The Relationship Between IgE and Allergic Disease

Official reprint from UpToDatewww.uptodate.com ©2014 UpToDate

AuthorsJeff Stokes, MD, FAAAAI, FACAAIThomas B Casale, MD

Section EditorBruce S Bochner, MD

Deputy EditorAnna M Feldweg, MD

The relationship between IgE and allergic disease

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: May 2014. | This topic last updated: Jul 16, 2013.

INTRODUCTION — Allergen-specific IgE is integral to the pathogenesis of allergic disorders. However, the utilityof measuring total serum IgE or allergen-specific IgE for purposes of diagnosis and management is variable. It isimportant to recognize that levels of total IgE rarely provide information about IgE to specific allergens, and thatthe presence of IgE to a specific allergen does not necessarily equate to a clinically meaningful allergic response tothat substance. It is also necessary to demonstrate that the individual develops appropriate signs and symptomsupon exposure to the allergen in question.

This topic will review basic concepts concerning the generation of the allergic response and provide an overview ofthe roles of total and allergen-specific IgE in various allergic diseases. The biology of IgE and the diagnosis ofspecific allergic diseases are discussed separately. (See "The biology of IgE" and "Diagnosis of asthma inadolescents and adults" and "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis" and"Epidemiology, clinical manifestations, and diagnosis of atopic dermatitis (eczema)".)

TERMINOLOGY — The terms atopy, sensitization, and allergy are often used loosely in the medical literature,although each has a distinct definition.

Atopy — Atopy is the genetic predilection to produce specific IgE following exposure to allergens. At a cellularlevel, atopy appears to result, in part, from a predisposition toward a certain response on the part of CD4+ Thelper cells, called a Th type 2 (Th2) response [1]. Th2 cells secrete large quantities of IL-4 and IL-13, whichpromote the production of allergen-specific IgE by plasma cells. (See "T helper subsets: Differentiation and role indisease" and "The biology of IgE", section on 'Regulation of synthesis'.)

Sensitization — Sensitization refers to the production of allergen-specific IgE. Sensitization to an allergen is notsynonymous with being allergic to that allergen, because individuals may produce IgE to allergens in a givensubstance, but not develop symptoms upon exposure to that substance. It is unclear why some individualsdemonstrate only sensitization while others have active allergic disease.

Sensitization is usually demonstrated by skin testing or in vitro immunoassays for IgE to specific allergens(sometimes referred to as RAST testing, although this term describes an antiquated form of the test). Thus,sensitization is necessary but not sufficient for the development of allergic disease. Because a person can besensitized to an allergen but not react to it upon exposure, it is prudent to limit allergy testing to those allergenswhich are implicated by the clinical history.

The production of allergen-specific IgE is summarized briefly here in simplified form and reviewed in greater detailelsewhere. (See "The biology of IgE", section on 'Synthesis' and "Immunoglobulin genetics" and "Normal B and Tlymphocyte development".)

Once a substance enters the body (through ingestion, inhalation, or injection), it is degraded, and allergens (usuallyproteins but occasionally carbohydrates) are taken up by antigen presenting cells, including macrophages, CD1+dendritic cells, B cells, and possibly epithelial cells. Antigen presenting cells further degrade the allergen andpresent peptide fragments of it on the cell surface, in the setting of class II (MHC) molecules. The peptide/MHC IIcomplexes are recognized by Th2 cells. (See "Antigen presenting cells".)

Th2 cells then interact with B cells and, in the presence of various costimulatory signals, stimulate the B cell tomature into a plasma cell that produces IgE specific to the component of the allergen in question. B cell maturation

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primarily occurs within mucosal lymphoid tissue.

After IgE antibodies specific for a certain allergen are synthesized and secreted, they diffuse throughout the body,binding to high-affinity receptors (FcεRI) on mast cells in the tissues and basophils in the circulating blood (figure1).

