR were used for measuring transepithelial resistance and passage to fluorescein isothiocyanate-dextran 4 kDa (FD4). Ex vivo transtissue resistance and FD4 permeability of nasal mucosal explants were measured. TJ expression was evaluated by using real-time quantitative PCR and immunofluorescence. In addition, the effects of IL-4, IFN-γ, and fluticasone propionate (FP) on nasal epithelial cells were investigated in vitro. An HDM murine model was used to study the effects of allergic inflammation and FP treatment on transmucosal passage of FD4 in vivo. RESULTS: A decreased resistance in vitro and ex vivo was found in patients with HDM-induced AR, with increased FD4 permeability and reduced occludin and zonula occludens-1 expression. AR symptoms correlated inversely with resistance in patients with HDM-induced AR. In vitro IL-4 decreased transepithelial resistance and increased FD4 permeability, whereas IFN-γ had no effect. FP prevented IL-4-induced barrier dysfunction in vitro. In an HDM murine model FP prevented the allergen-induced increased mucosal permeability. CONCLUSION: We found impaired nasal epithelial barrier function in patients with HDM-induced AR, with lower occludin and zonula occludens-1 expression. IL-4 disrupted epithelial integrity in vitro, and FP restored barrier function. Better understanding of nasal barrier regulation might lead to a better understanding and treatment of AR.