The Journal of Allergy and Clinical Immunology
Volume 112, Issue 2 , Pages 252-262, August 2003

Allergic and nonallergic forms of atopic diseases☆☆☆

Department of Dermatology, University of Bonn, Bonn. Bonn, Germany

Received 7 February 2003; received in revised form 5 April 2003; accepted 16 April 2003.

Article Outline

Abstract 

Atopic dermatitis, allergic rhinitis, and asthma are atopic diseases that develop on a complex genetic background, the so-called atopic diathesis. Although they target different organs, in most patients they are characterized by the presence of elevated total serum IgE levels. However, a subgroup of atopic patients exhibits normal IgE levels and mechanisms contributing to the so-called “intrinsic” or “nonallergic form” have been the matter of intensive research work in the last years. Because of the rapid advancements in the research field of atopic diseases, it now becomes possible for the first time to delineate a new disease classification of allergic and nonallergic subtypes of atopic diseases, thereby bringing hope to the clinician for a more specific treatment approach for each subgroup of these patients. (J Allergy Clin Immunol 2003;112:252-62.)

Keywords:  Atopic diseases, atopic dermatitis, asthma, rhinitis, allergic, nonallergic, IgE

Abbreviations:  Fc RI: , High-affinity receptor for IgE

 

Atopy is an inherited condition that makes individuals more likely to have a familiar group of diseases of growing importance in Western societies develop, including rhinitis, asthma, and atopic dermatitis.1, 2 It is thought that the key factors behind this rising incidence are increased exposure to sensitizing allergens and reduced stimulation of the immune system by parasitic and microbial components, which are believed to switch the TH2 profile of the immune response in a TH1 profile, related to a steady decline in infectious diseases during critical periods of development such as early infancy.3, 4 In addition to these environmental factors, the genetic basis of atopy is still a matter of intensive research, and efforts have been expended in mapping the chromosomal locations of genes involved in the susceptibility to atopic diseases.5

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The role of IgE 

Since Prausnitz and Kustner described the existence of a human serum factor that reacts with allergens in 1921, much effort has been made to characterize the effector molecule of immunologic hypersensitivity responses in depth.6 Today, we know that the antibody called IgE, which was discovered in 1967 by Ishizaka et al7 is composed of 2 identical heavy and 2 identical light chains. These chains form the variable antigen binding and the constant Fc domain, through which the IgE molecule binds to its cell surface receptors. Most individuals react with an increase of serum IgE levels as a defensive response to parasitic infections. However, some individuals also display an abnormally enhanced ability to produce IgE antibodies in response to certain allergens, such as house dust mite, ragweed, or cat dander, which activate the immune system after ingestion, inhalation, or diffusion through the skin.

Although the theory describing atopic diseases as highly IgE dependent has persisted over a long time, new data have raised the question of the precise role of IgE in atopy.

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Allergic or nonallergic disease? 

The term “allergy” was introduced in 1906 by Clemens P. Pirquet, who used it to describe the reactions of protective immunity and hypersensitivity.8 Later there was a tendency to use the word “allergy” to describe all kinds of unpredictable reactions in the skin and the mucosa.9 Today, the term “allergy” is frequently used synonymously with IgE-mediated allergic diseases and will be used in this sense here. However, it has also been observed that serum IgE levels might lie within the normal range in mild, moderate, or even in a few cases of severe atopic diseases, such as severe atopic dermatitis without concomitant asthma or rhinitis. A cornerstone in this context was the contribution of Rackemann,10 in the middle of the 20th century, who first recognized that patients with negative skin prick tests to inhalants have a late onset of disease and have the intrinsic form of asthma. Today atopic diseases can be divided into 2 distinct variants: the extrinsic, allergic variant, which occurs in the context of sensitization toward environmental allergens and is accompanied by elevated serum IgE levels, and the intrinsic, nonallergic variant, with no detectable sensitization and with low serum IgE levels.11 Since then, it has become increasingly clear that allergic and nonallergic forms exhibit specific clinical and immunologic characteristics.

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Allergic and nonallergic atopic dermatitis 

Allergic atopic dermatitis 

Clinical parameters 

With regard to the diagnosis of atopic dermatitis (AD), numerous scoring strategies and diagnostic criteria have been developed. The criteria of Diepgen et al,12 Hanifin,13 the United Kingdom Working Party's Diagnostic Criteria for Atopic Dermatitis,14 and the Millennium Criteria for the Diagnosis of Atopic Dermatitis15 are most often used. In the definition of Hanifin, an elevated serum IgE level is not essential for diagnosis, and it can be defined by a syndrome of skin lesions, which are not strictly associated with IgE sensitization.

Most patients with atopic dermatitis have the allergic form, characterized by high serum IgE levels and positive skin prick test reactions to common environmental allergens such as food or aeroallergens (Table I).16

Table I. Characteristics of allergic and nonallergic atopic dermatitis
Nonallergic atopic dermatitisAllergic atopic dermatitisReference
Clinical parameters
Skin manifestationSimilarSimilar12-16,36
Onset of eczemaEarly (in childhood)Early (in childhood)16
SexFemale predominanceNo female predominance16,35,36
Frequency16%-45% of atopic dermatitis patients55%-84% of atopic dermatitis patients16,37
Skin prick testNegativePositive16
Parameters in the peripheral blood
Total serum IgE<150 kU/L>150 kU/L16
Specific IgENegativePositive16
Blood eosinophilia↑↑34,35
Eosinophil survival↑↑34,35
CD137 expression of eosinophils↑↑↑34,35
Eosinophilic cationic protein in the blood↑↑34,35
T cells in the peripheral bloodHLA-DR expression similarHLA-DR expression similar18-20
Cytokines in the peripheral blood↑IL-5↑IL-535
↑IL-4↑IL-4
↑↑ IL-13↑IL-13
↑sIL-4R↑sIL-4R
B-cell activationCD23+ B cells ↑CD23+ B cells ↑↑16
Stimulated PBMCs↑↑IL-13 release↑IL-13 release43
Phenotype of monocytes↓FcϵRI, FcϵRII↑↑FcϵRI, FcϵRII35
↓IL-4Rα↑IL-4Rα
↓CD40↑CD40
Parameters in the skin
Phenotype of epidermal dendritic cells↑FcϵRI↑↑FcϵRI43
FcϵRI/FcγRII ratio < .5FcϵRI/FcγRII ratio > 1.5
Cytokines derived from lesional skin↑IL-5, IL-13↑↑IL-5, IL-1318-20
Parameters on the genetic level
IL-4Rα promoter polymorphism C-3223-T↑↑frequency↓ frequency36
IL-4 promoter polymorphism C-590-T↓frequency↑frequency35

