European Journal of
Review
Pediatrics
Eur J Pediatr (1992) 151 : 870-873
9 Springer-Verlag1992
Recent advances in the pathogenesis of atopic dermatitis H. P. Van Bever Departments of Paediatrics and Immunology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem-Antwerp, Belgium Received August 28, 1990 / Accepted after revision January 10, 1992
Abstract. Atopic dermatitis (AD) is an inflammatory skin disorder affecting 5%-10% of children. Although basic mechanisms remain largely speculative, recent studies on the pathogenesis have elucidated new insights, pointing to the importance of food and inhalant allergens. The pathogenesis of AD can be more easily explained by the model of late skin reaction occurring after mast cell activation. The present report highlights some of the more recent developments in the mechanisms of AD which can be important in understanding and treating this troublesome disease. Key word: Atopic dermatitis
Introduction Although atopic dermatitis (AD) is the commonest chronic skin disorder in children, its pathogenesis remains largely unexplained. It has been estimated that about 5%-10% of all children suffer at one time from AD, and there is evidence showing its frequency is still increasing [15, 31]. It is not yet known whether this is an absolute or a relative increase (the more attention is focussed on a disorder, the better it is defined). Studies in twins point to a hereditary disposition for the disease but expression of the genetic trait seems to be dependent on a multitude of environmental factors [18]. Observations derived from bone marrow transplantation have demonstrated the marrow as the site of the primary defect in AD [2].
Clinical presentation AD has no specific skin signs and comprises a number of atypical dermatological characteristics such as erythema, excoriation, scratching lesions, lichenification, and hypopigmentation [14]. Children do not have symptoms Correspondence to: H. P. Van Bever Abbreviations: AD = atopic dermatitis; DBPCPT = double-
blind placebo-controlled provocation test: FcER = Fc receptor for IgE; Lc = Langerhans cell
from birth, but they usually appear before the age of 3 months. The lesions appear before the age of I year in 80% of children and before 5 years in 90%. The most invariable symptom is pruritus which can sometimes be very intense and cause severe insomnia. The distribution profile of the disease varies with age and is characterized by the predominance of certain skin lesions. The diagnosis of AD is generally not difficult, but in some cases the symptoms are poorly defined. In this event the diagnostic criteria of Hanifin and Lobitz [16] are useful. The clinical course is characterized by variability and unpredictability. The asymptomatic intervals usually became extended as the child ages. It is estimated that in 60% of children with severe AD (requiring hospitalization), symptoms are still present at the age of 20. In 95% of milder cases, symptoms disappear around the age of 20. Several aspects of AD have particular clinical and social importance; these include cutaneous infections, common warts and molluscum contagiosum, ocular complications, contact dermatitis and, sleep disturbances and learning difficulties.
IgE-mediated hypersensitivity in atopic dermatitis Most AD patients also have atopic respiratory disease. Usually, the respiratory symptoms begin later than the skin symptoms and many clinicians have noted the peculiar and unexplained tendency for AD and asthma to alternate in their courses. This phenomenon is not constant, however, as both can flare together. The highest IgE levels can be detected in patients who suffer from both AD and asthma. It is not yet known whether there is a causal relationship between these high IgE levels and AD, or whether this is just an expression of the atopic constitution. In some patients, however, IgE is important in the pathogenesis of the AD symptoms, while in others it is not. The following observations have been made: 1. Increased total serum IgE has been recorded in 80% of patients. In addition, there is a correlation between total serum IgE and the severity of AD. 2. Positive prick tests and positive IgE to a number of inhaled allergens and food allergens are found in the majority of patients.
