Atopic dermatitis: from the genes to skin lesions (2000)

Atopic dermatitis (AD) is a common skin disease which has been known from antiquity. According to the Roman biographer Suetonius, the emperor Augustus suffered from this disease ( 1). The increasing incidence of allergic diseases in general, and especially AD, has recently focused public interest on these diseases. Numerous articles and books by nonmedical professionals, various self-help groups for all kinds of allergic diseases, and even dedicated news groups on the Internet are stressing this phenomenon. The direct cost to treat these disorders, as in the charges of medical professionals and the cost of medication, as well as the indirect socioeconomic cost, e.g., as a result of lost working days, has been calculated to be several hundred million dollars every year in the US and the UK ( 2, 3), and the annual cost to society was put at 7 billion Deutschmarks in Germany ( 4). Despite intensive research and significant progress in the field of immunodermatology, a unifying pathogenetic concept of AD has still not been established. The term “atopy” was coined by Arthur Fernandez Coca and Robert Cooke in a paper, published in 1923, “On the classification of the phenomena of hypersensitivity” ( 5). In general, the atopic diathesis describes a certain morbid susceptibility to hay fever, asthma, and AD but is not regarded as a disease entity in itself. Since atopic subjects develop their diseases at some particular point during their lifetime, it is widely accepted that latent atopy derives from a complex genetic background. Unfortunately, we have no exact marker of atopy. Since the term “atopy” is clinically meaningful and useful, it is widely used in clinical medicine throughout the world. However, there is no generally accepted precise definition of atopy ( 6). During the last 10 years, some excellent textbooks ( 7, 8) and review articles ( 9–12) on the clinical and pathogenetic aspects of this condition have been published. New approaches, which may become important for our understanding of the disease ( 13, 14), as well as novel therapeutic strategies ( 15–17), have evolved in the last decade of the 20th century. This review touches on clinical and therapeutic aspects, but focuses on the current knowledge of the genetic background and immunopathogenesis of AD. AD is a chronic inflammatory skin disease with a wide variety of clinical manifestations. Regardless of the patient's age, mild to severe erythema, scaling, and excoriations that reflect the severe itch are generally present. The distribution pattern of the skin lesions changes during the patient's lifetime from more generalized eruptions with oozing and crusted lesions to the adult distribution pattern of flexural eczema with lichenification and a scaly, xerotic, dry uninvolved skin. This so called “dryness of skin” actually describes the reduced softness, smoothness, and water and lipid content of the skin surface ( 7, 18). The stigmata of an atopic constitution are features known to be characteristic of atopy. Dry skin (xerosis), hyperlinearity of the palms and soles, an infraorbital fold (Dennie–Morgan's sign), white dermographism, facial pallor, orbital darkening, thinning of the lateral part of the eyebrows (Hertoghe's sign), and a low hairline may help the clinician identify atopic patients with a single glance. However, these stigmata are more related to the atopic state and – with the exception of dry skin – are not specific for AD ( 19). A high serum-IgE level can be considered an immunologic stigma of the atopic constitution ( 20). Bacterial superinfection, mostly with Staphylococcus aureus, is the most common complication of AD. An appropriate antibiotic treatment reduces the amount of topical glucocorticosteroids needed to control this exacerbation of disease. A generalized superinfection with the herpes simplex virus, known as eczema herpeticum, or Kaposi's varicelliform eruption, is the most severe and feared complication of AD. Immediate antiviral chemotherapy and hospitalization are needed in most such patients. Widespread infection of AD lesions with human papilloma virus or the molluscum contagiosum virus, known as eczema verrucatum, or eczema molluscatum, are seen less frequently, mostly in younger patients. The diagnosis of AD is easy if the patient presents with lichenified flexural eczema; however, this is not the rule. A thorough history, together with a skillful allergologic workup, should lead to the identification of the individual triggering factors for each patient ( 21). At present, therapeutic options are based on proper skin care, avoidance of individual triggering factors, and transient anti-inflammatory treatment, depending on the actual skin status of the patient. If all disease features are present, AD has a highly characteristic phenotype. Incomplete or minimal disease forms are encountered frequently in clinical practice and lead to a wide gray area of cases that some dermatologists would label as AD and others would not. This may cause a major problem if results are to be compared between different investigators or even different centers. However, the clinical diagnosis of AD is usually much