Allergy — Individuals are considered to have clinically significant allergy or allergic disease when they have bothallergen-specific IgE and develop symptoms upon exposure to substances containing that allergen. Therefore,greater numbers of people are sensitized to an allergen then are clinically allergic to it. This was illustrated in theNational Health and Nutrition Examination Survey (NHANES) 2005-6, in which over 8000 people from the generalpopulation of the United States were interviewed and tested (using in vitro blood tests) for sensitization to 19common inhalant allergens [2]. Specific IgE antibodies to at least one allergen were present in 44 percent,whereas only 34 percent had symptoms suggestive of allergic disease. Similar findings have been documented forfood allergy. In a population-based birth cohort study in the United Kingdom, 12 percent of children were sensitizedto peanut at eight years of age, but only 2 percent were allergic [3].

A sensitized person may develop symptoms when re-exposed to the relevant allergen, if the allergen is able to bindto IgE antibodies on the surface of mast cells and basophils in sufficient numbers to cause clustering (called cross-linking) of the IgE molecules. Cross-linking of enough IgE receptors results in the generation of activating signals.Upon activation, mast cells and basophils release preformed and newly-formed chemical and protein mediators,which directly and indirectly lead to the signs and symptoms of allergic reactions. These mediators includehistamine, prostaglandins, leukotrienes, platelet activating factor, cytokines, and others. (See "Mast cell derivedmediators".)

Common allergic diseases include allergic asthma, allergic rhinitis, atopic dermatitis, food allergy, stinging-insectvenom allergy, and drug allergy.

The atopic march — Atopic dermatitis (AD), allergic rhinitis, and asthma often affect the same patients anddevelop in temporal succession. This progression from atopic dermatitis in infancy to allergic rhinitis and asthma inchildhood and young adulthood is referred to as the “allergic march” or “atopic march” [4-7]. Nearly 80 percent ofchildren with AD will subsequently develop allergic rhinitis or asthma [8].

RELATIONSHIPS BETWEEN TOTAL IgE LEVELS AND ALLERGIC DISEASE — A total serum IgE level of 100int. unit/mL is typically cited as the upper limit of normal in older adolescents and adults. Elevations in total serumIgE are seen in several types of disorders, including allergic diseases, some primary immunodeficiencies, parasiticand viral infections, certain inflammatory diseases, some malignancies, and a handful of other diseases (table 1).Thus, elevated total serum IgE is not specific to allergic disease. Studies concerning allergic diseases arereviewed here, while studies of IgE in other diseases are reviewed separately. (See "The biology of IgE", sectionon 'Increased total IgE'.)

Elevated total serum IgE — Many patients with allergic disorders have elevated levels of total IgE; however,there is no specific cutoff value that discriminates patients with allergic disease from those without, and there isconsiderable overlap [9,10]. Thus, total IgE by itself is rarely adequate to diagnose allergic disease. The followingstudies are illustrative:

Adults with IgE >66 int. unit/mL have a 37-fold greater risk of having allergen-specific IgE antibodies toaeroallergens compared to those patients with the lowest levels of total IgE [11].

In one study, school-aged children had a mean IgE level of 51 int. unit/mL. Children with both atopicdermatitis and asthma had mean IgE levels of 985 int. unit/mL, asthma alone 305 int. unit/mL, eczema alone273 int. unit/mL, and allergic rhinitis 171 int. unit/mL [12].

Among atopic patients of all ages, those with atopic dermatitis tend to have the highest IgE levels followedby atopic asthma, perennial allergic rhinitis, and seasonal allergic rhinitis [9].

Using a total serum IgE level of 100 int. unit/mL to discriminate allergic from nonallergic patients, thesensitivity was 78 percent for patients with asthma and 60 percent for rhinitis, but 20 percent of patientswere misclassified [13].


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Low or normal levels of total serum IgE — The authors and editors of UpToDate know of no studies to suggestthat low levels of total serum IgE can be used to exclude the presence of atopic disease, because of the wideoverlap in total serum IgE among atopic and nonatopic populations. Patients with low or normal serum IgE levelscould still have local production of allergen-specific IgE in the tissues. (See "The biology of IgE", section on'Localized IgE production'.)

Utility in predicting the development of allergic disease — Because elevations in total serum IgE areassociated with established allergic disease, researchers have questioned whether IgE levels predict itsdevelopment. Studies suggest that elevated total IgE is associated with an increased risk of allergic disease,although there is significant overlap between affected individuals and normals, such that the measurement is mostuseful in the context of population studies, rather than in the diagnosis or management of an individual.