Intranasal or bronchial inhalation challenge with aeroallergens such as house dust mite or animal dander can lead to the development or worsening of AD skin lesions, and the degree of IgE sensitization to aeroallergens is directly associated with the severity of the disease, whereas the reduction of exposure to some common allergens such as house dust mite is associated with a significant improvement in AD.17

Parameters in the skin 

Numerous studies have demonstrated the importance of activated CD4+ T cells in skin lesions of patients with AD. Immunohistologic investigations have shown that the dermal infiltrate in the skin lesions is mainly composed of CD4+ and CD8+ cells, with a CD4/CD8 ratio similar to that observed in peripheral blood.16, 18, 19 It is well known that the human immune system harbors a powerful army of cutaneous T cells. In both the allergic and nonallergic form of AD these T cells seem to be highly activated and bear the cutaneous lymphocyte antigen on their surface, which enables them to be immediately recruited into the skin on invasion of foreign antigens.20, 21, 22 Cutaneous T cells that produce soluble factors such as IL-4, IL-5, and IL-13 predominate in the acute phase of AD. In contrast, T cells that produce IFN-γ predominate in the chronic phase.23

Eosinophilic granule proteins are characteristically deposited in the skin lesions of AD.24 Because eosinophils and their granule proteins have potent inflammatory functions, this finding indicates that they might play a critical role in AD (Fig 1).

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  • Fig. 1. 

    Pathophysiologic puzzle of atopic dermatitis. Differences between the allergic subtype of atopic dermatitis (AD) (left side) and the nonallergic subtype of AD are indicated in yellow . In addition, immunohistochemical stainings of the FcϵRI on CD1a+ Langerhans cells and inflammatory dendritic epidermal cells (indicated by arrows ) are shown on the bottom of each figure. Fc ϵRI, High-affinity receptor for IgE; Eo, eosinophils.

One of the most important features of allergic AD is the prominent skin infiltration with hyperstimulatory cells of the dendritic lineage. Dendritic cells play a primary role in cutaneous immune surveillance. Two different dendritic epidermal cell populations have been identified in the skin of AD patients, Langerhans cells and inflammatory dendritic epidermal cells, which bear the high-affinity receptor for the Fc region of IgE (FcϵRI) on their cell surface (Fig 1).25 It has been suggested that FcϵRI plays a pivotal role in antigen focusing by enabling epidermal dendritic cells to absorb allergens invading the impaired epidermal skin barrier by means of FcϵRI-bound IgE, leading to efficient antigen presentation to T cells. In support of this concept, the successful application of aeroallergens such as cat dander in the so-called atopy patch test shows that it is possible to elicit eczematous skin lesions solely by external application of aeroallergens to the skin.26 In patients with positive atopy patch test reactions, a higher number of IgE-bearing dendritic cells were found in the epidermis and dermis than in patients with negative atopy patch test reactions.27 Therefore, an intermittent or a continuous flow of aeroallergens into the process of facilitated antigen presentation might define the pathophysiologic basis of the recurrent or self-perpetuating course of allergic AD, as frequently seen in untreated patients.

Similar to rhinitis or asthma, inflammatory processes as consequences of microbial infection play a major role in both the allergic and nonallergic form of the disease. The skin of patients with AD exhibits a striking susceptibility to colonization and infection with microbial components such as Staphylococcus aureus, Pityrosporum ovale, or Candida albicans.

S aureus is found in more than 90% of patients with chronic AD skin lesions, reaching a density of approximately 1 million/cm2 and might be an important trigger factor in the proinflammatory process.28, 29 These bacteria secrete toxins, which are known to act as superantigens, such as S enterotoxin A or B and toxic shock syndrome toxin-1, and amplify the inflammatory reactions of the skin. The level of endogenous antimicrobial peptides, such as cathelicidins and β-defensins, is reduced on the skin of patients with AD,30 which together contribute to the increased susceptibility of atopic skin infection. Recently it has been shown that exclusively allergen-specific IgE against microbial components could be found in 50% of the patients with AD with low IgE serum levels. This observation raises the question whether a hyperreactivity to microbial components might be a trigger factor of this subtype of AD.25

Parameters in the blood 

Research during the last decade has established that several abnormalities in soluble factors, cellular characteristics, and other mediators in the blood are characteristic of the complex pathogenesis of AD.

An elevation in total serum IgE and in the serum levels of specific IgEs to aeroallergens and food allergens is characteristic of allergic AD. In addition, elevated levels of soluble mediators such as IL-4, IL-5, and the soluble form of the low-affinity receptor for IgE are characteristic features of patients with allergic AD. Recently, IgE autoantibodies directed against human proteins have been observed exclusively in the peripheral blood and skin of patients with allergic AD. These IgE-reactive autoantigens are designated as Hom s 1-5 and DSF70 and have been cloned from human epithelial cDNA expression libraries. They are primarily intracellular proteins found in IgE-immune complexes from sera of patients with AD.31 It is assumed that they increase allergic responses and in this way contribute to the severity and exacerbation of AD.

Another phenomenon observed in the allergic form of AD is increased activity of cyclic adenosine monophosphate-phosphodiesterase. This leads to reduced intracellular levels of cyclic adenosine monophosphate, which has a permissive effect on various cell functions in patients with AD.32

Eosinophils play a major role in AD and become active by releasing their toxic eosinophilic granules, which constitute a major portion of their cellular protein content. Notably, in both forms of AD, increased serum levels of eosinophils with enhanced survival are found. In contrast, the expression of the functional CD137 receptor, which stimulates T-cell activation and differentiation, is restricted exclusively to eosinophils in patients with allergic AD.33, 34

The question of a defect on the level of monocytes has been an issue of intensive research for a long time. It has been suggested that monocytes in atopic individuals display enhanced survival and release distinct soluble mediators. Monocytes of patients with allergic AD display enhanced surface expression of the high-affinity and low-affinity receptor for IgE (FcϵRI and FcϵRII) and the IL-4Rα chain and in this way can be distinguished from monocytes in patients with nonallergic AD.35

Nonallergic atopic dermatitis 

Clinical parameters 

In patients with the nonallergic form of AD, the disease is not associated with sensitization to food or aeroallergens, and serum IgE levels lie within the normal range, even though these patients display exactly the same skin lesions as patients with increased serum IgE levels.16 Recent studies have found that the frequency of the nonallergic form of AD ranges from 16% to 45%, depending on the country and the criteria for definition.36, 37 A higher prevalence of nonallergic AD in preschool children in the former East Germany and an increase in allergic forms of atopic disorders in this region as a consequence of “westernization” since reunification indicate that environmental factors might play an important role in triggering the development of both forms of AD. Interestingly, a predominance of female patients has been observed among patients with nonallergic AD in several studies. These gender differences might be due to the influence of sex hormones, which influence mucosal allergic reactivity.38, 39

The hypothesis of a dynamic relationship between the 2 forms of AD is supported by data from a study investigating the persistence of AD during the development of respiratory allergic diseases. In this study, children with AD who were negative to the skin prick test became positive to the skin prick test within a period of 10 years.40 Nonallergic AD might therefore be considered as the pure or transitional form in the natural history of AD.40 The influence of environmental factors might contribute to the development of the allergic, mixed form of AD, accompanied by sensitization to environmental factors and increasing IgE serum levels. At present, it has not been evaluated whether patients with allergic AD, in contrast to patients with nonallergic AD, have a higher risk of allergic rhinitis or allergic asthma developing. In addition, it would be interesting to evaluate the frequency of concomitant nonallergic rhinitis and/or nonallergic asthma in the nonallergic subgroup of AD in the future.

