IgE-mediated Diseases Research Articles

Immunological Treatments for Occupational Allergy

Although avoidance of occupational triggers remains the primary step in the management of work-related allergies, immunological treatments (including biological agents and specific immunotherapy) can be regarded as potential therapeutic options for IgE-mediated diseases; for example, many studies with allergen-specific immunotherapy have been carried out on latex allergy, showing overall favorable results, at least with sublingual immunotherapy. On the other hand, only few case reports have suggested the efficacy of immunotherapy in baker's asthma as well as in laboratory animal-induced asthma. The new technologies, including component-resolved diagnosis and recombinant allergens, are expected to improve the quality and efficacy of specific immunotherapy in the future. Also the use of omalizumab may represent a suitable therapeutic choice in very selected cases of occupational allergy, as well as an approach to reduce side effects of venom immunotherapy in subjects with previous severe reactions to the treatment.

Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis

Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an "allergic"/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly TH2/TH22 polarization, and epidermal barrier defects. We sought to define whether both variants share a common pathogenesis. We stratified 51 patients with severe AD into extrinsic AD (n = 42) and intrinsic AD (n = 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry. A significant correlation between IgE levels and SCORAD scores (r = 0.76, P < 10(-5)) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including TH2) was detected in patients with intrinsic AD, particularly TH17 and TH22 cytokines. Positive correlations between TH17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and TH2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin). Although differences in TH17 and TH22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a TH2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions.

Chapter 17: Immunomodulation of allergic sinonasal disease.

IgE hypersensitivity is important to the pathogenesis of allergic diseases and the development and persistence of airway inflammation. Allergic immunomodulation encompasses various therapies that attempt to suppress or modify the immune mechanisms responsible for IgE-mediated disease. These include allergy immunotherapy (AIT) in the forms of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), as well as the emergence of biological agents, such as anti-IgE, for allergic respiratory disease. Clinical evidence strongly supports the efficacy and safety of AIT for the treatment of allergic rhinitis, allergic conjunctivitis, and allergic asthma, but for chronic rhinosinusitis evidence is lacking. In allergic rhinitis, the decision to initiate AIT depends on the degree to which symptoms can be reduced by avoidance and medication, the amount and type of medication required to control symptoms, the adverse effects of medication, the severity and duration of symptoms, and their effect on quality of life. AIT has the potential to produce sustained long-lasting immune modulation and possibly avoid or reduce lifelong requirements for medical therapy. Although SLIT is currently being evaluated, SCIT remains the preferred form of AIT in the United States because of robust efficacy data, availability of allergen extracts, and current Food and Drug Administration approval. However, SLIT holds the potential for greater patient safety and convenience. Other immunomodulators such as anti-IgE also hold promise, but require further investigation.

Variance of melatonin and cortisol rhythm in patients with allergic rhinitis

ObjectiveAllergic rhinitis is an IgE-mediated inflammatory disease which effects 10%–50% of the normal population. The mechanism of its formation and the circadian rhythm of cortisol and melatonin in allergic rhinitis have not been investigated. Study designSalivary levels of melatonin and cortisol were measured by radioimmunoassay in 35 newly diagnosed allergic rhinitis patients and in 23 control subjects matched for age and gender. ResultsIn the study group; amplitude, baseline and peak levels of salivary melatonin were significantly decreased compared with healty controls (p<0.001). No differences were found in the acrophase and the peak duration of salivary melatonin between the study and control groups (p>0.05).In the study subjects, the circadian rhythm of cortisol was flattened when compared with the control group. The amplitude and the 24h mean levels of salivary cortisol in the study group were significantly lower than in the control group and the acrophase was delayed in patients compared with control subjects (p<0.001). ConclusionThe circadian rhythms of salivary melatonin and cortisol were found to be disrupted in patients with allergic rhinitis. These results may also be contributive data to explain the pathogenesis of allergic rhinitis and also they can be applicable as adjunctive therapeutic tools in the future and melatonin drugs might be an alternative in the therapy of resistant allergic rhinitis patients or allergic rhinitis patients who cannot use cortisol drugs.