Cord blood — Cord blood IgE levels have been studied in an attempt to identify newborns who are atincreased risk for the development of allergic disease. Maternal IgE does not normally cross the placenta, althoughfetal cord blood can be contaminated by maternal blood during late pregnancy and delivery and must be carefullycollected [14]. The majority of studies suggest that elevated total IgE in cord blood is an indicator of higher risk. Asexamples, studies have shown that newborns with elevated cord IgE levels had an increased risk of developingurticarial food reactions at one year of age [15], atopic dermatitis by age two [16], allergen sensitization andwheezing at seven years [17], or allergic rhinitis by 11 and 20 years of age [18]. However, no relationship wasfound between cord blood IgE levels and the development of asthma, allergic rhinitis or atopic dermatitis by thetime the child was 18 to 21 years of age despite a modest association with total IgE levels at those ages inanother study [19]. (See "The biology of IgE", section on 'Childhood levels'.)

Childhood IgE levels — Elevated IgE in young children appears to be an early predictor of the subsequentdevelopment of allergen-specific IgE and of allergic disease [20]. However, the clinical utility of this is limited by theextensive overlap between normals and atopic individuals, and the fact that patients with asthma have higher totalIgE compared with nonasthmatics, regardless of atopic status. (See 'Relationships between total IgE levels andallergic disease' above and 'Asthma' below.)

Timeline of sensitization — In most cases, the presence of allergen-specific IgE precedes the onset ofsymptoms by several years. In a study of nearly 1000 college students, subjects were evaluated initially and again7 and 16 years later using questionnaires and skin testing [21]. At the seven-year follow-up, subjects with priorpositive skin tests demonstrated an increased risk of developing allergic rhinitis and asthma. When these samepatients were reassessed 16 years later, a 2.3-fold greater risk of developing allergic rhinitis was found in thosesubjects with positive allergen skin tests [22]. Positive allergy skin tests and allergic rhinitis increased the likelihoodof developing asthma threefold.

In a small minority of patients, sensitization occurs only in the affected tissues, presumably due to low levels ofallergen-specific IgE being produced by local mucosal plasma cells. This phenomenon of local IgE production istermed “entopy”. In such patients, allergen-specific IgE is not demonstrable by either allergy skin testing or bloodwork, which presents diagnostic challenges. This is best described for some patients with rhinitis who havenegative skin and in vitro tests for allergen-specific IgE, yet react to challenge with inhaled allergen. (See "Chronicnonallergic rhinitis", section on 'Diagnosis'.)

THE ROLE OF IgE IN SPECIFIC DISORDERS — The role of total and allergen-specific IgE levels in pathogenesisand diagnosis differs among the leading allergic disorders.

Asthma — Children and adults with asthma tend to have higher IgE levels than individuals without asthma, althoughthere is no absolute cutoff that distinguishes between the two groups [23]. Conversely, nonatopic patients with highlevels of IgE are more likely to have asthma than those with normal IgE levels [24]. In one study, nonallergicpatients with a total serum IgE level greater than 150 int. unit/mL were at a fivefold higher risk of having asthma[25]. Still, the increase in elevated total IgE in asthmatics compared to nonasthmatics is generally driven by atopicindividuals [26].

Increased expression of the high affinity IgE receptor (FcεRI) has been demonstrated on cells in the airways ofboth atopic and nonatopic asthma patients compared to nonatopic control patients [27-29]. IgE positively regulatesFcεRI levels, so both IgE and FcεRI tend to increase or decrease in parallel. Patients with atopic dermatitis andasthma are more likely than controls to have mutations in the alpha subunit of FcεR1 (the subunit that directly binds


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to IgE) associated with increased serum IgE levels [30].

In allergic patients with asthma, anti-IgE therapy (omalizumab) improves symptoms, reduces exacerbations andmedication requirements, and decreases multiple inflammatory markers, demonstrating the role of IgE in allergicasthma. Total IgE levels are required for appropriate dosing of omalizumab in persistent asthma patients.

(See "Anti-IgE therapy", section on 'Efficacy'.)