Parameters in the skin 

Atopic skin is characterized by a perivascular infiltrate of highly activated T cells. Although cutaneous T cells seem to be similar in the 2 forms of AD, the nature of their soluble signals varies. Cutaneous T cells of patients with nonallergic AD produce similar amounts of IL-5 and IFN-γ but less of the TH2 cytokines IL-4 and IL-13 (known to increase IgE synthesis) than cells of allergic patients.19 This distinct cytokine pattern might be both cause and effect of the lower IgE levels found in patients with nonallergic AD.19

The reduced amount of TH2 cells producing IL-4 and IL-13, together with the lower FcϵRI expression of epidermal dendritic cells in nonallergic AD, indicate that proinflammatory mechanisms are predominant.

As with patients with allergic AD, the skin of patients with nonallergic AD harbors a large number of epidermal dendritic cells, which characteristically display lower surface expression of the high-affinity receptor for IgE (FcϵRI).41 Interestingly, positive atopy patch test reactions to aeroallergens can also be induced even in the absence of elevated allergen-specific serum IgE in some of the patients with nonallergic AD, indicating a putative role of local IgE in AD.27

Parameters in the blood 

The common presence of peripheral blood eosinophilia and elevated serum levels of eosinophilic granule proteins suggests that eosinophil degranulation also plays a major role in the nonallergic form of AD. In contrast to the allergic form, in nonallergic AD, serum levels of both total and allergen-specific IgE lie within the normal range. In addition, the IgE-binding receptors, FcϵRI and FcϵRII, are not elevated on monocytes. This might be due to lower serum IgE levels, which, in combination with low IL-4Rα expression, result in reduced IL-4 responses from monocytes in these patients.35

Another approach suggests that IL-13 plays an unexpected and crucial role in atopic diseases. This is underlined by the finding that T cells producing IL-13 (the earliest indicator of atopy) can be found in large amounts in the cord blood of children who have atopic diseases develop later on in life.42

In view of these data, the increased level of IL-13 in the sera of patients with nonallergic AD35 indicates that IL-13 might be involved in the pathogenesis of this form of AD by stimulating eosinophils, interacting with B cells, altering the IL-13R signal transduction pathway, or activating other unknown mechanisms.43 Increased peripheral blood IL-4 and IL-13 production in nonallergic atopic dermatitis even in the absence of enhanced IgE levels indicates the predominance of an immune response of the TH2 type in this subtype.35

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Allergic and nonallergic asthma 

Allergic asthma 

Clinical parameters 

In general, asthma can be subdivided into 3 forms: the extrinsic/allergic asthma, which is clearly caused by an allergen, the intrinsic/nonallergic asthma, which is not linked to such an allergen, and the mixed form. It is well accepted that in all 3 variants local phenomena occurring in the mucosal tissue, such as bronchoconstriction of the smooth muscles as a consequence of local or systemic inflammation of the airways, are the central pathophysiologic mechanisms of asthma.

The sensitivity of extrinsic/allergic patients with asthma to allergens such as pollen, house dust mite, or food is clearly documented by positive skin prick test reactions and elevated IgE/allergen-specific IgE serum levels, which document sensitizations to environmental allergens in these patients (Table II).44, 45

Table II. Characteristics of allergic and nonallergic asthma
Nonallergic asthmaAllergic asthmaReference
Clinical parameters
Onset of the diseaseLaterEarlier44,46,47,51,65
Severity of the diseaseHigherLower46,47,51,65
SexFemale predominanceNo female predominance46,47,51,65
FrequencyAbout 30%About 70%44-47,51,65
Total serum IgELowHigh44-47
Specific IgENegativePositive44-47
Skin prick testNegativePositive44-47
Parameters in the peripheral blood
Perforin-positive lymphocytes in the peripheral blood↑↑↑77
CD4+CD11b+ lymphocytes in the peripheral blood↓↑63,64
Phenotype of B cells↓CD23↑CD2360
Number of CD8+ lymphocytes in the peripheral blood↑↑60,61
Number of blood eosinophils↑↑60
CD68+ macrophages↑↑↑69
Parameters in the bronchial tissue
IL-3, IL-4, IL-5, IL-13, GM-CSF↑↑46,47
Number of GMSFRα-positive cells↑↑↑49,74,75
FcϵRI-positive cells↑↑50,52,53
Iϵ/Cϵ in bronchial biopsies↑↑58-61

Parameters in the bronchial mucosa 

In biopsies of the respiratory mucosa, enhanced expression can be found of TH2 type cytokines and chemokines such as IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13, which trigger the T-cell response.46, 47 In addition, mRNA for the germline transcript (Iϵ) and the ϵ heavy chain of IgE (Cϵ)48, 49, 50, 51 and increased numbers of cells expressing the high-affinity receptor for IgE (FcϵRI) predominate in these tissues (Fig 2).50, 52, 53

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  • Fig. 2. 

    Characteristic features of asthma. Differences between the allergic and nonallergic asthma variant in bronchial mucosa are marked in yellow . Increased levels of Iϵ and Cϵ RNA+ cells can be found in the bronchial mucosa of both allergic and nonallergic patients with asthma. The amount of RANTES in the bronchoalveolar fluid of nonallergic patients with asthma is higher than in patients with allergic asthma. M, Mast cells; T, T cell; MØ, macrophage.

