Although the original term atopy provides a general framework of understanding about allergic clinical conditions, this big umbrella now includes a group of patients who have heterogeneous clinical and laboratory-defined characteristics. Similarly, atopic dermatitis , the skin atopy, characterizes a group of patients with heterogeneous clinical and laboratory-based findings.
Since the immune milieu in children is a dynamic system, atopic dermatitis manifested in childhood may have a different pathomechanism than those occurring in adulthood.
The intrinsic subtype of atopic dermatitis, with its absence of an elevation in serum immunoglobulin E (IgE), may differ from the extrinsic subset of atopic dermatitis in pathophysiology, as IgE is a direct product of the important Th2 cytokine interleukin-4 (IL4).
The atopic dermatitis patients with filaggrin gene mutation may manifest skin disease differently than those patients with intact skin barrier proteins, since skin barrier defect favors easy entry of pathogens and allergens, leading to triggering of cutaneous inflammatory processes.
The potential pathophysiologic differences of onset age, IgE, and skin barrier protein mutation, together with varied clinical responses to targeted immune modulators, point to the need for redefining atopic dermatitis or for defining specific subsets according to their verified pathomechanisms. Refining atopy will facilitate more accurate and personalized management of atopic dermatitis.
In this chapter, we intend to discuss redefining the term atopy . Before we begin the process, however, we should first clearly delineate the meaning of the original term. Thus we first ask, What is atopy? and What defines atopy?
According to Merriam-Webster Dictionary online, atopy (2019) is “a genetic disposition to develop an allergic reaction (such as allergic rhinitis or asthma) and produce elevated levels of IgE upon exposure to an environmental antigen and especially one inhaled or digested.”
Another definition of atopy provided by is “a personal and/or familial tendency, usually in childhood or adolescence, to become sensitized and produce IgE antibodies in response to ordinary exposure to allergens, usually proteins.”
The , an educational and training organization of nearly 7000 members of allergists and immunologists and a trusted information source for patients, states atopy is “the genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema). Atopy is typically associated with heightened immune responses to common allergens, especially inhaled allergens and food allergens”.
Historically, atopy was first described by Coca and Cooke in their article on the classification of hypersensitive phenomena. The term as they introduced it is derived from the Greek words a and topos , meaning “without” and “place,” respectively. They aimed to designate a terminology place for disorders such as hay fever and asthma ( ). While the abovementioned definitions provide a general framework of understanding atopy, detailed evidence, as delineated later in this chapter, points to a need to redefine or to subdivide this diverse group of patients who were currently categorized in the single and large disease entity of atopy. These challenging data include heterogeneous clinical manifestations, existence and nonexistence of skin barrier protein defect, presence and absence of elevated levels of serum IgE, different degrees of altered immune milieu, and favorable and unfavorable clinical responses to targeted immunomodulatory therapy. In this chapter we provide evidence to argue for such a need for redefinition or subdivision, with the focus on skin perspective.
Clear definition of atopic dermatitis
The current lack of uniform clinical definition and objective test that could unequivocally confirm the diagnosis of atopic dermatitis has led to significant differences in determination of disease prevalence, performance of prediction models, and risk factors ( ). The diagnostic criteria proposed by was deemed too complicated, and other diagnostic criteria were used in different geographic locations ( ). Since diagnostic criteria define disease entity, the effect of imperfect definition could result in misleading laboratory and clinical research data.
Childhood-onset versus adult-onset subsets
The immune system in childhood has many differences compared to that in adulthood ( ). First, some immune components are not fully mature during childhood. In particular, many changes occur during the first year of life ( ). Another difference is that adulthood, compared to childhood, has encountered more immune challenges and developed a lot more immune memories to these challenges, whether they are pathogenic or allergic in nature. As a result, the proportion of antigen-encountered lymphocytes becomes expanded in adults compared to that in childhood, which has a larger percent of naïve lymphocytes ( ). In addition, we must consider a naturally occurring immune cell “aging” process that renders immune cells more “permissive” later in adult life ( ). Immunologic parameter studies also point to a dynamic immune milieu occurring in infancy and childhood ( ). Some known differences between the childhood and adult immune milieu are depicted here. Newborns predominantly rely on maternal circulation-containing antibodies for their immune defense, but over the first few months of life their thymus pours out substantial amounts of T cells, which become various subsets over the next few years ( ). The CD4+ and CD8+ T cells in the peripheral blood increase from childhood to adulthood with an interesting decrease of B cells ( ). The reduction of peripheral B cells in adulthood may simply reflect a greater entry of those cells from peripheral blood into the solid lymphoid organs ( ). On the contrary, monocytes, NK cells, and regulatory T cells are decreasing from early childhood to adulthood ( ). The differences between childhood and adult immune milieu are manifested not only in cell number but also in cell function. The innate immunity in the early postnatal period, for example, is represented by NK cells predominantly in cytokine-producing mode rather than in cytotoxic activities ( ). Responses to toll-like receptor stimulation are lower early in life ( ). IL10, one of the Th2 cytokines important in atopic dermatitis development, is higher in early infancy. Interestingly, the IL10 level decreases to a level below the adult’s during infancy but then increases again until it reaches adult level ( ). So in theory, immune-mediated diseases that have onset during childhood differ from those that have onset during adulthood in terms of the immune system’s ability to handle certain challenges and how the immune system responds to challenges, at least from an immunologic perspective. Even if childhood atopic dermatitis persists into adulthood, the different adult immune milieu could still modify the disease to some extent. Therefore appropriate treatments for childhood-onset disease may need to tailor-suit the immature and dynamic nature of immune milieu in the childhood, and the same for the adult-onset disease.