more reliable than the application of diagnostic criteria to an individual patient. Diagnostic criteria for AD have been proposed by several dermatologists. All of these have some major drawbacks, since they are either 1) not widely accepted; 2) too complicated for daily use; 3) too insensitive, because they do not detect mild disease forms; or 4) too unspecific, because they would, for example, identify nickel contact dermatitis in a patient with hay fever as AD. While highly specific criteria provide a good basis for definition of clinical trial populations, their usually low sensitivity makes them unsuitable for epidemiologic use. Essentially, the classical criteria proposed by Hanifin & Rajka in 1980 are still the most widely used to define AD study populations ( 22). The diagnostic criteria developed by Diepgen et al. ( 23) in Erlangen (Germany) seem to have a higher sensitivity and specificity but are not as widely accepted in the medical community. The UK working party's diagnostic criteria, established in Nottingham in 1994 ( 24), have been validated by the proposing authors ( 25). The attempt to validate these criteria by an independent group from Tehran (Iran) in a population sample of 416 patients revealed the high specificity but low sensitivity of these criteria, making them useful for clinical trials, but not for epidemiologic studies ( 26). The usefulness of the newly designed “millennium criteria” ( 27) has still to be confirmed. These criteria raise the issue of the “extrinsic” form, i.e., IgE-associated dermatitis, and the “intrinsic” form, i.e., dermatitis without increased IgE serum level (see below). In conclusion, the choice of the diagnostic criteria used in clinical trails and epidemiologic studies may have a substantial influence on the results. Approximately 20% of patients suffer from a skin disease which clinically resembles the skin lesions and distribution pattern of AD, but is not associated with elevated total serum IgE levels and does not exhibit sensitization to environmental or food allergens. Therefore, the pathogenesis of this “intrinsic” AD (IAD) ( 28) seems to be different from that of the disease known as classical, or “extrinsic”, AD (EAD). Diagnostic criteria for IAD have not formally been proposed, but, according to Wüthrich (personal communication) and our own understanding, these should run as follows: a clinical phenotype of AD, fulfilling the diagnostic criteria of Hanifin & Rajka ( 22) low or moderate total serum IgE levels (<200 kU/l) in combination with negative in vitro IgE screening for aeroallergens and food allergens (e.g., SX1-RAST and SX-5 RAST), as well as negative prick test results for standard aero- and food allergens absence of other atopic diseases such as allergic rhinoconjunctivitis or allergic bronchial asthma. Hence, patients may initially be suspected to have IAD, but during the allergologic work-up they may need to be reclassified as having EAD. Recent immunodermatologic investigations show differences in T-cell cytokine secretion, immunohisto-logy, and the immunophenotype of the epidermal dendritic cells between EAD and IAD ( 29, 30). This argues strongly against the hypothesis ( 14) that a mere replacement of aeroallergens by the recently characterized autoantigen Hom s 1 is the basis for IAD. Several epidemiologic studies by different groups have clearly shown the increasing incidence of AD ( 31–34). Furthermore, there is evidence of a higher incidence of AD in second than firstborn children ( 35). This may be causally linked either to the birth rank or to the age of the mother. There is much discussion of the beneficial effects of breast-feeding, but there is no conclusive evidence of this effect from the epidemiologic data available ( 36–39). More recent studies indicate that the most important risk factor for the development of AD is the “Western lifestyle”, although we do not know exactly which factor of our sociocultural behavior is relevant to disease development ( 40). The immunohistology of AD is stage dependent and includes spongiosis, epidermal hyperplasia, thickening of the papillary dermis, and parakeratosis, as well as a superficial perivascular inflammatory infiltrate. An unequivocal diagnosis of AD by histologic means alone is difficult for the following reasons: there is already uncertainty about the clinical aspect of the primary lesion scratching and prolonged rubbing of the pruritic skin results in various secondary histologic changes the histopathology of AD shares certain similarities with contact, nummular, and dyshidrotic dermatitis ( 41). Therefore, many authors tend to regard the histologic findings of clinical lesions in AD as nonspecific ( 42, 43). However, epidermal dendritic cell phenotyping, a recently standardized technique based on the flow cytometric analysis of epidermal single-cell suspensions from inflammatory skin lesions, has the advantage of high sensitivity and specificity in combination with the potential to analyze individual skin lesions ( 44, 45). This method is based on the immunophenotype of the two CD1a-positive epidermal cell populations present in inflammatory human skin; namely, Langerhans cells and inflammatory dendritic epidermal