It is well known that activation of FcϵRI on the effector cells of anaphylaxis (ie, mast cells and basophils) induces the release of preformed vasoactive mediators, which rapidly elicit edema of the bronchial mucosa, mucus production, and smooth muscle constriction. Together, these factors cause the local inflammation in the mucosal tissue, which is assumed to play a pivotal role in the development of the disease. Persistent airflow inflammation might develop in response to bacterial infection such as Mycoplasma pulmonis or Chlamydia pneumoniae infection, in particular in severe longstanding allergic and nonallergic asthma.54 In addition, it has been speculated that, analogous to atopic dermatitis and rhinitis, S aureus might play a role as a trigger factor in asthma, and IgE antibodies to S aureus enterotoxins were found more frequently in patients with severe asthma than in normal control subjects and were linked to the severity of the diseases (ie, eosinophilic inflammation).55 Moreover, an enhanced level of T cells expressing the selected T-cell receptor β-chain variable region, which is known to be induced by microbial superantigens, was detected in bronchoalveolar lavage fluid of patients with asthma.56, 57 Another immunologic key factor in both forms is the recently described local IgE production, which is a pathognomic parameter in both allergic and nonallergic diseases of the respiratory tree, such as asthma and rhinitis.

Furthermore, the increase in FcϵRI-bearing cells in mucosal tissues, in combination with the increase in mRNA for the germline transcript (Iϵ) and the ϵ heavy chain of IgE, in the absence of an increase in B-cells supports this hypothesis of a local IgE synthesis in both subtypes of asthma.58 To initiate the synthesis of IgE, inhaled allergens must encounter FcϵRI-bearing antigen-presenting cells that line the airway. After successful antigen uptake, these antigen-presenting cells migrate to the draining lymph nodes, where they present their processed antigens to T cells and B cells.

Parameters in the blood 

Many more differences between patients with allergic and nonallergic asthma can be found in peripheral blood than in mucosal tissue. The most important inducers of the increase in serum levels of total and allergen-specific IgE in patients with allergic asthma are the cytokines IL-4 and IL-13, which are found at increased concentrations in the sera of these patients.59 Moreover, these cytokines initiate transcription of the ϵ-class constant region of the IgE heavy chain and trigger the production of IgE. In addition, the surface expression of the low-affinity receptor for IgE (FcϵRII/CD23) on B cells, which is capable of augmenting the serum levels of IL-4 and IL-13, is enhanced in patients with allergic asthma. There is ample evidence that chemokines found in high concentrations in the sera of patients with asthma such as RANTES and monocyte chemoattractant protein-1 and -3 play a role in ongoing lung inflammation, lung leukocyte infiltration, bronchial hyperresponsiveness, and the recruitment of eosinophils in the pathogenesis of asthma.60

Other cellular characteristics that can be detected exclusively in the blood of patients with allergic asthma are an increase in the CD4+ T-cell sublineage, an elevated expression of the β-1 integrin CD11b on CD4+ cells, and an elevated number of suppressor cells expressing CD8+.61, 62

Nonallergic asthma 

Clinical parameters 

In contrast, 10% to 33% of all patients with asthma have the nonallergic form, which has a later onset, a more severe clinical course in adults, and is significantly associated with nasal polyps in combination with aspirin idiosyncrasy.48, 49, 63, 64 Precipitating factors in the nonallergic variant of asthma are viral or bacterial infections such as chlamydia or fungal infections, for example, with dermatophytes that cause local inflammation.54, 65, 66 The lower levels of IL-10 and IL-12 and the lack of a putative homeostatic mechanism to decrease lung inflammation in the nonallergic form of this entity might predispose these subjects to bronchial inflammation.67 In addition, irritants such as smoke or fumes, physical or emotional stress, gastroesophageal reflux, and exercise represent the cause of the nonallergic form of asthma. As with AD and rhinitis, a clear female predominance can be observed.

Parameters in the bronchial mucosa 

Increases in Iϵ and Cϵ RNA+ cells in the bronchial mucosa provide evidence for a local IgE synthesis in patients with asthma58 even in the absence of a known antigen or allergen triggering this process.48, 58, 68 One of the few differences between the mucosal tissue of patients with allergic and nonallergic asthma is the concentration of the chemokine RANTES,69, 70, 71 which is known to be produced by specific macrophage subtypes.69 Interestingly, the amount of RANTES in the bronchoalveolar lavage fluid of patients with nonallergic asthma is higher than in patients with allergic asthma. This might be 1 reason for the enhanced number of eosinophils infiltrating the mucosal tissue in the nonallergic form and indicates a distinct predominance of specific tissue macrophage subtypes in nonallergic versus allergic asthma.

Parameters in the blood 

Nonallergic asthma is seen with a marked eosinophilia. Some studies found lower IL-4 production in patients with nonallergic asthma than in patients with allergic asthma, which might explain the low circulating IgE serum levels.72 In contrast, other studies did not detect any difference in IL-4 levels between the asthmatic subgroups.73 In addition, in nonallergic asthma a marked increase in macrophages was found, which was demonstrated on the basis of the increase in the expression of the monocyte/macrophage specific marker CD68 in combination with GM-CSF receptor α-subunit bearing cells.49, 74, 75 An inverse correlation between the number of GM-CSF receptor α-bearing cells and the FEV1 (FEV1 % predicted) suggests that these parameters mirror the severity of disease in the nonallergic form.75 In contrast, sputum macrophage numbers were not higher in patients with nonallergic asthma.67 In addition, some differences in the expression of transcription factors have been described. The number of cells expressing the transcription factor GATA-3 and cMAF, which are involved in the mediation of the IL-4 and IL-5 synthesis, was high in patients with allergic and nonallergic asthma. In contrast, reduced signal transducer and activator of transcription 6 expression and consequently a reduced IL-4R signaling is a feature of nonallergic asthma.76

Furthermore, analyses of lymphocyte subpopulations in the peripheral blood of patients with nonallergic asthma show that an increased percentage of CD4+ cells expresses the cytotoxic molecule perforin. This molecule has been shown to play a pivotal role in autoimmune diseases77 and seems to be of major relevance in nonallergic asthma.77

Taken together, in consideration of the inflammatory processes in both forms of asthma, there seem to be more similarities than differences between the allergic and nonallergic form of this disease.

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Allergic and nonallergic rhinitis 

Allergic rhinitis 

Clinical parameters 

Seasonal or perennial allergic rhinitis, which has an overall prevalence of 9% to 42%,78 arises in atopic individuals with an increased tendency to generate IgE antibodies against common environmental allergens, such as ragweed, pollen, or house dust mite. This form is characterized by mucosal infiltration and activity of plasma cells, mast cells, and eosinophils.78, 79 Typically, positive skin prick test reactions toward aeroallergens can be observed in these patients (Table III).