Genome-wide methylation profiling of the bronchial mucosa of asthmatics: relationship to atopy

BackgroundAsthma is a common respiratory disease that is characterized by bronchial hyperresponsiveness and airway obstruction due to chronic airway inflammation. Atopic asthma is a typical IgE-mediated disease in which the enhanced production of IgE is driven by the activation of Th2 cells, which release a distinct pattern of cytokines, including interleukin 4 (IL4) and IL3, in response to specific antigen presentation. To evaluate the methylation status of the whole genomes of bronchial mucosa tissues from subjects who lacked or had sensitization to Dermatophagoides farina (Df) and Dermatophagoides pteronyssinus (Dp).MethodsThe genome-wide DNA methylation levels in the bronchial mucosa tissues of atopic asthmatics (N = 10), non-atopic asthmatics (N = 7), and normal controls (N = 7) were examined using microarrays.ResultsIn the bronchial mucosa of atopic asthmatics, hypermethylation was detected at 6 loci in 6 genes, while hypomethylation was detected at 49 loci in 48 genes compared to those of non-atopic asthmatics. Genes that were assigned the ontologies of multicellular organismal process, response to organic substance, hormone metabolic process, and growth factor receptor binding were hypomethylated. The methylation levels in the mucosa of asthmatics and normal controls were similar.ConclusionsThe bronchial mucosa of asthmatics who are atopic to Df or Dp have characteristic methylation patterns for 52 genes. The genes and pathways identified in the present study may be associated with the presence of atopy in asthmatics and therefore represent attractive targets for future research.

Frequency of migraine in patients with allergic rhinitis

Allergic rhinitis (AR) is an IgE mediated disease which is released by activation of mast cells and basophils, and often leads to sinus headache. Histamine which is the key mediator in the pathogenesis of AR, also plays an important role in the pathogenesis of migraine with nitric oxide (NO). Aim of our study was to investigate the frequency of migraine in patients with AR. Headache assessment and neurological examination was performed on patients diagnosed as AR in the outpatient ear nose and throat clinic with age-matched controls. Participants with headache were classified according to the International Headache Society criteria, and migraine frequency was investigated in the patients with AR and control groups. Migraine headache was detected in 50% of the patients with AR. Among these, 95% were migraine without aura, and 5% were migraine with aura. Migraine frequency in the control group was 18.75% in the control group, and all was migraine without aura. Migraine frequency in the patients with AR was four times higher when compared with the control group. While a histamine and IgE associated common mechanism is responsible in the pathogenesis of AR and migraine, not only sinus headache but also migraine headache should be kept in mind. Headache assessment of the patients with AR, and in case of headache existence, referral of these patients to neurology outpatient clinics for differential diagnosis and, to maintain appropriate therapy should not be forgotten.

Phosphatidylinositol-3-Kinase C2B and TRIM27 Function to Positively and Negatively Regulate IGE Receptor Activation of Mast Cells

Cross linking of the IgE receptor (FceRI) on mast cells plays a critical role in IgE-dependent allergy including allergic rhinitis, asthma, anaphylaxis, and immediate type hypersensitivity reactions. Previous studies have demonstrated that the K+ channel, KCa3.1, plays a critical role in IgE-stimulated Ca2+ entry and degranulation in both human and mouse mast cells. We now show that the class II phosphatidylinositol 3 kinase C2b (PI3KC2b) is necessary for FceRI stimulated activation of KCa3.1, Ca2+ influx, cytokine production and degranulation of bone marrow derived mast cells (BMMC). In addition, we found that the E3 ubiquitin ligase, tripartite motif containing protein 27 (TRIM27), negatively regulates FceRI activation of KCa3.1, and downstream signaling by ubiquitinating and inhibiting PI3KC2b.TRIM27-/- mice are also more susceptible in vivo to acute anaphylaxis. These findings identify TRIM27 as an important negative regulator of mast cells in vivo, and suggests that PI3KC2b is a potential new pharmacologic target to treat IgE mediated disease.

Diagnosis and management of non‐IgE‐mediated cow's milk allergy in infancy ‐ a UK primary care practical guide

The UK NICE guideline on the Diagnosis and Assessment of Food Allergy in Children and Young People was published in 2011, highlighting the important role of primary care physicians, dietitians, nurses and other community based health care professionals in the diagnosis and assessment of IgE and non-IgE-mediated food allergies in children. The guideline suggests that those with suspected IgE-mediated disease and those suspected to suffer from severe non-IgE-mediated disease are referred on to secondary or tertiary level care. What is evident from this guideline is that the responsibility for the diagnostic food challenge, ongoing management and determining of tolerance to cow’s milk in children with less severe non-IgE-mediated food allergies is ultimately that of the primary care/community based health care staff, but this discussion fell outside of the current NICE guideline. Some clinical members of the guideline development group (CV, JW, ATF, TB) therefore felt that there was a particular need to extend this into a more practical guideline for cow’s milk allergy. This subset of the guideline development group with the additional expertise of a paediatric gastroenterologist (NS) therefore aimed to produce a UK Primary Care Guideline for the initial clinical recognition of all forms of cow’s milk allergy and the ongoing management of those with non-severe non-IgE-mediated cow’s milk allergy in the form of algorithms. These algorithms will be discussed in this review paper, drawing on guidance primarily from the UK NICE guideline, but also from the DRACMA guidelines, ESPGHAN guidelines, Australian guidelines and the US NIAID guidelines.