Lung function correlates with IgE — IgE levels correlate with asthma severity; serum IgE levels areproportionately higher in asthmatic patients with lower lung function (FEV1) [31]. This may also be true for allergen-specific IgE; in patients with lower respiratory symptoms to specific aeroallergens (eg, cat), levels of allergen-specific IgE correlated well with asthma symptoms and lung function [32].

One of the key features of asthma is airway hyperresponsiveness, typically measured by bronchoprovocationchallenges. In patients with asthma, elevated total IgE levels are associated with positive responses tomethacholine challenges [33]. Airway hyperresponsiveness in children correlates closely with total IgE level evenafter exclusion of children with asthma [34]. However, airway hyperresponsiveness was more closely correlated topositive allergen skin test reactions than total IgE levels in children [35].

Smoking is associated with increased IgE levels in a dose-dependent fashion, possibly due to the lack of expecteddecreases in IgE levels with aging [36]. The inverse relationship between IgE levels and lung function was strongerin asthmatic patients in both current and never smokers, compared with nonasthmatic subjects [37].

Allergic bronchopulmonary aspergillosis — Allergic bronchopulmonary aspergillosis (ABPA) is one of the fewdisorders in which total IgE values are used directly in diagnosis and treatment. ABPA typically occurs in patientswith asthma or cystic fibrosis. The ubiquitous mold Aspergillus fumigatus causes localized immunologic-mediateddamage in the lung. Diagnostic features include increased total IgE (>417 kU/L for patients with asthma and >1000kU/L for those with cystic fibrosis) and evidence of increased specific IgE and IgG to A fumigatus [38]. Levels oftotal IgE increase during exacerbations of ABPA, and fall with successful therapy. (See "Allergic bronchopulmonaryaspergillosis", section on 'Diagnosis'.)

Allergic rhinitis — Allergic rhinitis is associated with positive skin-test reactions (or allergen-specific IgEantibodies), but is independent of total IgE levels [39]. Measurement of total IgE has low sensitivity (44 percent)for identification of patients with current allergic rhinitis [40]. In patients with perennial allergic rhinitis, total IgElevels did not correlate with either skin test reactivity or in vitro specific IgE testing [41]. In addition, a normal IgElevel does not rule out allergic rhinitis [42]. The diagnosis of allergic rhinitis, seasonal or perennial, requires asuggestive history and physical exam and the demonstration of specific IgE to clinically-relevant aeroallergens [43].(See "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis".)

Atopic dermatitis — Even though it is called atopic dermatitis (AD), about 30 percent of patients are nonatopic,as determined by the absence of other allergic diseases, negative skin tests for common inhalant and foodallergens, and normal total serum IgE levels [44]. The importance of allergic triggers remains controversial. (See"Role of allergy in atopic dermatitis (eczema)".)

Elevated total IgE levels can be demonstrated in 80 to 85 percent of patients with AD, although the preciserelationship between the elevated IgE levels and disease pathogenesis is unclear [45]. Some individuals haveextremely high total IgE levels. Children with very high IgE (ie, >10,000 kU/L) are at greater risk for severe AD,sensitization to food and inhaled allergens, and anaphylaxis, compared to children with lesser elevations (ie, 1000to 4000 kU/L) [46].

In patients with AD, the rate of sensitization to foods ranges from 30 to 80 percent, depending upon the populationstudied, although the actual rate of confirmed food allergy is much lower. The diagnosis of food allergy in patientswith atopic dermatitis is reviewed in detail separately. (See "Role of allergy in atopic dermatitis (eczema)", sectionon 'Allergen sensitization'.)

Food allergy — Assessment of food-specific IgE is predominantly useful for the evaluation of immediateallergic reactions, such as those that cause hives, wheezing, or anaphylaxis. Foods are also associated with othertypes of adverse reactions including celiac sprue (gluten sensitivity) and lactose intolerance, neither of which areIgE-mediated. (See "Clinical manifestations of food allergy: An overview", section on 'Non IgE-mediated


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reactions'.)

The gold standard testing for food allergy is the double blind placebo-controlled oral challenge. This can be a laborintensive procedure with potential severe allergic reactions resulting from testing. Therefore, alternatives such asprick skin testing and in vitro food-specific IgE testing have been used as a substitute. Total IgE levels should notbe used to make a diagnosis of food allergy [47]. (See "Oral food challenges for diagnosis and management offood allergies" and "Diagnostic evaluation of food allergy".)