Table III. Characteristics of allergic and nonallergic rhinitis
Nonallergic rhinitisAllergic rhinitisReference
Clinical parameters
Skin prick testNegativePositive78,79
SexFemale predominanceNo female predominance45,84,86
Frequency9% to 42%91% to 58%78
Frequency of ASA triad↑83-85
Parameters in the peripheral blood
Total serum IgELowLow to high81,82
Specific IgENegativePositive81,82
Eosinophil count↑↑↑↑81,82
Parameters in the nasal mucosa
Mast cells in the tissue↑↑78,79
IgE-positive cells↑↑80,81
Cytokines in the nasal mucosa↑ IL-13 mRNA↑ IL-4 and IL-13 mRNA80,81
Number of CD20+ B cells↑↑↑80,81
Number of Iϵ/Cϵ+ cells↑↑↑80,81
Imbalance of nervous system↑83

Parameters in the mucosal tissue 

Allergic rhinitis is associated with an elevated mRNA expression of IL-4 and IL-13 in combination with augmented numbers of CD20+ B cells and cells expressing Iϵ and Cϵ in sinus biopsy specimens (Fig 3).80

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  • Fig. 3. 

    Differences in the nasal mucosa of patients with allergic and nonallergic forms of rhinitis are indicated in yellow . Nasal epithelium exhibits mast cells and IgE-positive cells in both the allergic and nonallergic form of rhinitis. In contrast to nonallergic rhinitis, allergic rhinitis is associated with an elevated mRNA expression of IL-4 and IL-13 in combination with augmented numbers of CD20+ B cells and cells expressing Iϵ and Cϵ in sinus biopsy specimens. M, Mast cell; B, B cell; T, T cell; Eo, eosinophil.

Parameters in the blood 

Although most patients with allergic forms of rhinitis display an increased serum (IgE) level of total and allergen-specific IgE, in some patients IgE levels are only slightly elevated or lie within the normal range. In addition, serum levels of IL-4, IL-5, and the soluble form of the low-affinity receptor for IgE (sCD23) are elevated in the sera of these patients, indicating a pivotal role of these parameters in IgE-mediated immunologic pathways.45, 81 Most interestingly, endogenous signals for cell death, such as the serum-soluble Fas ligand in concentrations often associated with autoimmune diseases, have been shown to be specifically increased in patients with allergic forms of rhinitis.82

Nonallergic rhinitis 

Clinical parameters 

In contrast, nonallergic rhinitis is a diagnosis of rhinitis without any IgE mediation, as documented by allergen skin testing. Similar to atopic dermatitis and asthma, sex might be a risk factor in nonallergic rhinitis, because 58% to 74% of patients with nonallergic rhinitis are female. It is assumed that nonallergic rhinitis is a heterogeneous syndrome consisting of at least 2 subtypes: the noneosinophilic and eosinophilic type. The noneosinophilic type includes various subtypes of rhinitis such as occupational, hormonal, drug-induced, gustatory, and vasomotor rhinitis. The eosinophilic type, also known as nonallergic rhinitis with eosinophilia syndrome, is characterized by nasal eosinophilia and frequent evolution to nasal polyposis or the triad of intrinsic asthma, nasal polyposis, and aspirin idiosyncrasy (ASA triad).83, 84, 85 This syndrome has an overall prevalence of 10% to 15% and a clear female predominance.45, 84, 86

Although nonallergic rhinitis is a well-recognized diagnosis, its prevalence has not been studied definitely. It frequently occurs in combination with allergic diseases and is seen as the so-called mixed rhinitis.78

Parameters in the mucosal tissue 

The nasal epithelium exhibits mast cells and IgE-positive cells in both the allergic and nonallergic form of rhinitis.

Although IgE-positive cells are also found in the nonallergic form of rhinitis, IL-13 is the predominant cytokine detectable in the sinus biopsy specimens of patients with nonallergic rhinitis.87 A distinguishing feature of nonallergic rhinitis with eosinophilia syndrome is an elevated eosinophil count of 5% to 25% in nasal smears.

Although the exact pathophysiology of nonallergic rhinitis is not fully understood, in some cases it might result from an imbalance between the nasal sympathetic and parasympathetic nervous system.83 In general, autonomic stimuli such as isotonic exercise or changes in temperature have a greater effect on patients with nonallergic rhinitis. Similar to asthma, there has been a debate about the relationship of the allergic and nonallergic variant of rhinitis in the context of bacterial infections, which might trigger the pro-inflammatory process in this disease.

Because the role of staphylococcal superantigens in other atopic diseases has recently been recognized, new evidence suggests that similar mechanisms might be relevant in airway diseases such as rhinitis. It is hypothesized that the higher carrier rate of S aureus in patients with allergic and nonallergic rhinitis might aggravate the clinical course of the disease.88 In recent studies it has been suggested that there is an association between increased levels of total IgE, specific IgE, and eosinophilic inflammation in nasal polyps and the presence of specific IgE to S aureus enterotoxin A and S aureus enterotoxin B. Together these findings might link to a possible role of bacterial superantigens in this disease.89

Parameters in the blood. Patients with nonallergic rhinitis display low total and allergen-specific IgE serum levels and negative skin prick test reactions to food allergens and aeroallergens. Several lines of evidence support the hypothesis of local IgE synthesis at mucosa sites. IgE can be found located in the mucosal tissues even in patients with the nonallergic subtype. In addition, concentrations of IgG subclass 1 and IgG subclass 4 anti-IgE autoantibodies are far lower than those found in patients with allergic rhinitis.90 In contrast to the allergic form, Fas ligand is not detectable in sera of patients with nonallergic forms of rhinitis.

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Conclusion 

The genetic, humoral, and cellular differences between patients with allergic and nonallergic forms of atopic diseases mirror a complex network of distinct properties, which together determine the outcome of the allergic or nonallergic variants of atopic diseases. As a common feature, local IgE production in the affected tissue and the relevance of allergic and nonallergic (infectious) inflammatory processes seem to play a major role in all subtypes of atopic diseases.

Perhaps the most interesting aspect is the characterization of the underlying pathomechanisms of each of these forms, which is indispensable for the development of clear-cut diagnostic criteria and exact definitions of atopic disorders in clinical and scientific practice. Promising future directions of research in the nonallergic forms of atopic diseases include the possible identification of novel allergens or autoantigens, detailed descriptions of the mechanisms involved in local IgE production within inflammatory tissues, and long-term studies to investigate the putative transition of nonallergic to allergic forms of atopic diseases in the same individual. Moreover, effective new treatment strategies for the allergic and nonallergic form would then become a real possibility. These might be quite different from most of the recent therapeutic strategies, which are based on the concept of a predominance of IgE-mediated mechanisms, as the treatment with anti-IgE antibodies.91

In addition, the data reviewed here show that it is necessary to reassess the role of IgE and to consider a redef-inition of our current terminology.

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Acknowledgements 

We thank Dr Thomas A. E. Platts-Mills for the critical revision and helpful discussion of the manuscript, Elisabeth Geiger for critically reviewing this manuscript, and Natalie McGauran for editorial support.