Update on the Performance and Application of Basophil Activation Tests

The basophil activation test (BAT) is a flow-cytometry-based functional assay that assesses the degree of cell activation after exposure to a stimuli. Though no standardized technique currently exists, recent advances have improved the performance of this assay, including identification of new basophil-specific markers and comparisons of the expression of CD63 to CD203c during activation. The basophil activation test has also been validated for many IgE-mediated disease conditions, which have been extensively reviewed elsewhere. This review focuses on the most recent applications of this test to the diagnosis of allergy to drugs, foods, venoms, and pollens, and the evolving role of the BAT in monitoring immunotherapy.

The Usefulness of the Multiple Allergen Simultaneous Test-Chemiluminescent as Compared to the Phadia Immunocap IgE Test Panel System in Children and Adolescents

Several patents of methods for diagnostic work-up of IgE-mediated disease have recently been acclaimed. The aim of the present study was to assess the diagnostic usefulness of the Multiple allergen simultaneous testchemiluminescent assay® (MAST CLA) as compared to the Phadia Immunocap® (Phadia CAP) allergen-specific IgE test panel system. The design was a prospective, observational study in which MAST CLA and Phadia CAP test panels were assessed in 105 children aged 1 to 17 years (46 girls and 59 boys) with a suspected diagnosis of rhinoconjunctivitis, asthma, eczema or food allergy. The MAST CLA screening panel included 23 and 13, the Phadia CAP 10 inhalant and 6 food allergens. The MAST CLA screening panel found 353 sensitizations which were not detected by Phadia CAP, 93 (26.3%) of which were class 3 or 4 results. The sensitizations gave clinically useful information in 7 patients (6.6%). As compared to the Phadia CAP the MAST CLA screening test panel adds little to the diagnostic work-up of IgE mediated disease in children and adolescents. Keywords: Allergy, allergic rhinitis, asthma, eczema, IgE, IgE tests, multiple allergen simultaneous test-chemiluminescent assay, Phadia CAP test, IgE panel screening tests, rhinoconjunctivitis

The Usefulness of the Multiple Allergen Simultaneous Test-Chemiluminescent as Compared to the Phadia Immunocap IgE Test Panel System in Children and Adolescents

Several patents of methods for diagnostic work-up of IgE-mediated disease have recently been acclaimed. The aim of the present study was to assess the diagnostic usefulness of the Multiple allergen simultaneous test-chemiluminescent assay (MAST CLA) as compared to the Phadia Immunocap (Phadia CAP) allergen-specific IgE test panel system. The design was a prospective, observational study in which MAST CLA and Phadia CAP test panels were assessed in 105 children aged 1 to 17 years (46 girls and 59 boys) with a suspected diagnosis of rhinoconjunctivitis, asthma, eczema or food allergy. The MAST CLA screening panel included 23 and 13, the Phadia CAP 10 inhalant and 6 food allergens. The MAST CLA screening panel found 353 sensitizations which were not detected by Phadia CAP, 93 (26.3%) of which were class 3 or 4 results. The sensitizations gave clinically useful information in 7 patients (6.6%). As compared to the Phadia CAP the MAST CLA screening test panel adds little to the diagnostic work-up of IgE mediated disease in children and adolescents.

Self-Amplification Mechanisms of Mast Cell Activation: A New Look in Allergy

Allergic diseases are major diseases involving approximately 22% of world population. In recent years, accumulated evidence suggests that apart from IgE, allergens may provoke immediate allergic reactions via other pathways such as IgG, toll like receptor (TLR) dependent ones. In addition, large numbers of low molecular weight molecules (LMWM) such as sphingosine-1-phosphate and iodinated contrast agents have been observed to cause allergy. Therefore, the current definition of allergy, a group of IgE mediated diseases appears difficult to cover all allergic reactions. Since even IgE dependent allergic reactions are carried out through activation of mast cells and basophils, and all allergens mentioned above can activate these cells, we hypothesize that allergic reactions are mast cell and basophil mediated inflammatory process as it is the activated mast cells and basophils that initiate the pathological process of the immediate allergic reactions, whereas IgE only serves as one of the activators of these cells.

Immunotherapy in polysensitized patients: new chances for the allergists?