Venom allergy — Patients who have experienced a systemic allergic reaction to a stinging insect (ie, bee, wasp,etc) or fire ants, or select patients with severe large local reactions to insect stings, should be evaluated for venomallergy [48]. Skin testing is the preferred method of diagnosing venom allergy. If initial testing is negative, in vitrotesting for venom-specific IgE can be performed, or skin testing can be repeated [49].

Measurement of total IgE has no role in the diagnosis of venom allergy. Patients with confirmed venom allergyshould be offered venom immunotherapy, which is highly effective at reducing the risk of reactions to subsequentstings. (See "Diagnosis of Hymenoptera venom allergy".)

Drug allergy — In patients with a history suggestive of an immediate hypersensitivity allergic reaction, skin testingcan be helpful to confirm the diagnosis [50]. Penicillin is the only drug with validated testing available, although skintesting is performed with other medications as well. (See "An approach to the patient with drug allergy", section on'Testing for immediate reactions'.)

In vitro testing for drug-specific IgE is not generally useful, because its sensitivity is inferior to skin testing [51].Total serum IgE is of no value in the evaluation of drug allergy.

Chronic urticaria — Chronic idiopathic urticaria is defined as spontaneous wheals and/or angioedema daily ornear daily for more than six weeks without any identifiable cause. About 40 percent of these patients produce IgGautoantibodies to either IgE or its high affinity receptor, FcεRI. Despite IgE levels not being associated with thisdisease, the use of anti-IgE (omalizumab) therapy has been effective in reducing signs (number of hives) andsymptoms (itch severity) in patients who remain symptomatic despite standard treatments [52,53]. (See "Chronicurticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)

RATIO OF ALLERGEN-SPECIFIC IgE TO TOTAL IgE — The ratio of allergen-specific IgE to total IgE has beentermed the “specific activity” [54]. Its utility has been examined in the diagnosis of several allergic disorders, and inpredicting individuals’ responses to omalizumab therapy. One study found that, in the diagnosis of food allergy, thespecific activity was no more useful than allergen-specific IgE alone [55]. However, in the treatment of asthma withomalizumab, a specific activity greater than 3 to 4 percent was predictive of a reduced response to omalizumabtherapy [56]. At present, the ratio of allergen-specific IgE to total IgE remains largely a research tool and overallclinical usefulness has not been established.

SUMMARY

Allergen-specific IgE production is a fundamental component of the pathogenesis of allergic disease.However, the measurement of total IgE and allergen-specific IgE has variable utility in the diagnosis andmanagement of allergic disorders. (See 'Introduction' above.)

Atopy refers to the genetic predilection to produce allergen-specific IgE. Sensitization refers to the presenceof allergen-specific IgE, in the absence of clinical disease. Individuals are considered to have clinicallysignificant allergy or allergic disease when they have both allergen-specific IgE and develop symptoms uponexposure to that allergen. (See 'Terminology' above.)

Elevated total IgE is seen with some allergic disorders, as well as several nonallergic diseases (table 1).Many patients (although not all) with allergic disorders have elevated levels of total IgE; however, there is nospecific cutoff value that discriminates patients with allergic disease from those without, and there isconsiderable overlap. (See 'Relationships between total IgE levels and allergic disease' above.)

Elevated total IgE is associated with an increased risk of allergic disease, although there is significantoverlap between affected individuals and normals, such that the measurement is most useful in the contextof population studies, rather than in the diagnosis or management of an individual. Allergen-specific IgE is


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usually detectable several years before a person becomes reactive to that allergen, although only a subsetof sensitized people will ever develop symptoms. (See 'Utility in predicting the development of allergicdisease' above.)

The role of total and allergen-specific IgE levels in pathogenesis and diagnosis differs among the leadingallergic disorders. Asthma correlates with increased total IgE levels, regardless of atopic status. Allergicrhinitis is associated with allergen-specific IgE antibodies, although not with total IgE levels. Patients withatopic dermatitis may have very elevated levels of total IgE, although only a minority of patients (mostlychildren with severe AD) has clinically-apparent allergic reactions to food. Thus the usefulness of measuringtotal IgE in allergic rhinitis and atopic dermatitis is very limited. (See 'The role of IgE in specific disorders'above.)