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References 

  1. Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med. 2001;344:30–37
  2. Kay AB. Allergy and allergic diseases. Second of two parts. N Engl J Med. 2001;344:109–113
  3. Erb KJ. Atopic disorders: a default pathway in the absence of infection?. Immunol Today. 1999;20:317–322
  4. von Mutius E. Environmental factors influencing the development and progression of pediatric asthma. J Allergy Clin Immunol. 2002;109:S525–S532
  5. Steinke JW, Borish L, Rosenwasser LJ. Genetics of hypersensitivity. J Allergy Clin Immunol. 2003;111:495–501
  6. Bacharier LB, Geha RS. Regulation of IgE synthesis: the molecular basis and implications for clinical modulation. Allergy Asthma Proc. 1999;20:1–8
  7. Ishizaka K, Ishizaka T, Hornbrook MM. Allergen-binding activity of gamma-E, gamma-G and gamma-A antibodies in sera from atopic patients. In vitro measurements of reaginic antibody. J Immunol. 1967;98:490–501
  8. Bukantz SC. Clemens von Pirquet and the concept of allergie. J Allergy Clin Immunol. 2002;109:724–726
  9. Wuthrich B. What is atopy? Condition, disease or a syndrome?. Curr Probl Dermatol. 1999;28:1–8
  10. Rackemann FM. Nervous factors in asthma. Trans Am Clin Climatol Assoc. 1969;80:50–53
  11. Wuthrich B. Atopic dermatitis flare provoked by inhalant allergens. Dermatologica. 1989;178:51–53
  12. Diepgen TL, Sauerbrei W, Fartasch M. Development and validation of diagnostic scores for atopic dermatitis incorporating criteria of data quality and practical usefulness. J Clin Epidemiol. 1996;49:1031–1038
  13. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 1980;92:44–47
  14. Williams HC, Burney PG, Hay RJ, Archer CB, Shipley MJ, Hunter JJ, et al.  The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994;131:383–396
  15. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T, et al.  A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56:813–824
  16. Schmid-Grendelmeier P, Simon D, Simon HU, Akdis CA, Wuthrich B. Epidemiology, clinical features, and immunology of the “intrinsic” (non-IgE-mediated) type of atopic dermatitis (constitutional dermatitis). Allergy. 2001;56:841–849
  17. Tan BB, Weald D, Strickland I, Friedmann PS. Double-blind controlled trial of effect of housedust-mite allergen avoidance on atopic dermatitis. Lancet. 1996;347:15–18
  18. Akdis M, Simon HU, Weigl L, Kreyden O, Blaser K, Akdis CA. Skin homing (cutaneous lymphocyte-associated antigen-positive) CD8+ T cells respond to superantigen and contribute to eosinophilia and IgE production in atopic dermatitis. J Immunol. 1999;163:466–475
  19. Akdis CA, Akdis M, Simon D, Dibbert B, Weber M, Gratzl S, et al.  Role of T cells and cytokines in the intrinsic form of atopic dermatitis. Curr Probl Dermatol. 1999;28:37–44
  20. Akdis CA, Akdis M, Trautmann A, Blaser K. Immune regulation in atopic dermatitis. Curr Opin Immunol. 2000;12:641–646
  21. van Reijsen FC, Bruijnzeel-Koomen CA, Kalthoff FS, Maggi E, Romagnani S, Westland JK, et al.  Skin-derived aeroallergen-specific T-cell clones of Th2 phenotype in patients with atopic dermatitis. J Allergy Clin Immunol. 1992;90:184–193
  22. Abernathy-Carver KJ, Sampson HA, Picker LJ, Leung DY. Milk-induced eczema is associated with the expansion of T cells expressing cutaneous lymphocyte antigen. J Clin Invest. 1995;95:913–918
  23. Grewe M, Bruijnzeel-Koomen CA, Schopf E, Thepen T, Langeveld-Wildschut AG, Ruzicka T, et al.  A role for th1 and th2 cells in the immunopathogenesis of atopic dermatitis. Immunol Today. 1998;19:359–361
  24. Grewe M, Czech W, Morita A, Werfel T, Klammer M, Kapp A, et al.  Human eosinophils produce biologically active IL-12: implications for control of T cell responses. J Immunol. 1998;161:415–420
  25. Novak N, Allam JP, Bieber T. Allergic hyperreactivity to microbial antigens—a trigger factor of the intrinsic form of atopic dermatitis? J Allergy Clin Immunol. In press.
  26. Ring J, Darsow U, Behrendt H. Role of aeroallergens in atopic eczema: proof of concept with the atopy patch test. J Am Acad Dermatol. 2001;45:S49–S52
  27. Kerschenlohr K, Decard S, Darsow U, Ollert M, Wollenberg A. Clinical and immunologic reactivity to aeroallergens in “intrinsic” atopic dermatitis patients. J Allergy Clin Immunol. 2003;111:195–197
  28. Leung DY. Atopic dermatitis and the immune system: the role of superantigens and bacteria. J Am Acad Dermatol. 2001;45:S13–S16
  29. Leung DY, Harbeck R, Bina P, Reiser RF, Yang E, Norris DA, et al.  Presence of IgE antibodies to staphylococcal exotoxins on the skin of patients with atopic dermatitis. Evidence for a new group of allergens. J Clin Invest. 1993;92:1374–1380
  30. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al.  Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–1160
  31. Valenta R, Natter S, Seiberler S, Wichlas S, Maurer D, Hess M, et al.  Molecular characterization of an autoallergen, hom s 1, identified by serum ige from atopic dermatitis patients. J Invest Dermatol. 1998;111:1178–1183
  32. Hanifin JM, Lloyd R, Okubo K, Guerin LL, Fancher L, Chan SC. Relationship between increased cyclic AMP-phosphodiesterase activity and abnormal adenylyl cyclase regulation in leukocytes from patients with atopic dermatitis. J Invest Dermatol. 1992;98:100S–105S
  33. Heinisch IV, Bizer C, Volgger W, Simon HU. Functional CD137 receptors are expressed by eosinophils from patients with IgE-mediated allergic responses but not by eosinophils from patients with non-IgE-mediated eosinophilic disorders. J Allergy Clin Immunol. 2001;108:21–28
  34. Wedi B, Raap U, Lewrick H, Kapp A. Delayed eosinophil programmed cell death in vitro: a common feature of inhalant allergy and extrinsic and intrinsic atopic dermatitis. J Allergy Clin Immunol. 1997;100:536–543
