**1. Introduction**

212 Atopic Dermatitis – Disease Etiology and Clinical Management

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Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting between 10-20% of children and 1-3% of adults in the general population. It is associated with high morbidity and has major public health implications. AD is associated with hyper-reactivity of the skin to environmental trigger factors that are harmless in normal individuals. Major contributors to this hyperactivity are the many immune and inflammatory changes taking place in the skin and peripheral blood in AD individuals. AD can be classified into several subgroups, each with different immune and pathological features, suggesting a multifactorial disease and heterogeneity. Historically two types of AD have been identified. They include the "extrinsic or allergic" type of AD, which is characterized by Immunoglobulin E (IgE) mediated sensitization (immediate, type I hypersensitivity) and occurs in 70-80% of individuals. The "non-allergic or intrinsic" type of AD affects 20-30% of individuals and is defined by a more T-cell driven feature (delayed, type IV hypersensitivity), with low IgE levels and absent IgE sensitization. More recently a transition from the intrinsic to the extrinsic type has been reported in young children, and AD individuals can show a combination of above mentioned phenotypes or complete absence of the known features. The clinical diagnosis of AD does not cause major difficulties as there are fairly well defined criteria. Identifying the underlying pathophysiology for the affected individual can be more of a challenge, as there is no gold standard test available for AD and the AD individual might move from one pathophysiological "type" of AD to another. Clinically AD is divided into acute, subacute and chronic forms with correlated histopathological changes. The transition from one clinical form to another is fluent and can be very rapid. AD individuals frequently give a personal and or a family history of asthma and allergic rhinitis, the so called atopic triad. Exacerbation of one of the disorders in this triad can cause concomitant exacerbation of the other two suggesting some underlying common pathways and interdependence (Reitamo et al., 2008).

Predisposing factors for AD are multifactorial and involve genetic susceptibility, defects in skin barrier function, immune dysregulation, western life style and exposure to environmental trigger factors. The development of disease is an interplay of gene-gene and gene-environment interactions. The early age of onset and familial predisposition as well as the high concordance rate of AD in monozygotic (77%) and dizygotic (15%) twins suggest a

Trigger Factors, Allergens and Allergy Testing in Atopic Dermatitis 215

AD has a Th2 cell predominant immune profile in its active stage. Th2 cells produce IL-4, IL-5, IL-6, IL-13, which induce IgE production and activation of eosinophils, producing the acute signs and symptoms of AD. Genetic factors, reduced bacterial stimulation in early infancy and a disruption in skin barrier and function are thought to contribute to the Th1-Th2 cell imbalance of skin in AD. Eczematous skin lesions evolve as a result of complex interactions between IgE bearing antigen presenting cells, T cell activation, mast cell degranulation, keratinocytes, eosinophils, and a combination of immediate and cellular immune response. A number of environmental factors have been reported to induce and perpetuate this inflammatory response of the skin including food and aeroallergens, microbes and irritants. All four classic types of hypersensitivity reactions have been implicated in the pathophysiology of AD including pseudo allergy. They can occur either alone or in

AD is a common chronic skin condition associated with high morbidity and major public health implications. As prevention of disease is not yet a real option, reducing morbidity is main aim of treatment. Identifying the underlying pathophysiology of the individual's AD is very crucial. To date no standard test is available to diagnose AD. Sensitization to various allergens is a major part of triggering and perpetuating the inflammatory skin response in AD. Various tests have been developed to investigate the underlying type(s) of hypersensitivity reaction(s) involved in AD patients. None of the available tests so far have proven sensitive and specific enough to identify reliably relevance between clinical disease and test result. Precise understanding of these tests including their limitations together with accurate correlation of patient symptoms and signs are required in order to differentiate between allergy, intolerances and hypersensitivities, and achieve an appropriate clinical

Allergy tests commonly used in practice include measurement of total levels of IgE and allergen specific IgE levels in serum (radio-allergosorbent test/RAST), skin prick testing (SPT) and atopy patch testing (APT). A different positive predictive cut off point exists for each allergen tested respectively and similar test results do not imply a similar clinical

SPT is performed to detect the presence of allergen specific IgE to foods, aeroallergens, antibiotics and latex. A drop of a solution containing the allergen is applied to the skin and a lancet used to prick the skin. The allergen binds to IgE on mast cells causing degranulation and the release of histamine. This manifests as a weal and flare reaction, the diameter of which can be measured. SPT is easy to perform and results are immediately available. It can trigger off allergic reactions including anaphylaxis. Various medications including antihistamines, H2-antagonists, tricyclic antidepressants and neuroleptics can interfere with SPT and need to be withheld prior to testing. A positive SPT result indicates only sensitization and does not always equate to clinically relevant allergy. It must be interpreted in the context of clinical history, clinical signs and allergen exposure. The size of the weal does not necessarily correlate with severity of clinical reaction (Robinson & Smart, 2008 & Goodwin, 2008). The RAST detects free allergen specific IgE in serum. It is less sensitive and specific than SPT and is particularly useful where SPT is contraindicated. Testing is available for a wide range of food and environmental allergens. The RAST results are not affected by prior drug use and can be performed in patients with widespread skin disease. The RAST can be reported semi quantitatively as a score or as quantitative measurement by using the CAP RAST technology. The process involves an allergy-impregnated disc being incubated with patient's serum. Allergen specific IgE, if present binds to allergen. The disc is

combination in AD individuals (Reitamo et al., 2008 & Burns et al., 2004).

