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Eosinophils and Airway Inflammation | OMICS International

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Respiratory diseases associated with the presence of eosinophilia include, asthma, rhinitis, chronic rhinosinusitis, nasal polyposis, ASA triad Acetil Salicilic Acid aspirin triad: The airway inflammation mediated by eosinophils appears in a metachronou s form in the superior and inferior airways during the chronic phase of the disease [ 4 ].

Regarding the treatment of airway and other eosinophil mediated diseases, is of high interest to know that current data suggest that deficiency of eosinophils is not associated with any characteristic abnormality. So, the reduction of eosinophils appears to have no characteristic ill effects on normal health, and monoclonal antibodies that deplete eosinophils have the potential to be widely employed in the treatment of eosinophil-associated diseases [ 5 ]. Asthma Asthma is a chronic inflammatory disease of the lower airways, characterized by hyper-reactivity that is translated into bronchial constriction episodes and increased secretions in response to one or more trigger factors.

Classically, asthma can be classified into two groups: Eosinophilia is characteristic of the two types of asthma, both in tissue and in exudates, so it is thought that eosinophils play an important role in its pathogenesis. In eosinophilic asthma refractory to treatment with corticosteroids, treatment with anti-IL5 antibody reduces asthma exacerbations together with a corticosteroid-sparing effect [ 7 ].

In the majority of asthmatic patients there is an increasing amount of eosinophils, both in the tissue and in the secretions, and the degree of eosinophilia is related with the degree of the symptoms. These cells have also been implicated in the underlying mechanisms of tissue remodeling in asthma and in chronic rhinosinusitis [ 9 ]. The association between asthma and chronic rhinosinusitis with nasal polyps CRSwNP is more frequent in patients with higher tissue eosinophilia, and the disease is more severe, both in the upper and lower airways [ 10 ].

Corticosteroids are probably the most effective treatment for airway inflammation with eosinophilia. No wonder that several studies have shown that sputum eosinophilia is associated with a favorable response to treatment with corticosteroids in both asthma and chronic obstructive pulmonary disease COPDand tailored strategies aimed to normalize sputum eosinophils have resulted in a significant reduction of the exacerbation rates [ 11 ].

Rhinosinusitis Eosinophils are possibly the most important inflammatory cells in the pathogenesis of CRSwNP [ 12 ] and eosinophil degranulation is the mechanism by which these cells exert their inflammatory action.

Cytolysis and piecemeal degranulation are the principal degranulation modes of eosinophils in nasal polyposis, in contrast to apoptosis, which is very infrequent. Nasal polyposis shows a correlation between the eosinophil degranulation mode, the clinical and radiological stage and the degree of tissue eosinophilia of the case of origin [ 13 ]. In the case of CRSwNP, but also extrapolated to other eosinophilic inflammatory diseases, chronicity could result from the creation of a micro-ambient in the affected tissue as well as from the autocrine capacity of the cells involved [ 14 ].

Nasal polyposis could be an inflammatory reaction, self-perpetuated by growth factors and cytokines produced within the same polyps, which would create a micro-environment that would extend the life of the eosinophil and where it would be available to participate in immune reactions with structural cells, such as epithelial cells and fibroblasts.

In normal conditions tissue eosinophils are programmed to die by apoptosis within a few days, but some cytokines can inhibit this process. For example GM-CSF is produced in significant amounts in nasal polyps [ 15 ], where it can prolong the survival, proliferation, differentiation and activation of granulocytes. The rhinosinusal polyposis can be initiated by an immunologic recognition error [ 17 ]. Fungus or bacteria, which are not normally pathogenic, could generate an inflammatory process in which eosinophils predominate, that might result in the formation of a micro-environment, where autocrine cell effects can provoke the perpetuation of the inflammatory process.

A key function of the eosinophil is related to its involvement in immunity to parasitic helminths. The nasal mucosa seems to react as it would do it if it was colonized by parasitic worms. The immunologic error provokes the release of cytokines and chemokines that recruit eosinophils, setting up a local eosinophilic inflammatory reaction. The eosinophils arrive from the vessels, travelling throughout the chorion, reaching the epithelium and finally arriving to the mucosal surface, without finding parasites.

Although the majority of them are cleared with mucociliary clearance, some of them release their cytotoxic granule proteins generating more inflammation and leading to the chronicity of the symptoms. Clinically, the eosinophilia in tissues and in polyp exudates correlates with the severity of the disease and to polyp resurgence following surgical excision [ 1318 ].

In this disease, the colonization of the nasal mucosa by bio-films is also related with severity, although the precise pathogenic mechanism is not known with certainty. The possibility that the evolution of NARES could be driven by nasal polyposis-related genes was not confirmed by an epidemiologic study [ 20 ], although occassionally micropolyps are observed in NARES.