cells (IDEC) ( 46). Pathophysiologic puzzle of atopic dermatitis. Circled letters refer to respective pathophysiologic aspects, corresponding to discussion under lettered headings in text. Most of the clinical aspects of AD involve components of the skin immune system. This system may be regarded as the interactive network of all cells and signals that are either resident in the cutaneous environment (static component) or are actively recruited into the skin during inflammatory processes (dynamic component) ( 47, 48). AD has been shown to occur in a previously nonatopic patient after allogenic bone-marrow transplantation ( 49). This key case indicated that a bone-marrow-derived cell plays a pathogenetic role in the formation of AD lesions. An overview of the different pieces from the pathophysiologic puzzle of AD is given in Fig. 1, and the single components will be discussed in the following subsections. There is no doubt of the genetic background in the pathogenesis of AD ( 50). The many genetic studies on AD published have been recently reviewed ( 51). These may be classified into two different approaches: linkage analysis studies and candidate gene studies. The former aim to detect an association of the AD phenotype with any of the chromosome regions. To detect associations with polymorphisms of previously unknown genes, such studies need high numbers of investigations. On the other hand, the candidate gene studies investigate the association of gene polymorphisms of a specific gene with the atopic phenotype ( Table 1) . They are restricted to the investigation of a single, already known gene locus but are easier to perform in limited numbers of patients. Most of these studies focus on components of the skin immune system, such as cytokines or cell-surface receptors. As is the case with many other diseases, HLA-type combinations have been identified with increased frequency in either elevated IgE levels or specific atopic disorders ( 52). However, in subsequent studies, a cosegregation of these markers could not be demonstrated ( 51). This may have been due to the heterogeneous causes of the atopic diseases. In 1968, Szentivanyi proposed his “beta adrenergic blockade theory of the atopic abnormality” ( 53), with reference to a pulmonary atopic disease phenotype with the respective gene located at 5q32–q33. Some reports agree with this hypothesis, but newer data suggest that alteration in the β-adrenergic system is a consequence rather than a cause of respiratory atopic disease ( 54). The association of a gene locus on 5q, encoding the IL-4 gene cluster, has been reported to be associated with the total serum IgE level ( 55), but this could not be confirmed by other investigators ( 56). The gene locus 11q13, a region encoding for the β chain of the high-affinity IgE receptor FcεRIβ, has been linked to the AD phenotype by the studies of Cookson et al. and other groups ( 57, 58). However, this association failed to be confirmed by studies in Japan and the UK ( 59, 60). A gene which has been thought to be specifically linked to AD, but not to other atopic diseases, is that of the mast-cell chymase, encoded at 14q11.2 ( 61, 62). However, this association could not be confirmed by another Japanese study ( 63). In 1998, linkage analysis showed a gene encoded at 16p11.2–12 to be linked to the total serum-IgE level ( 64). This gene region is the location of the IL-4-receptor gene alpha, which is located at 16p11.2–12.1 ( 65). Initially, it was suspected that a mutation putatively leading to increased IL-4 receptor activity (Q576R) could be responsible for elevated IgE secretion ( 66). However, subsequent analyses have shown that polymorphisms affecting at least four different amino acids in the cytoplasmic domain of IL-4Rα may significantly influence the outcome of IL-4 receptor signaling and consequently IgE secretion ( 67). In conclusion, there are numerous reports of associations between gene loci and atopic disease, but contradictory results have frequently been published by groups after the of a newly identified In these reports are mostly related to IgE and less frequently to respiratory disease, and are specific to the cutaneous of AD. it been that atopic patients may have a in the of in reduced levels of demonstrated in the of atopic and a was proposed as the basis of atopy ( other studies, a recently published study could not this activity in allergic ( The activity of from AD patients is higher than that in nonatopic leading to a level of and consequently a higher formation of the in the patients ( has been shown to and to the IL-4 of cells ( These studies, in are in good with the clinically relevant immune of AD patients but do not the phenotype of cutaneous atopic disease. Furthermore, clinical topical have shown but not of skin lesions ( The of human based on their cytokine secretion into the and is generally cells may be to of the following secretion cells and and cells IL-4 and On a clinical secretion are associated with such as the the secretion pattern is associated with such as allergic ( AD is associated with an immune immune in the of a certain susceptibility to skin such as skin common or molluscum If these immune the basis