871 3. Positive familial antecedents of atopic diseases are found in 66% of patients. 4. Of subjects with AD, 50%-80% suffer also from asthma and/or rhinitis. The presence of specific IgE or a positive skin test to an allergen still does not mean that the AD lesions are triggered by this particular allergen. The prick test and the determination of specific IgE via the RAST are both known to yield frequent false-positive and false-negative results [25]. A possible explanation for the false-negative results is that the allergen can induce skin lesions by nonIgE-dependent mechanisms. A positive prick test corresponds to a clinically detectable allergy (by a provocation test) in only about 25% of AD patients, although in young children prick tests are frequently negative. The search for specific IgE offers no more diagnostic possibilities than the prick test. These two tests are comparable in specificity and sensitivity. If both RAST and prick test are used together in one patient, the diagnostic precision remains the same as for separate interpretation of each test. The anamnestic features usually contain insufficient information to establish a clear link between exposure to an allergen and the appearance of skin lesions. Parents often report their child to be "allergic" to a particular food, but when a provocation test is carried out, this food seldom seems to have any effect on the eczematous lesions. The opposite is often equally true: clearly positive provocation results are obtained by foods which the parents did not suspect. At the moment, the best method to demonstrate that an allergen triggers AD is the double-blind placebo-controlled provocation test (DBPCPT). In children with severe AD challenged by Sampson and McCaskill 63 children out of 113 (56%) showed positive reactions to food, using the DBPCPT [27]. Milk, eggs, and peanuts were responsible for 72% of the positive DBPCPT. In another study, on 25 children with severe AD, we could demonstrate, by DBPCPT, that foods are able to induce exacerbations of AD in 24 out of 25 of the subjects. In that same study it was also found that food additives, tyramine and acetylsalicylic acid were able to cause exacerbations of AD [32]. Skin biopsies of AD shows epidermal spongiosis and mononuclear cell infiltration of the dermis, suggesting a type IV hypersensitivity reaction. On the other hand, different studies point to the importance of IgE-mediated reactions in AD [26]. The relationship between IgE-mediated reactions and cellular infiltration has to be linked to the occurrence of the late cutaneous reaction (see below) [12]. For some years, it has been shown that IgE-mediated processes are able to induce two types of reactions: immediate reactions, characterized by the release of mast cell mediators, especially histamine, and most frequently appreciated in the skin as a wheal-andflare response, and late reactions characterized by the infiltration of different cells, especially eosinophils and lymphocytes. These late reactions have been described in the bronchi (asthma) [9], nose (rhinitis) [30], eye (conjunctivitis) [4] and skin [13]. At present, it is accepted by many investigators that AD is the natural occurring equivalent of a late cutaneous reaction, initiated
by mast cell degranulation. Theoretically, two types of allergens should be able to induce mast cell degranulafion: inhaled allergens and ingested allergens.
Inhaled allergens In a great number of patients with AD, positive reactions (prick test and specific IgE) can be found to many inhaled allergens. These reactions are not usually directly linked to the skin symptoms; they are merely a manifestation of an atopic constitution (i.e. the capacity to produce IgE against a variety of allergens). There is as yet no clear evidence that inhaled allergens trigger AD directly, after inhalation and IgE induction. There are, however, anecdotal reports of AD induced by inhaled allergens (e.g. after contact with pets or grass pollen). In a study by Platts-Mills et al., it was shown that AD improved by cleaning the patients' bedrooms [23]. On the other hand, it was demonstrated that inhaled allergens, applied epicutaneously by patch test, may penetrate the skin and induce eczematous skin lesions. These skin reactions which are delayed in time (positive 24 h-72 h after patch testing) did not occur in allergic asthma and allergic rhinitis and, therefore, seemed to be specific for AD [1, 5, 8, 11, 20]. Microscopy of the patch test reactions shows many similarities to the clinically involved skin of AD [21]. Therefore, inhaled allergens are believed to be involved only by direct contact in a number of patients with AD who have a concomitant allergy to inhaled allergens, especially to house dust mite. It is consequently reasonable to advise elimination of inhaled allergens (e.g. by removing house dust) in some patients with AD and a house dust mite allergy.