The pathogenic mechanism could be initiated by an alteration in the regulation of the autonomous nerve system in the nasal mucosa, which would then introduce neurogenic inflammation that would facilitate eosinophil migration.

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Epithelial damage may stimulate the sensitive unmyelinated nerve fibers resulting in the release of P substance by an antidromic reflex. The newly recruited eosinophils in the epithelium would release further quantities of cytotoxins and pro-inflammatory substances, thereby maintaining and amplifying the inflammation [ 21 ]. Eosinophilic Fungal Sinusitis or Allergic Fungal Sinusitis The eosinophilic fungal sinusitis or allergic fungal sinusitis shows histological resemblance with allergic bronchopulmonary aspergillosis.

Sinusitis due to aspergillus infection of the sinus maxillary was described by Millar in [ 22 ] and Katzenstein inwho observed the presence of groups of necrotic eosinophils, crystals of Charcot-Leyden and noninvasive fungal hyphae in the sinus mucosa of patients affected by chronic sinusitis [ 23 ], designating it as allergic sinusitis by aspergillus. It was thought that it was a pathology mediated by IgE, in response to diverse fungi mainly aspergillus, that can proliferate in the eosinophilic sinus mucosa.

The theory was supported by the observation of specific IgE in the crops. Today the most accepted hypothesis excludes an allergic factor and suggests the importance of eosinophilic fungal sinusitis [ 2425 ]. This is based on the negative results of the skin-prick test observed in many of these patients.

Because eczema and food allergy can co-exist in infants, it is also unclear whether the observed association is related to co-manifestation of other allergic conditions such as eczema and allergic rhinitis that predict asthma or if it is a consequence of food allergy itself. It is important to have large population-based prospective cohorts to include food allergy as a baseline outcome to further investigate whether food allergy truly represents an initial step of the atopic march in infants with shared environmental and genetic determinants or whether it is an independent predictor.

Animal Models Supporting the Atopic March Environmental and genetic studies provide evidence that a defect in epithelial barrier integrity may contribute to the onset of AD and progression of the atopic march. Many studies in animal models demonstrate that epidermal barrier dysfunction can be caused by repeated sensitization to allergens to the skin, which leads to phenotypes of AD systemic sensitization and increased risk of allergic rhinitis lung inflammation and airway hyperresponsiveness [ 4243 ].

A study in a mouse model showed that epicutaneous aeroallergen exposure induces systemic Th2 immunity that predisposes to allergic nasal responses, suggesting that the skin is a potent site for antigen sensitization in the development of experimental allergic rhinitis [ 44 ].

In addition, the progression from AD to asthma in mice is supported by the data that epicutaneous sensitization with ovalbumin induces localized AD and airway hyperresponsiveness to methacholine after challenge with aerosolized ovalbumin [ 43 ].

Indeed, murine models have shown that epicutaneous exposure to ovalbumin and peanut after the removal of the stratum corneum induces a strong systemic Th2 immune responses characterized by elevated IL-4 secretion by T cells from draining lymph nodes and high levels of allergen specific IgE and IgG1 [ 3845 ]. However, its role in the atopic march in humans remains to be defined. TSLP, when overexpressed by skin keratinocytes, is a systemic driver of bronchial hyperresponsiveness and its deletion prevents the atopic march from occurring, suggesting that keratinocyte-produced TSLP may be involved in the link of AD to asthma [ 50 ].

Trefoil Factor 2 is another mediator with important functions in epithelial barrier function and repair that rapidly induces IL during allergic asthma. A possible role of IL in the atopic march is supported by a study showing that ovalbumin inhalation by epicutaneously-sensitized mice induced expression of IL and bronchial hyperreactivity, which are reversed by IL blockade [ 42 ].

Patients with AD have a unique predisposition to colonization or infection by Staphyloccous aureus. We and others showed in murine models of AD that when combined with allergens, SEB has an additive and synergistic effect on driving cutaneous eczematoid skin changes [ 5960 ] and promotes airway hyperreactivity and lung inflammation upon allergen challenge [ 59 ]. Potential Mechanisms and Speculations Underlying the Atopic March Previous approaches to understanding AD have centered on mechanisms in the adaptive immune system, often with an emphasis on the Th1-Th2 paradigm.

The conceptual focus has been increasingly shifting to include a primary defect in the epithelial barrier as a threshold event in AD. The epidermis provides an essential attribute to the integrity of the occlusive interface barrier, restricting both water loss from the body and ingress of pathogens. This barrier is formed after complex and integrated biochemical events. Epithelial keratinocytes replace their plasma membrane with a tough, insoluble layer termed the cornified envelope to achieve and maintain this barrier to prevent infectious agents and allergens from gaining access to the body.