1081-1206/12/$36.00 see front matter 2012 A http://dx.doi.org/10.1016/j.anai.2012.09.006 Allergic rhinitis (AR) and asthma are the most frequent IgEmediated diseases and may affect up to 40% of the general population, causing substantial social and economic burdens.1 In fact, school or work performance (including school or work absences), daily activities, and quality of life (QoL) are significantly impaired in both children and adults with respiratory allergy.2 Moreover, the progressively increasing number of sensitizations (such as polysensitization) in the same allergic patient seems to characterize the natural history of allergy and represent a common feature of allergic patients. In addition, the component-resolved diagnostic techniques have documented that atopic infants usually start withmonosensitization (sensitization to only one class of allergens) but soon tend to become sensitized to other allergens over time.3 Polysensitization is an immunologic phenomenon that is clinically and epidemiologically relevant. The presence of polysensitization has beenwell documented in both children and adults in general population surveys or allergic population-based studies.4e6 The increasing number of sensitizations seems to characterize the natural history of the allergic patient and may represent a typical evolution of allergy. In a patient survey study analyzing retrospectively 165 asthmatic patients, who were initially monosensitized, Silvestri and colleagues7 found that 43.6% of the patients became polysensitized at the second survey (after 10 years). The transition from monosensitization to polysensitization observed in the entire population was present also in preschool-aged and school-aged children when analyzed separately. In addition, the authors found that house dust mite sensitization and, at a lower degree, pollen sensitization appear to play a triggering role in the development of polysensitization because a high proportion of children initially monosensitized to house dust mites or pollens then became polysensitized.

Current Issues in Atopic Comorbidities and Preventing the Atopic March

The individual, family, and public health burden of atopic dermatitis (AD) is considerable. The prevalence of AD is high, the signs and symptoms of the disease adversely affect quality of life for patients and their families, and the comorbid conditions associated with AD can increase considerably the negative impact of the disease. These comorbid conditions patients with AD are susceptible to include skin infectious, IgE-mediated diseases, and mental health disorders. New research identifies the skin barrier as not only an important initiator of atopic dermatitis but may even be a site for allergic sensitization to protein antigens. The skin barrier represents a potential new target for novel atopic prevention strategies.

Phosphatidylinositol-3-kinase C2β and TRIM27 function to positively and negatively regulate IgE receptor activation of mast cells.

Cross-linking of the IgE receptor (FcεRI) on mast cells plays a critical role in IgE-dependent allergy, including allergic rhinitis, asthma, anaphylaxis, and immediate-type hypersensitivity reactions. Previous studies have demonstrated that the K(+) channel, KCa3.1, plays a critical role in IgE-stimulated Ca(2+) entry and degranulation in both human and mouse mast cells. We now have shown that the class II phosphatidylinositol-3-kinase C2β (PI3KC2β) is necessary for FcεRI-stimulated activation of KCa3.1, Ca(2+) influx, cytokine production, and degranulation of bone marrow-derived mast cells (BMMC). In addition, we found that the E3 ubiquitin ligase, tripartite motif containing protein 27 (TRIM27), negatively regulates FcεRI activation of KCa3.1 and downstream signaling by ubiquitinating and inhibiting PI3KC2β. TRIM27(-/-) mice are also more susceptible in vivo to acute anaphylaxis. These findings identify TRIM27 as an important negative regulator of mast cells in vivo and suggest that PI3KC2β is a potential new pharmacologic target to treat IgE-mediated disease.

Experiences from occupational exposure limits set on aerosols containing allergenic proteins.

Occupational exposure limits (OELs) together with determined airborne exposures are used in risk assessment based managements of occupational exposures to prevent occupational diseases. In most countries, OELs have only been set for few protein-containing aerosols causing IgE-mediated allergies. They comprise aerosols of flour dust, grain dust, wood dust, natural rubber latex, and the subtilisins, which are proteolytic enzymes. These aerosols show dose-dependent effects and levels have been established, where nearly all workers may be exposed without adverse health effects, which are required for setting OELs. Our aim is to analyse prerequisites for setting OELs for the allergenic protein-containing aerosols. Opposite to the key effect of toxicological reactions, two thresholds, one for the sensitization phase and one for elicitation of IgE-mediated symptoms in sensitized individuals, are used in the OEL settings. For example, this was the case for flour dust, where OELs were based on dust levels due to linearity between flour dust and its allergen levels. The critical effects for flour and grain dust OELs were different, which indicates that conclusion by analogy (read-across) must be scientifically well founded. Except for subtilisins, no OEL have been set for other industrial enzymes, where many of which are high volume chemicals. For several of these, OELs have been proposed in the scientific literature during the last two decades. It is apparent that the scientific methodology is available for setting OELs for proteins and protein-containing aerosols where the critical effect is IgE sensitization and IgE-mediated airway diseases.