  35. Novak N, Kruse S, Kraft S, Geiger E, Kluken H, Fimmers R, et al.  Dichotomic nature of atopic dermatitis reflected by combined analysis of monocyte immunophenotyping and single nucleotide polymorphisms of the interleukin-4/interleukin-13 receptor gene: the dichotomy of extrinsic and intrinsic atopic dermatitis. J Invest Dermatol. 2002;119:870–875
  36. Schafer T, Dockery D, Kramer U, Behrendt H, Ring J. Experiences with the severity scoring of atopic dermatitis in a population of German pre-school children. Br J Dermatol. 1997;137:558–562
  37. Schafer T, Heinrich J, Wjst M, Adam H, Ring J, Wichmann HE. Association between severity of atopic eczema and degree of sensitization to aeroallergens in schoolchildren. J Allergy Clin Immunol. 1999;104:1280–1284
  38. Stubner UP, Gruber D, Berger UE, Toth J, Marks B, Huber J, et al.  The influence of female sex hormones on nasal reactivity in seasonal allergic rhinitis. Allergy. 1999;54:865–871
  39. Yamatomo T, Okano M, Ono T, Nakayama E, Yoshino T, Satoskar AR, et al.  Sex-related differences in the initiation of allergic rhinitis in mice. Allergy. 2001;56:525–531
  40. Novembre E, Cianferoni A, Lombardi E, Bernardini R, Pucci N, Vierucci A. Natural history of “intrinsic” atopic dermatitis. Allergy. 2001;56:452–453
  41. Oppel T, Schuller E, Gunther S, Moderer M, Haberstok J, Bieber T, et al.  Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic forms of atopic dermatitis. Br J Dermatol. 2000;143:1193–1198
  42. Slager SL, Schaid DJ. Case-control studies of genetic markers: power and sample size approximations for armitage's test for trend. Hum Hered. 2001;52:149–153
  43. Williams TJ, Jones CA, Miles EA, Warner JO, Warner JA. Fetal and neonatal IL-13 production during pregnancy and at birth and subsequent development of atopic symptoms. J Allergy Clin Immunol. 2000;105:951–959
  44. Romanet-Manent S, Charpin D, Magnan A, Lanteaume A, Vervloet D. Allergic vs nonallergic asthma: what makes the difference?. Allergy. 2002;57:607–613
  45. Bousquet J, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108:S147–S334
  46. Yasruel Z, Humbert M, Kotsimbos TC, Ploysongsang Y, Minshall E, Durham SR, et al.  Membrane-bound and soluble alpha IL-5 receptor mRNA in the bronchial mucosa of atopic and nonatopic asthmatics. Am J Respir Crit Care Med. 1997;155:1413–1418
  47. Humbert M, Durham SR, Ying S, Kimmitt P, Barkans J, Assoufi B, et al.  IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity. Am J Respir Crit Care Med. 1996;154:1497–1504
  48. Humbert M, Grant JA, Taborda-Barata L, Durham SR, Pfister R, Menz G, et al.  High-affinity IgE receptor (FcepsilonRI)-bearing cells in bronchial biopsies from atopic and nonatopic asthma. Am J Respir Crit Care Med. 1996;153:1931–1937
  49. Humbert M, Menz G, Ying S, Corrigan CJ, Robinson DS, Durham SR, et al.  The immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than differences. Immunol Today. 1999;20:528–533
  50. Walker C, Bode E, Boer L, Hansel TT, Blaser K, Virchow JC. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis. 1992;146:109–115
  51. Ying S, Robinson DS, Meng Q, Rottman J, Kennedy R, Ringler DJ, et al.  Enhanced expression of eotaxin and ccr3 mrna and protein in atopic asthma. association with airway hyperresponsiveness and predominant co-localization of eotaxin mrna to bronchial epithelial and endothelial cells. Eur J Immunol. 1997;27:3507–3516
  52. Bentley AM, Durham SR, Kay AB. Comparison of the immunopathology of extrinsic, intrinsic and occupational asthma. J Investig Allergol Clin Immunol. 1994;4:222–232
  53. Kroegel C, Jager L, Walker C. Is there a place for intrinsic asthma as a distinct immunopathological entity?. Eur Respir J. 1997;10:513–515
  54. ten Brinke A, van Dissel JT, Sterk PJ, Zwinderman AH, Rabe KF, Bel EH. Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. J Allergy Clin Immunol. 2001;107:449–454
  55. Bachert C, Gevaert P, Howarth P, Holtappels G, van Cauwenberge JSG, Johansson SGO. IgE to Staphylococcus aureus enterotoxins in serum is related to severity of asthma. J Allergy Clin Immunol. 2003;111:1131–1132
  56. Herz U, Ruckert R, Wollenhaupt K, Tschernig T, Neuhaus-Steinmetz U, Pabst R, et al.  Airway exposure to bacterial superantigen (SEB) induces lymphocyte-dependent airway inflammation associated with increased airway responsiveness—a model for non-allergic asthma. Eur J Immunol. 1999;29:1021–1031
  57. Hauk PJ, Wenzel SE, Trumble AE, Szefler SJ, Leung DY. Increased T-cell receptor vbeta8+ T cells in bronchoalveolar lavage fluid of subjects with poorly controlled asthma: a potential role for microbial superantigens. J Allergy Clin Immunol. 1999;104:37–45
  58. Ying S, Humbert M, Meng Q, Pfister R, Menz G, Gould HJ, et al.  Local expression of epsilon germline gene transcripts and RNA for the epsilon heavy chain of IgE in the bronchial mucosa in atopic and nonatopic asthma. J Allergy Clin Immunol. 2001;107:686–692
  59. Lee YC, Lee KH, Lee HB, Rhee YK. Serum levels of interleukins (IL)-4, IL-5, IL-13, and interferon-gamma in acute asthma. J Asthma. 2001;38:665–671
  60. Conti P, DiGioacchino M. MCP-1 and RANTES are mediators of acute and chronic inflammation. Allergy Asthma Proc. 2001;22:133–137
  61. Aberle N, Gagro A, Rabatic S, Reiner-Banovac Z, Dekaris D. Expression of CD23 antigen and its ligands in children with intrinsic and extrinsic asthma. Allergy. 1997;52:1238–1242
  62. Kochman S, Bernard J, Cazabat A, Lavaud F, Lorton C, Liehn JC. Double phenotyping of immunoregulatory T cell subsets in patients with allergic asthma. Clin Allergy. 1987;17:579–588
  63. Wuthrich B, Schindler C, Leuenberger P, Ackermann-Liebrich U. Prevalence of atopy and pollinosis in the adult population of Switzerland (SAPALDIA study). Swiss Study on Air Pollution and Lung Diseases in Adults. Int Arch Allergy Immunol. 1995;106:149–156
  64. Wuthrich B, Schindler C, Medici TC, Zellweger JP, Leuenberger P. IgE levels, atopy markers and hay fever in relation to age, sex and smoking status in a normal adult Swiss population. SAPALDIA (Swiss Study on Air Pollution and Lung Diseases in Adults) Team. Int Arch Allergy Immunol. 1996;111:396–402