of AD, the phenotype of the cutaneous atopic disease would be lesions. However, the phenotype of AD resembles a corresponding to contact dermatitis i.e., it rather resembles a skin disease. of cells has been in AD lesions ( a pathophysiologic role for cells in this disease. Furthermore, it has been shown that cells may be an of IL-4 in the lesions, a cytokine which may the cells in a ( An increased of cells anti-inflammatory activity have been demonstrated in skin of AD and eczema ( and may be to the mast-cell proposed as a candidate gene for AD. During their of the of the The of this epidermal is even in the clinically uninvolved skin of AD as may be seen in the increased water However, it is this of the epidermal is the cause or the result of the atopic disease ( 18). it has in AD patients have an that these clinically most important In this an of by from AD patients has been shown in to and gene and in atopic and control could be reduced by ( Furthermore, from from AD, together with could and of into dendritic cells ( of by may to the and of AD in to the increased and of the dendritic of allergens has been considered a key in the pathogenesis of AD ( this of cells in the of their to This known as or has been shown to be by different research groups in different cell ( IgE are the between the IgE and the Recent research on the identification and of IgE on the cell surface of the cells has to the identification of different IgE on the cell surface of human epidermal Langerhans namely, the IgE receptor ( the high-affinity ( and the ( Therefore, seems to be the most and relevant ( the of allergens to cells may be to high of This IgE may in to the on the a of flow cytometric has demonstrated a significant of on the epidermal dendritic cells from skin in AD ( 46). the Langerhans a second cell population this Langerhans could be demonstrated the by and ( 46). The immunophenotype and of the cell the have been characterized ( but and are still under Since a of the in of Langerhans cells and could be demonstrated ( and cell have been shown to on their cell surface ( a of may be is to that not ( but which are the relevant cell the the immune during their of the skin into a immune The or flow of aeroallergens or ( 14) into the of may define the pathophysiologic basis of the or of AD frequently seen in patients. The application of aeroallergens such as in the recently standardized atopy test ( that it is to skin lesions by application of aeroallergens to the skin. on the of AD, the need for an identification of the individual factors in each patient for diagnostic based on the IgE ( 21). of and various may be after a thorough prick test and in vitro IgE diagnostic AD patients frequently are by in the exacerbation of skin lesions, may be from most of these skin lesions, and many of these are of ( On hand, these are as in the of the complex to the respective On the other hand, the the complex and are of the complex to all cells with the of their these as well as T-cell lead to signals the of the skin immune system, the of of from this clearly the effect seen in an antibiotic or topical treatment of AD. Since the oozing skin lesions of the AD patients provide for these this may be relevant to the of the AD lesions. clinical that factors, such as are important in exacerbation of AD. On the other hand, of the disease has been in patients after from a such as a dermatologists are to the exact of between the system and the immune system. is a and that are associated with Langerhans cells the human have shown that may the by Langerhans cells ( Therefore, may have effects in Furthermore, it has been shown that under appropriate i.e., which in seem to the secretion of ( These may be in negative signals the inflammatory in the skin. with a inflammatory and immunologic which have recently been reviewed ( are and However, the exact of the are still under There is no known of AD as However, individual skin lesions may be by a variety of topical treatment of the dry skin in AD with is for the patient but are frequently by and the patients is of the to patients not to this of the skin lesions have application is still the reference standard of anti-inflammatory This is due to the of topical glucocorticosteroids in AD the avoidance of a the wide variety in the therapeutic of the as well as of the which as therapeutic is frequently in AD, a and therapeutic to the topical The is as but should be restricted to the more severe forms in adult patients due to the potential of this therapeutic The therapeutic of is to that of but the is and the are still may be a for some but due to the high and of treatment, this should be limited to severe cases ( of human have been in a of patients and not show any ( A highly topical treatment of AD are the recently developed topical of ( The key ( as well as the ( has been shown to be in the control of AD, and clinical with ( and ( as well as a study with ( have been in this disease. AD is the clinical basis for a of research The results of epidemiologic investigations in the and the of AD will be of The role of in the and of the inflammatory skin lesions is under clinically research will be needed to our current knowledge of in this disease.