The lack of dermal integrity is clearly an important part that begins allergic sensitization in the atopic march. Another theory is that lack of exposure to microorganisms helps facilitate an allergic phenotype. These findings support the hygiene hypothesis and pinpoint the importance of the dermal microbiome in the development of allergy and asthma [ 61 ]. Although it has become evident that the mechanisms by which allergen exposure occurs through impaired skin barriers can initiate systemic allergy and predispose individuals to AD, allergic rhinitis, and asthma, the cause of AD remains incompletely understood, and the mechanisms of the atopic march are still largely unknown.

Skin Barrier Defects in AD and the Atopic March The epidermis functions as a primary defense and biosensor to the external environment. Skin barrier defects promote easy entry for pathogens, allergens and other environmental insults such as toxins, irritants, pollutants and are now considered the primary mechanism of development of AD [ 62 ].

The skin barrier function is impaired in AD as a consequence of multiple abnormalities responsible for the barrier defect including reduced lipids ceramide and sphingosine and abnormal keratinization due to dysfunctional filaggrin, a critical component in the cornified envelope formation [ 63 - 68 ].

Clinically the disrupted skin barrier is supported by the increased transepidermal water loss TEWL observed in both lesional and nonlesional skin [ 626970 ]. AD keratinocytes have an aberrant response to environmental triggers and are able to produce a unique profile of cytokines including IL, TSLP, and chemokines that promote Th2 predominant inflammatory responses in acute AD lesions followed by chronic AD characterized by prominent Th1 inflammation [ 72 ].

Studies have also demonstrated exaggerated expression of IL and IL in both acute and chronic lesions of patients with AD [ 74 ]. Both Th2 and Th22 cytokines inhibit epidermal differentiation and thereby contribute to the reduced filaggrin expression and anti-microbial peptide production which leads to increased susceptibility to S. Respiratory infections such as RSV bronchiolitis can also predispose to wheeze, and because prophylaxis with pavlizumab is associated with reduced frequency of subsequent childhood wheezing, bronchiolitis seems to have a causal effect [ 51 ], suggesting respiratory and skin infections play a role in atopy development.

The dysfunctional skin barrier in atopic dermatitis predisposes patients to early infection and allergic sensitization. Studies show that resultant aeroallergen sensitization is associated with asthma, and one study showed that positive skin prick tests to house dust mite in children 1 or 2 years of age predicted wheeze at age 12 years. Children with AD, wheeze, or both who were sensitized to house dust mite were also at greater risk for wheeze at age 12 than those who were not sensitized, respectively [ 86 ].

Findings from the German Multicenter Allergy Study found that allergic rhinitis until the age of 5 years is associated with wheezing between the ages of 5 and 13 years, though this association was not attributable to eczema, perhaps because early allergen sensitization occurred through another mechanism [ 87 ].

Interestingly, one study that showed that children with eczema before age 2 years have an increased risk of eczema in preadolescence, but more specifically, those children with eczema in their first year of life but not their second year of life, have a markedly lower risk of eczema in preadolescence than do other children with infantile eczema, in contrast to the view that early onset is associated with worse prognosis, but this group did have increased risks for asthma and rhinitis.

That group may represent a particular atopic phenotype, or perhaps the early treatment of eczema altered the risk of subsequent eczema, but not other atopic disease, possibly because early allergic sensitization through the impaired skin barrier already occurred [ 23 ].

Findings based on the TLH Study suggested that childhood eczema, especially in association with childhood rhinitis, is strongly associated with atopic asthma in middle age adults that is often still symptomatic.

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Role of Filaggrin Mutation in AD and in the Atopic March Many of the key structural proteins in the outermost layer of the epidermis involved in cornification are encoded for in a locus on chromosome 1q21, which is termed the epidermal differentiation complex EDC [ 89 ]. Genes found within this locus encode for filaggrin FLGa key member of the EDC, in addition to other proteins such as loricrin, involucrin, small proline-rich proteins, late envelope proteins, and the S calcium-binding proteins.

These genetic studies lend strong support to the role of filaggrin in the pathogenesis of AD and in the subsequent progression in the atopic march [ 91 ]. The FLG mutations are currently considered a major risk factor for AD, particularly in patients who have onset of AD at 2 years or younger [ 92 ].

One study found FLG mutations increased the risk of eczema and food sensitization but not clinical food allergy among 1-year-old infants, suggesting that decreased skin barrier function increases the risk of food sensitization, but other factors may be important in the development of food sensitization to allergy [ 93 ]. A longitudinal study evaluated the expected prognosis caused by FLG null mutations among a community-based, physician-diagnosed AD cohort receiving continuous care for almost 5 years, therefore allowing for the waxing and waning nature of atopic dermatitis.

In particular, those with the RX variant were unlikely to achieve symptom-free skin without topical treatment and were about two times more likely to use topical steroids during any 6-month interval as compared to all others in the cohort [ 94 ].