Food allergens As already mentioned, the strangest stories are told concerning food and AD. At the moment, the gold standard in diagnosing food allergy is the DBPCPT, as both anamnestic features and determination of a IgE-mediated allergy (by prick test or determination of specific IgE) frequently show false-positive and false-negative results [25, 27, 32]. In view of the fact that it is difficult to demonstrate the existance of a food allergy, the following rules and procedure are recommended: 1. Food is important as a triggering factor in children with severe AD (about 10% of all cases). The importance of food in children with mild AD is unknown. 2. Certain foods and food additives can induce AD by various mechanisms, some being IgE-mediated. 3. Prick tests and specific IgE determination are frequently false-positive and false-negative in AD. They may act as a guideline in defining the atopic state, but often they are useless as routine tests. 4. If the clinician relies on the results of prick tests and IgE determination, inadequate modifications of the diet will be prescribed resulting in poor compliance and ineffectiveness.
872 5. Since DBPCPTs are often impossible to perform, a trial diet is justified in some patients with severe AD, unresponsive to a simple standard therapy of lubricants, topical corticosterois and antihistamines. Such a trial diet should be maintained for 4 weeks before reassessment is performed. From our own experience and from the literature, we advise a trial diet which excludes milk, eggs, nuts, and additives [27, 32]. If this diet has a beneficial effect, the clinician will try to determine which foods are responsible for the AD. For this purpose the diet is gradually relaxed, including reintroduction of one food at a time. It should, however, be noted at this point that after avoiding a food for some time its reintroduction into the diet is not always safe and that anaphylactic reactions have been described [10].
Cellular interactions in atopic dermatitis (Fig. 1) The histopathology of AD shows the presence of a lymphocyte infiltrate, being the equivalent of the late skin reaction. In chronic lesions, an increased number of mast cells and Langerhans cells (LC) is found. After intradermal injection of staphylococcal antigens, basophilic infiltration has also been demonstrated in AD [17]. Although patients with AD frequently show elevated blood eosinophil counts, increased numbers of eosinophils are seldom found in the skin lesions. On the other hand, it was demonstratet that AD lesions contain large amounts of eosinophilic major basic protein, suggesting that eosinophils may also play a role in the pathogenesis of AD [19]. Another important cell in the pathogenesis of AD is the LC [24]. In the later 1970s the antigenpresenting function of the LC and its central role in the immune response of the skin-associated lymphoid tissue were recognized definitively. The LC possesses surface receptors for a variety of molecules of the immune system. In fact, they have receptors for complement (C3), for the Fc fragment of IgG, and for interleukin-2. Recently it was discovered that in patients with AD, LCs also express the presence of a receptor for IgE (FcER) [6]. In contrast, normal non-atopic controls do not possess this FcER. It was also found that the receptor on the LC is of the same type as on eosinophils, platelets, and macrophages (FcER-II), but differs structually from the FcER on human B lymphocytes (CD23 positive). An important characteristic of the LC is its ability to produce and release interleukin-1, and to induce T-lymphocyte proliferation by a Allergen
strong antigen presenting capacity [3, 28, 29]. There also exists much evidence that LCs generate, directly or indirectly, an eosinophilic chemotactic factor [7]. In 1986, Peterson et al. were able to demonstrate an inhibitory effect of ECP on lymphocyte profileration in vitro [22]. This observation suggests an inhibitory function of eosinophils upon the allergen-induced lymphocyte response.
Pathogenesis of atopic dermatitis About 20% of patients with AD have normal or low serum IgE levels without a specificity to inhaled or ingested allergens. The clinical characteristics of these patients do not differ from AD patients with elevated serum IgE levels. Therefore, in those patients, IgEmediated reactions may not be responsible for the AD lesions. Thus, other non-IgE-mediated mechanisms, leading to mast cell degranulation, should be involved in the pathogenesis of AD. Analogous to bronchial asthma, but still largely speculative, the basic condition for AD seems to be the existance of a cutaneous hyperreactivity, induced by a number of allergic (food, inhalants) and non-allergic triggers (itching, stress, humidity) (Fig. 2) [9, 32].