Intrinsic versus extrinsic subsets
Although, historically, all patients affected by atopic dermatitis are considered uniformly extrinsic, with a common finding of elevated serum IgE level, subsequently the concept of intrinsic atopic dermatitis, which characterizes a subgroup of patients who do not have abnormally high total serum IgE level or antigen-specific IgE, emerges ( ). The robustness of this intrinsic form of atopic dermatitis is unsettled. While some academicians have named this intrinsic form of disease “nonallergic atopic dermatitis” or “atopiform dermatitis,” other academic physicians did not utilize the same criteria to define this subtype of dermatitis in their clinical investigations ( ). Some academic physicians argued that this intrinsic form of skin inflammation may not necessarily be atopic at all and that the term atopiform dermatitis would be more appropriate since atopiform will not indicate the disease as atopic or atopy, per se ( ).
Since the Th2 cytokine IL4 is a prerequisite for IgE production in humans and a high IgE level could point to an upregulation of IL4, patients with intrinsic atopic dermatitis and a normal level of IgE may not have a prominently altered immune system that manifests with IL4 upregulation ( ). So in theory, the patients affected by intrinsic atopic dermatitis may have had no altered internal immune milieu or have an altered immune milieu other than IL4 upregulation. From the clinical data, the intrinsic patients are primarily female and are the significant majority in infant atopic dermatitis ( ). On the genetic level, a higher percentage of patients with extrinsic atopic dermatitis have IL4/IL13 receptor polymorphism, whereas a higher percentage of patients with intrinsic counterpart have β 2 -adrenergic receptor polymorphism, probably implicating weakened adrenergic responses in intrinsic patients ( ). In a study completed in 2000, the phenotypes of epidermal dendritic cells between these atopic subtypes were found to have some differences. Specifically, the expression of Fc epsilon RI in CD1a+ dendritic cells of extrinsic atopic dermatitis is significantly higher than that of intrinsic counterpart ( ).
The study of in vivo cytokine mRNA expressions did indeed reveal some differences between the skin of patients with intrinsic atopic dermatitis, compared to that of patients with extrinsic atopic dermatitis. The number of dermal eosinophil infiltration and the cytokine levels of IL5, IL13, and IL1β were higher in the skin of extrinsic atopic dermatitis patients than that of intrinsic atopic dermatitis patients, although these cytokine levels from both groups of patients were higher than normal subjects without atopic dermatitis. Interestingly, IL4 and IL10, the two major Th2 cytokines involved in atopic dermatitis development, were equally elevated in the skin of both groups of atopic dermatitis patients compared to normal subjects without atopic dermatitis ( ). In addition, peripheral blood count of eosinophils, serum eosinophil cationic protein level, and IL5 were higher or more detectable in patients with extrinsic atopic dermatitis, compared to those with intrinsic atopic dermatitis, which further supports the eosinophil differential between these two subsets ( ).
Another study pointed out that intrinsic atopic dermatitis patients tend to have higher sweat concentrations of nickel and a correspondingly higher frequency of positive patch test to nickel, compared to the extrinsic atopic dermatitis patients. These intrinsic patients also have greater frequency of having cobalt allergy by patch test ( ). From the perspective of contact allergen reaction, it is probably not appropriate to name an intrinsic form of atopic dermatitis as nonallergic atopic dermatitis ( ). A study completed in 2013 showed that the patients affected with the intrinsic form of atopic dermatitis exhibited higher Th17 immune activation compared to those with extrinsic counterpart, although the Th2 immune activation is similar between the subtypes ( ). The presence of clinical and immunologic differences between these two subtypes of dermatitis suggests a somewhat different pathophysiology between them. However, to definitively sort out these differences, the academic community would need to reach consensus criteria on various subtypes to guide subsequent clinical and translational investigations that will lead to improved understanding of the disease. The differential characteristics between these two subsets are depicted in Table 2.1 .
|Characteristics||Intrinsic atopic dermatitis||Extrinsic atopic dermatitis|
|Onset||Mostly infant onset||Variable|
|Patient gender||Mostly females||Both males and females|
|Serum IgE level||Normal||Upregulated|
|Tissue eosinophilia||Less numerous than extrinsic||More numerous than intrinsic|
|Polymorphism||Lower percentage than extrinsic||Higher percentage than intrinsic|
|β 2 -Adrenergic receptor|
|Polymorphism||Higher percentage than extrinsic||Lower percentage than intrinsic|
|FcεRI in CD1a+|
|Dendritic cells||Lower upregulation than extrinsic||Higher upregulation than intrinsic|
|IL4 (skin)||Upregulated, equal to extrinsic||Upregulated, equal to intrinsic|
|IL10 (skin)||Upregulated, equal to extrinsic||Upregulated, equal to intrinsic|
|IL1β (skin)||Upregulated, lower than extrinsic||Upregulated, higher than intrinsic|
|IL5 (skin)||Upregulated, lower than extrinsic||Upregulated, higher than intrinsic|
|IL13 (skin)||Upregulated, lower than extrinsic||Upregulated, higher than intrinsic|
|Activation||Higher than extrinsic||Lower than intrinsic|
|Contact allergens||More frequent to nickel and cobalt than extrinsic||Less frequent to nickel and cobalt than intrinsic|