These studies not only demonstrate that FLG mutations increase the risk of eczema and sensitization, but also that clinical outcomes may vary by location of the FLG mutation and influence of other factors. One study showed a significant association of two filaggrin gene mutations with asthma and allergic rhinitis, but this association was only seen in subjects with the co-existence of AD and was not apparent in subjects without concomitant AD [ 67 ].

In addition, filaggrin has not been found to be expressed in the human bronchial epithelium nor beyond the inferior turbinates [ 9596 ]; hence, filaggrin mutations appear not to exert effects in the upper airway, suggesting that the association of filaggrin mutations with other atopic disorders is likely due to the common feature of allergen sensitization through the skin.

One study did find an association of FLG mutations with peanut allergy [ 97 ]. Although it is possible that some patients with peanut sensitization rather than true clinical allergy were included, this strong association persisted despite multiple variations in peanut allergy diagnostic criteria [ 98 ]. The association remained despite asthma status, and the presence of eczema strengthened the association though eczema did not seem to fully account for the association.

This study acknowledges that a dysfunctional skin barrier may play a role in the pathogenesis of peanut allergy, and thus supports the theory that sensitization in food allergy occurs in the skin in some patients [ 9798 ].

Peanut protein in household dust is biologically active and related to household peanut consumption, serving as a risk factor for the development of peanut allergy and as a possible nidus for transcutaneous peanut exposure to a young child with AD [ 99 ]. It is also possible that cross-sensitization with aeroallergens such as birch protein that share homology with peanut protein play a role in peanut sensitization in AD patients [ 98 ]. Oral exposure to allergen, versus transcutaneous exposure, is thought to be more tolerogenic.

However, intestinal permeability is increased in some patients with AD. It is unclear if this implies an additional route of allergen penetration. The extent of filaggrin expression in the gastrointestinal tract is currently unknown [ 9798 ]. There is experimental evidence to support the hypothesis that allergen penetration transcutaneously leads to systemic atopic response [].

The fact that asthma is found only in a subset of filaggrin mutation carriers with AD supports the hypotheses that asthma is secondary to allergic sensitization that occurs after epidermal skin barrier impairment. Filaggrin mutations seem likely to play a role in chronicity of disease and IgE sensitization in patients with AD. Studies show that patients with early-onset AD and filaggrin mutations have a tendency to have persistent disease into adulthood [ ].

AD patients carrying filaggrin mutations are significantly associated with the extrinsic form of the disease IgE-mediated sensitization to inhalant or food allergensand the development of allergic rhinitis and asthma [ 91, ]. The filaggrin mutations predisposing to asthma, allergic rhinitis, and allergic sensitization only in the presence of AD strongly support the role of filaggrin in the pathogenesis of AD and in the subsequent progression along the atopic march.

Clinical Analysis of Fractional Exhaled and Nasal Nitric Oxide in Allergic Rhinitis Children

Reduced expression of loricrin and involucrin, two cornified-envelope proteins, have been shown in the lesional skin of AD patients, which contributes to the skin barrier defects in AD [], and their expression was also down-regulated by Th2 cytokines [ ]. Experimental evidence for the hypothesis that antigens enter through an impaired epidermal barrier inducing systemic allergen-specific IgE responses is supported in mice with filaggrin frameshift mutation, analogous to human filaggrin mutation.

Epicutaneous application of allergen to these mice resulted in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of IgE antibody responses [ ]. Although genetic studies on filaggrin mutation indicate that defective barrier function plays an initial key role in the pathogenesis of AD in many patients, much is still unknown about the sequence of biologic and regulatory events that constitute the transition from an inherited barrier defect to clinical manifestations of eczematous dermatitis and susceptibility to related atopic disorders.

The filaggrin gene mutation leads to an epithelial barrier defect and reduced defense mechanisms that allow easy entry for pathogens, allergens and other environmental insults toxins, irritants, pollutants followed by polarized Th2 lymphocyte responses with resultant chronic inflammation.

Patients with ichthyosis vulgaris, an inherited dry, scaly skin disorder who have filaggrin mutations do not have apparent skin inflammation or infection, which are cardinal features of human AD [ ]. Therefore, additional factors may directly and or indirectly interact with filaggrin in the pathogenesis of AD. Conclusion Multiple lines of evidence clinical, genetic and experimental studies suggest that previous expression of AD is a prerequisite for the development of allergic rhinitis and asthma and specific sensitization, highlighting the importance of the epidermal barrier in the pathogenesis of these disorders.

The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma

Whether AD in the atopic march is necessary for progression to other atopic disorders remains to be defined. To establish a causal relationship from AD to airway allergic diseases, evidence of immunological mechanisms accounting for the association and randomized controlled trials demonstrating an effective intervention for AD with reduced subsequent asthma incidence are still needed.

It also is important to identify infants at risk for developing lifelong chronic atopic diseases and utilize the critical window of opportunity early in life for therapeutic intervention.