A critical role for the kainate receptor in both IgE production and IgE mediated allergic lung inflammation (57.8)

Abstract According to the American Lung Association, approximately 34.1 million Americans have been diagnosed with asthma. Despite the extremely high prevalence of this disease, there is still no preventative measure, only treatments to alleviate the symptoms. Thus, novel treatments for asthmatic disease are certainly warranted. Recently, our laboratory has discovered that glutamate signaling through the kainic acid receptor (KAR) leads to enhanced ADAM10 activity and as a result leads to increased production of soluble CD23 and IgE production in the human in vitro culture system. This finding is critical because it is one of the first to highlight the importance of a neurotransmitter receptor on B cells and that signaling by this receptor may play a role in IgE mediated disease. We have extended these studies to demonstrate that in the murine in vitro system, the KAR is also critical for the in vitro production of IgE and that signaling through this receptor also leads to increased ADAM10 activity, production of soluble CD23 release, and subsequent IgE production. Furthermore, we determined in vivo relevance for this receptor. Mice deficient in the KAR post antigen challenge produce significantly less IgE and display significantly reduced airway hyperreactivity in a murine model of allergic airway disease. Thus, KARs may serve as an innovative pharmacological target for the treatment of asthma and other IgE mediated disease.

Chapter 2: Skin testing in allergy

Skin tests are used in addition to a directed history and physical exam to exclude or confirm IgE-mediated diseases such as allergic rhinitis, asthma, and anaphylaxis to aeroallergens, foods, insect venoms, and certain drugs. There are two types of skin testing used in clinical practice. These include percutaneous testing (prick or puncture) and intracutaneous testing (intradermal). Prick testing involves introducing a needle into the upper layers of the skin through a drop of allergen extract and gently lifting the epidermis up. Other devices are available for prick testing. Intracutaneous (intradermal) testing involves injecting a small amount of allergen (0.01-0.02 mL) into the dermis. The release of preformed histamine from mast cells causes increased vascular permeability via smooth muscle contraction and development of a wheal; inflammatory mediators initiate a neural reflex causing vasodilatation, leading to erythema (the flare). Prick testing methods are the initial technique for detecting the presence of IgE. They may correlate better with clinical sensitivity and are more specific but less sensitive than intradermal testing. Sites of skin testing include the back and the volar aspect of the arm. Although the back is more reactive, the difference is minimal. By skin testing on the arm, the patient can witness the emergence and often sense the pruritus of the skin test reaction. Because more patients are sensitized (have IgE antibodies and positive skin test reactions) than have current symptoms, the diagnosis of allergy can be made only by correlating skin testing results with the presence of clinical symptoms.

Immunological and inflammatory responses to organic dust in agriculture

Agriculture represents a major industry worldwide, and despite protection against the development of IgE-mediated diseases, chronic exposure to agriculture-related organic dusts is associated with an increased risk of developing respiratory disease. This article will review the literature regarding new knowledge of important etiologic agents in the dusts and focus on the immunologic responses following acute and repetitive organic dust exposures. Although endotoxin remains important, there is an emerging role of nonendotoxin components such as peptidoglycans from Gram-positive bacteria. Pattern recognition receptors including Toll-like receptor 4 (TLR4), TLR2 and intracellular nucleotide oligomerization domain-like receptors are partially responsible for mediating the inflammatory consequences. Repeated organic dust exposures modulate innate and adaptive immune function with a resultant adaptation-like response. However, repetitive exposures cause lung parenchymal inflammation, chronic disease, and lung function decline over time. The immunological consequences of organic dust exposure in the farming industry are likely explained by the diversity of microbial motifs in dust that can elicit differing innate immune receptor signaling pathways. Whereas initial activation results in a robust inflammatory response, repetitive dust exposures modulate immunity. This can result in low-grade, chronic inflammation, and/or protection against allergic disease.

Comorbidity in Atopic Dermatitis

The negative impact of atopic dermatitis (AD) often extends beyond the skin. Children with AD experience increased rates of infectious, mental health, and allergic diseases compared to their non-atopic peers. The mechanisms underlying these associations remain elusive. New insights from genetic and epidermal research pinpoint the skin barrier as a primary initiator of AD. Epicutaneous sensitization represents an intriguing new model which links a disrupted skin barrier to the later development of IgE-mediated diseases in patients with AD. Recent epidemiological studies have identified new comorbidities linked to AD as well, including several mental health disorders and obesity. This manuscript reviews the recent literature regarding both classic and newly described AD comorbidities.