diagnosis (Robinson & Smart, 2008).

reaction to each allergen (Robinson & Smart, 2008).

genetically determined primary defect probably affecting the skin barrier thus playing a key role in the development of AD (Burns et al., 2004). The integrity of the skin barrier involves several components, including regulation of proteolysis of corneodesmosomes, the lipid lamellae and generation of natural moisturizing factor (MNF) from the breakdown products of the structural protein filaggrin. An imbalance of these components makes the epidermal barrier more susceptible to irritants, which in turn can lead to a disturbance of skin barrier function allowing penetration of microbes and allergens into the epidermis and dermis interdependence (Reitamo et al., 2008). In a recent meta-analysis filaggrin gene defects were shown to increase the risk of developing allergic sensitization, AD, and allergic rhinitis. The presence of filaggrin gene mutations correlated strongly with disease severity and treatment failure, and also increased the risk of asthma in AD patients (Van den Oord & Sheikh, 2009).

IgE is composed of two identical heavy and light chains, that form the constant Fc domain and the antigen-binding sites, through which the IgE molecule binds to its cell surface receptors. Raised serum IgE levels are most commonly seen in parasitic infections as a defensive response. IgE mediated hypersensitivity is largely regulated by T lymphocytes. AD is generally thought to be due to an imbalance between Th1 and Th2 cells, with a Th2 cell predominant immune profile in its active stage. Th2 cells produce interleukin (IL) -4, IL-5, IL-6 and IL-13, which induce IgE production and activation of eosinophils, producing the acute signs and symptoms of AD.

In general various cells contribute to the underlying pathomechanism of AD including Langerhans cells (LC), macrophages, T cells, B cells, keratinocytes, endothelial cells, eosinophils and mast cells. These cells communicate with each other in Th2 predominant cytokines as well as chemokines, prostanoids, proteases and reactive oxygen species products. High affinity IgE receptors play a crucial role in promoting this process.

A number of environmental factors can trigger and perpetuate the inflammatory skin cascade in AD including irritants, foods, aeroallergens, infection. All four classic Coombs' classification types of hypersensitivity (type I-IV) have been implicated in the pathophysiology of AD, including pseudo allergy. The hypersensitivity types can occur either alone or in combination in the AD individual. In the extrinsic type of AD high levels of specific IgE antibodies and raised total IgE levels in peripheral blood have been significantly associated with severity of dermatitis (Reitamo et al., 2008 & Burns et al., 2004).


**1. Introduction**

Understanding the structure-to-properties relationship is one of the most important problems in materials research. Thorough knowledge on structural arrangement namely in disordered systems like amorphous metallic alloys is essential for tailoring the functionalities, efficiency

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and performance of devices based on these materials. Because of their amorphous nature, these metallic alloys are often referred to as metallic glasses (MGs). Their suitable chemical composition ensures formation of crystallites that grow inside the amorphous matrix during thermal annealing and measure only several nanometres in size. Due to these dimensions, they provide beneficial magnetic properties in these the so-called nanocrystalline alloys (NCAs). At the same time, formation of nanograins stabilizes the whole structure against further thermal deterioration.

Changes in microstructure, crystallization behaviour, and magnetic states of NCAs have suggested that interface regions between nanocrystalline grains and the surrounding amorphous matrix play a significant role in propagation of ferromagnetic exchange interactions between the nanograins through the residual amorphous matrix. In order to understand the process of nanocrystallization, it is inevitable to study it in situ, that is, *during* annealing. For this purpose, we use in situ nuclear forward scattering (NFS) of synchrotron radiation. NFS provides information on changes in structural arrangement via hyperfine interactions in real time. In this respect, it is superior to other in situ techniques.

This contribution aims at providing insight into the studies of structural transformations that are taking place in iron-based metallic glasses exposed to elevated temperatures. Evolution of nanocrystalline grains during dynamical increase of temperature and isothermal annealing is discussed by the help of NFS technique. Before doing that, we provide brief description of MGs and NCAs. In addition, a short review of the methods used for their structural characterization is also offered. Prior to introducing the results of NFS investigations, basic principles of this method are presented, too.