Mechanism of the cellular interactions in atopic dermatitis Allergens can reach the skin after being ingested or after epicutaneous application. The allergen binds to IgE molecules on mast cells in the dermis and induces an immediate skin reaction, characterized by the release of mast cell mediators, especially histamine. On the other hand, it can be assumed that mast cell degranulation can also be induced by non-allergic triggers. The immediate reaction is most frequently appreciated as a wheal-andflare response. Mast cells also release an eosinophilic chemotactic factor, initiating the late skin reaction which constitutes of an infiltration and activation of eosinophils. On the other hand, epidermal LCs in patients with IgE (allergens)
Non-allergic triggers
Dermal hgperreaetivitg
/
Mast cell activation
\ /
Early skin reaction Mast cells (IgE)
Late skin reaction
Langerhans cells (IgE)
Increase in dermal hgperreaetivitg
/
Eosinophils 4 9 T-lymphocytes Fig. 1. Cellularinteractionsin atopic dermatitis
Symptoms provoked by minimal non-specific stimuli Fig. 2. Hypotheticalmodel of atopic dermatitis
873 A D also b e a r I g E molecules and therefore, part of the allergen m a y bind to allergen specific I g E on LCs. A f t e r binding of allergens to epidermal LCs two processes m a y be initiated. Firstly, since the L C has a strong antigen presenting capacity, a T - l y m p h o c y t e proliferative response m a y be i n d u c e d in the dermis. Secondly, eosinophilic infiltration and activation m a y be induced by an eosinophil chemotactic factor. F u r t h e r m o r e , activated T - l y m p h o c y t e s m a y attract eosinophils by the relase o f a l y m p h o k i n e which m a y act as an eosinophil chemotactic factor. A c t i v a t e d eosinophils b e c o m e degranulated, and deposit their granular contents, including m a j o r basic protein and eosinophilic cationic protein. All these events lead to a i n f l a m m a t o r y state in which mast cells, lymphocytes, L C , and eosinophils are involved. T h e complicated interplay of these ceils, including secretion of different mediators, makes up the clinical manifestations of A D . A l t h o u g h m a n y of these cellular interactions n e e d further study, several observations already suggest that A D is the equivalent of bronchial asthma, b o t h diseases being the result of an intense local inflamm a t o r y reaction. T h e r e f o r e , it seems logical to assume that s y m p t o m a t i c t r e a t m e n t of these diseases should be focussed towards these i n f l a m m a t o r y processes.
References 1. Adinoff AD, Tellez P, Clark RAF (1988) Atopic dermatitis and aeroallergen contact sensitivity. J Allergy Clin Immunol 81 : 736-742 2. Agosti JM, Sprenger JD, Lum LG, Witherspoon RP, Fisher LD, Storb R, Henderson WR Jr (1988) Transfer of allergenspecific IgE-mediated hypersensitivity with allogenic bone marrow transplantation. N Engl J Med 319 : 1623-1628 3. Bjercke S, Elg6 J, Braathen L, Thorsby E (1984) Enriched epidermal Langerhans cells are potent antigen-presenting cells for T cells. J Invest Dermatol 83 : 286-289 4. Bonini S, Adriani E, Bonini S, De Petrillo G, Loggi GG, Adabbo A, Pani M, Balsano F (1989) Allergy and asthma: distinguishing the causes from the triggers. An eye model for the study of inflammatory events following allergen challenge. Eur Respir J [Suppl 2] 6:497s-501s 5. Bruynzeel-Koomen CAFM, Bruynzeel PLB (1988) A role for IgE in patch test reactions to inhalant allergens in patients with atopic dermatitis. Allergy 43 : 15-21 6. Bruynzeel-Koomen C, Van der Donk EMM, Bruynzeel PLB, Capron M, De Gast GC, Mudde GC (1988) Associated expression of CD1 antigen and Fc receptor for IgE on epidermal Langerhans cells from patients with atopic dermatitis. Clin Exp Immunol 74:137-142 7. Bruynzeel-Koomen CAF, Van Wichen DF, Spry CJF, Venge P, Bruynzeel PLB (1988) Active participation of eosinophils in patch test reactions to inhalant allergens in patients with atopic dermatitis. Br J Dermatol 118 : 229-238 8. Carswell F, Thompson S (1986) Does natural sensitisation in eczema occur through the skin? Lancet II : 1315 9. Cockcroft DW (1983) Mechanism of perennial allergic asthma. Lancet II : 253-255