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Hamilton RG, MacGlashan DW Jr, Saini SS. IgE antibody-specific activity in human allergic disease. ImmunolRes 2010; 47:273.

54.

Mehl A, Verstege A, Staden U, et al. Utility of the ratio of food-specific IgE/total IgE in predictingsymptomatic food allergy in children. Allergy 2005; 60:1034.

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Johansson SG, Nopp A, Oman H, et al. The size of the disease relevant IgE antibody fraction in relation to'total-IgE' predicts the efficacy of anti-IgE (Xolair) treatment. Allergy 2009; 64:1472.

56.

Topic 83038 Version 2.0


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GRAPHICS

Allergen-specific IgE production and dissemination

Allergens (in this figure, aeroallergens) enter the tonsils within which theyare taken up and degraded by antigen presenting cells (APC). APCsthen interact with T helper cells type 2 (Th2) cells and B cells in the lymphnodes, leading to allergen-specific IgE production. The IgE enters the bloodstream, and then diffuses through tissues (especially the skin and mucosaltissues of the respiratory and gastrointestinal tracts). The IgE binds tohigh-affinity Fc receptors (FcepsilonRI) on the surface of the tissue mast cellsand circulating basophils. When these IgE-coated cells encounter that specificaeroallergen subsequently, they become activated, leading to the release ofinflammatory mediators, which results in the signs and symptoms ofIgE-mediated allergic reactions.


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IgE: immunoglobulin E.

Graphic 55328 Version 6.0


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Conditions associated with elevated serum IgE

Infectious diseases Parasitic Ascariasis

Schistosomiasis

Strongyloidiasis

HIV infection

Mycobaterium tuberculosis

Cytomegalovirus

Epstein-Barr virus (EBV)

Candidiasis

Atopic diseases Allergic bronchopulmonary aspergillosis (ABPA)

Allergic fungal sinusitis

Atopic dermatitis

Allergic asthma

Allergic rhinitis

Immunodeficiencies Hyperimmunoglobulin E syndrome

Wiskott-Aldrich syndrome

Netherton's disease

Immune dysregulation, polyendocrinopathy, enteropathy, X-linkedsyndrome (IPEX)

Omenn syndrome

Atypical complete DiGeorge syndrome

Inflammatorydiseases

Churg-Strauss vasculitis

Kimura disease

Neoplasms Hodgkin's lymphoma

Immunoglobulin E (IgE) myeloma

Others Tobacco smokers

Cystic fibrosis

Nephrotic syndrome

Bone marrow transplantation

Bullous pemphigoid

Graphic 83457 Version 6.0


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Disclosures: Jeff Stokes, MD, FAAAAI, FACAAI Nothing to disclose. Thomas B Casale, MD Grant/Research Support: Novartis [chronicurticaria (omalizumab)]; Genentech [asthma (omalizumab)]. Consultant/Advisory Boards: Novartis [chronic urticaria (omalizumab)];Genentech [asthma (omalizumab)]. Bruce S Bochner, MD Grant/Research/Clinical Trial Support: NIAID; NHLBI; GSK [Siglec-8, Siglec-9,asthma, COPD, anaphylaxis, imaging; eosinophilic granulomatosis with polyangiitis (Mepolizumab)]. Consultant/Advisory Boards: TEVA;Sanofi; Merck; Glycomimetics; Allakos; Biogen Idec; Svelte Medical Systems. Patent Holder: Siglec-8 and its ligand; anti-Siglec-8antibodies [held by Johns Hopkins University]. Employment: Northwestern University Feinberg School of Medicine. EquityOwnership/Stock Options: Glycomimetics; Allakos. Other Financial Interest: Elsevier [royalties]. Anna M Feldweg, MD Employee ofUpToDate, Inc.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referencedcontent is required of all authors and must conform to UpToDate standards of evidence.Conflict of interest policy

Disclosures


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The Relationship Between IgE and Allergic Disease

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