  65. Gern JE, Busse WW. The role of viral infections in the natural history of asthma. J Allergy Clin Immunol. 2000;106:201–212
  66. Martin RJ, Kraft M, Chu HW, Berns EA, Cassell GH. A link between chronic asthma and chronic infection. J Allergy Clin Immunol. 2001;107:595–601
  67. Zeibecoglou K, Ying S, Meng Q, Poulter LW, Robinson DS, Kay AB. Macrophage subpopulations and macrophage-derived cytokines in sputum of atopic and nonatopic asthmatic subjects and atopic and normal control subjects. J Allergy Clin Immunol. 2000;106:697–704
  68. Mehlhop PD, van de RM, Goldberg AB, Brewer JP, Kurup VP, Martin TR, et al.  Allergen-induced bronchial hyperreactivity and eosinophilic inflammation occur in the absence of IgE in a mouse model of asthma. Proc Natl Acad Sci U S A. 1997;94:1344–1349
  69. Ying S, Meng Q, Zeibecoglou K, Robinson DS, Macfarlane A, Humbert M, et al.  Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (intrinsic) asthmatics. J Immunol. 1999;163:6321–6329
  70. Humbert M, Ying S, Corrigan C, Menz G, Barkans J, Pfister R, et al.  Bronchial mucosal expression of the genes encoding chemokines RANTES and MCP-3 in symptomatic atopic and nonatopic asthmatics: relationship to the eosinophil-active cytokines interleukin (IL)-5, granulocyte macrophage-colony-stimulating factor, and IL-3. Am J Respir Cell Mol Biol. 1997;16:1–8
  71. Folkard SG, Westwick J, Millar AB. Production of interleukin-8, RANTES and MCP-1 in intrinsic and extrinsic asthmatics. Eur Respir J. 1997;10:2097–2104
  72. Kimura M, Tsuruta S, Yoshida T. IL-4 production by PBMCs on stimulation with mite allergen is correlated with the level of serum IgE antibody against mite in children with bronchial asthma. J Allergy Clin Immunol. 2000;105:327–332
  73. Walker C. The immunology of extrinsic and intrinsic asthma. Agents Actions. 1993;43:97–106
  74. Bentley AM, Menz G, Storz C, Robinson DS, Bradley B, Jeffery PK, et al.  Identification of T lymphocytes, macrophages, and activated eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and bronchial responsiveness. Am Rev Respir Dis. 1992;146:500–506
  75. Kotsimbos AT, Humbert M, Minshall E, Durham S, Pfister R, Menz G, et al.  Upregulation of alpha GM-CSF-receptor in nonatopic asthma but not in atopic asthma. J Allergy Clin Immunol. 1997;99:666–672
  76. Christodoulopoulos P, Cameron L, Nakamura Y, Lemiere C, Muro S, Dugas M, et al.  TH2 cytokine-associated transcription factors in atopic and nonatopic asthma: evidence for differential signal transducer and activator of transcription 6 expression. J Allergy Clin Immunol. 2001;107:586–591
  77. Arnold V, Balkow S, Staats R, Matthys H, Luttmann W, Virchow JC. Increase in perforin-positive peripheral blood lymphocytes in extrinsic and intrinsic asthma. Am J Respir Crit Care Med. 2000;161:182–186
  78. Settipane RA. Demographics and epidemiology of allergic and nonallergic rhinitis. Allergy Asthma Proc. 2001;22:185–189
  79. Skoner DP. Allergic rhinitis: definition, epidemiology, pathophysiology, detection, and diagnosis. J Allergy Clin Immunol. 2001;108:S2–S8
  80. Cameron LA, Durham SR, Jacobson MR, Masuyama K, Juliusson S, Gould HJ, et al.  Expression of il-4, cepsilon rna, and iepsilon rna in the nasal mucosa of patients with seasonal rhinitis: effect of topical cortico-steroids. J Allergy Clin Immunol. 1998;101:330–336
  81. Sanchez-Guerrero I, Albaladejo MD, Garcia-Alonso AM, Muro M, Hernandez J, Alvarez MR. Soluble CD23 (sCD23) serum levels and lymphocyte subpopulations in peripheral blood in rhinitis and extrinsic and intrinsic asthma. Allergy. 1994;49:587–592
  82. Kato M, Hattori T, Ito H, Kageyama M, Yamashita T, Nitta Y, et al.  Serum-soluble Fas levels as a marker to distinguish allergic and nonallergic rhinitis. J Allergy Clin Immunol. 1999;103:1213–1214
  83. Wilde AD, Cook JA, Jones AS. The nasal response to isometric exercise in non-eosinophilic intrinsic rhinitis. Clin Otolaryngol. 1996;21:84–86
  84. Moneret-Vautrin DA, Hsieh V, Wayoff M, Guyot JL, Mouton C, Maria Y. Nonallergic rhinitis with eosinophilia syndrome a precursor of the triad: nasal polyposis, intrinsic asthma, and intolerance to aspirin. Ann Allergy. 1990;64:513–518
  85. Sobol SE, Christodoulopoulos P, Hamid QA. Inflammatory patterns of allergic and nonallergic rhinitis. Curr Allergy Asthma Rep. 2001;1:193–201
  86. Fokkens WJ. Thoughts on the pathophysiology of nonallergic rhinitis. Curr Allergy Asthma Rep. 2002;2:203–209
  87. Ghaffar O, Laberge S, Jacobson MR, Lowhagen O, Rak S, Durham SR, et al.  Il-13 mrna and immunoreactivity in allergen-induced rhinitis: comparison with il-4 expression and modulation by topical glucocorticoid therapy. Am J Respir Cell Mol Biol. 1997;17:17–24
  88. Shiomori T, Yoshida S, Miyamoto H, Makishima K. Relationship of nasal carriage of Staphylococcus aureus to pathogenesis of perennial allergic rhinitis. J Allergy Clin Immunol. 2000;105:449–454
  89. Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J Allergy Clin Immunol. 2001;107:607–614
  90. Smith SJ, Jones NS, Shakib F. The prevalence of IgG1 and IgG4 autoantibodies to IgE in patients with allergic and non-allergic rhinitis. Clin Otolaryngol. 1995;20:540–543
  91. Berger WE. Monoclonal anti-IgE antibody: a novel therapy for allergic airways disease. Ann Allergy Asthma Immunol. 2002;88:152–160

☆ This work has been supported by a grant from the Deutsche Forschungsgemeinschaft DFG FOR 423 and NO454 1-1.

☆☆ Reprint requests: Natalija Novak, MD, Department of Dermatology, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.

PII: S0091-6749(03)01461-1

doi:10.1067/mai.2003.1595

The Journal of Allergy and Clinical Immunology
Volume 112, Issue 2 , Pages 252-262, August 2003

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