10. David TJ (1984) Anaphylactic shock during elimination diets for severe atopic eczema. Arch Dis Child 59 : 983-986 11. Desager K, Van Bever HP, Stevens WJ (1987) Contact sensitivity to aeroallergens in children with atopic dermatitis (AD) demonstrated by patch test. J Allergy Clin hnmunol 79:236 (abs 446) 12. Dolovich J, Hargreave FE, Chalmers R, Shier KJ, Gauldie J, Bienenstock J (1973) Late cutaneous allergic responses in isolated IgE-dependent reactions. J Allergy Clin Immunol 52: 38-46 13. Frew AJ, Kay AB (1988) The pattern of human late-phase skin reactions to extracts of aeroallergens. J Allergy Clin Immunol 81 : 1117-1121 14. Hanifin JM (1984) Atopic dermatitis. J Allergy Clin Immunol 73 : 211-222 15. Hanifln JM (1987) Epidemiology of atopic dermatitis. Monogr Allergy 21 : 116-131 16. Hanifin JM, Lobitz WC (1977) Newer concepts of atopic dermatitis. Arch Dermatol 113 : 663-670 17. Hdnocq E, Gaillard J (1981) Cutaneous basophil hypersensitivity in atopic dermatitis. Clin Allergy 11:13-20 18. Larsen FS, Holm NV, Henningsen K (1986) Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 15 : 487-494 19. Leiferman KM, Ackerman SJ, Sampson HA, Haugen HS, Venecie PY, Gleich GJ (1985) Dermal deposition of eosinphilgranule major basic protein in atopic dermatitis. N Engl J Med 313:282-285 20. Mitchell EB, Crow J, Chapman MD, et al (1982) Basophils in allergen-induced patch test sites in atopic dermatitis. Lancet I : 127-130 21. Mitchell EB, Crow J, Platts-Mills TAE (1986) Increase in skin mast cells following chronic house dust mite exposure. Br J Dermatol 114:65-73 22. Peterson CGB, Skoog V, Venge P (1986) Human eosinophil cationic proteins (ECP and EPX) and their suppressive effects on lymphocyte proliferation. Immunobiology 171 : 1-13 23. Platts-Mills TAE, Mitchell EB, Rowntree S, Chapman MD, Wilkins S (1983) The role of dust mite antigens in atopic dermatitis. Clin Exp Dermatol 8 : 233-243 24. Ruco LP, Uccini S, Baroni CD (1989) The Langerhans' cells. Allergy 44 [Suppl 9] : 27-30 25. Sampson HA (1983) Role of immediate food hypersensitivity in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 71 : 473-480 26. Sampson HA (1989) Role of immediate hypersensitivity in the pathogenesis of atopic dermatitis. Allergy 44 [Suppl 9] : 52-58 27. Sampson HA, McCaskill CC (1985) Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 107: 669-675 28. Sauder DN, Dinarello CA, Morhenn VB (1984) Langerhans' cell production of Interleukin-1. J Invest Dermatol 82:605607 29. Silberberg-Sinakin I, Gilgi I, Baer RL, Thorbecke GJ (1980) Langerhans' cells: role in contact hypersensitivity and relationship to lymphoid dendritic cells and to macrophages. Immunol Rev 53 : 203-232 30. Simons FER (1988) Allergic rhinitis: recent advances. Pediatr Clin North Am 35 : 1053-1074 31. Taylor B, Wadsworth M, Wadsworth J, Peckham C (1984) Changes in the reported prevalence of childhood eczema since the 1939-45 war. Lancet II : 1255-1257 32. Van Bever HP, Docx M, Stevens WJ (1989) Food and food additives in severe atopic dermatitis. Allergy 44 : 588-594
Review
Pediatrics
Eur J Pediatr (1992) 151 : 870-873
9 Springer-Verlag1992
Recent advances in the pathogenesis of atopic dermatitis H. P. Van Bever Departments of Paediatrics and Immunology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem-Antwerp, Belgium Received August 28, 1990 / Accepted after revision January 10, 1992
Abstract. Atopic dermatitis (AD) is an inflammatory skin disorder affecting 5%-10% of children. Although basic mechanisms remain largely speculative, recent studies on the pathogenesis have elucidated new insights, pointing to the importance of food and inhalant allergens. The pathogenesis of AD can be more easily explained by the model of late skin reaction occurring after mast cell activation. The present report highlights some of the more recent developments in the mechanisms of AD which can be important in understanding and treating this troublesome disease. Key word: Atopic dermatitis
Introduction Although atopic dermatitis (AD) is the commonest chronic skin disorder in children, its pathogenesis remains largely unexplained. It has been estimated that about 5%-10% of all children suffer at one time from AD, and there is evidence showing its frequency is still increasing [15, 31]. It is not yet known whether this is an absolute or a relative increase (the more attention is focussed on a disorder, the better it is defined). Studies in twins point to a hereditary disposition for the disease but expression of the genetic trait seems to be dependent on a multitude of environmental factors [18]. Observations derived from bone marrow transplantation have demonstrated the marrow as the site of the primary defect in AD [2].
Clinical presentation AD has no specific skin signs and comprises a number of atypical dermatological characteristics such as erythema, excoriation, scratching lesions, lichenification, and hypopigmentation [14]. Children do not have symptoms Correspondence to: H. P. Van Bever Abbreviations: AD = atopic dermatitis; DBPCPT = double-
blind placebo-controlled provocation test: FcER = Fc receptor for IgE; Lc = Langerhans cell
from birth, but they usually appear before the age of 3 months. The lesions appear before the age of I year in 80% of children and before 5 years in 90%. The most invariable symptom is pruritus which can sometimes be very intense and cause severe insomnia. The distribution profile of the disease varies with age and is characterized by the predominance of certain skin lesions. The diagnosis of AD is generally not difficult, but in some cases the symptoms are poorly defined. In this event the diagnostic criteria of Hanifin and Lobitz [16] are useful. The clinical course is characterized by variability and unpredictability. The asymptomatic intervals usually became extended as the child ages. It is estimated that in 60% of children with severe AD (requiring hospitalization), symptoms are still present at the age of 20. In 95% of milder cases, symptoms disappear around the age of 20. Several aspects of AD have particular clinical and social importance; these include cutaneous infections, common warts and molluscum contagiosum, ocular complications, contact dermatitis and, sleep disturbances and learning difficulties.
IgE-mediated hypersensitivity in atopic dermatitis Most AD patients also have atopic respiratory disease. Usually, the respiratory symptoms begin later than the skin symptoms and many clinicians have noted the peculiar and unexplained tendency for AD and asthma to alternate in their courses. This phenomenon is not constant, however, as both can flare together. The highest IgE levels can be detected in patients who suffer from both AD and asthma. It is not yet known whether there is a causal relationship between these high IgE levels and AD, or whether this is just an expression of the atopic constitution. In some patients, however, IgE is important in the pathogenesis of the AD symptoms, while in others it is not. The following observations have been made: 1. Increased total serum IgE has been recorded in 80% of patients. In addition, there is a correlation between total serum IgE and the severity of AD. 2. Positive prick tests and positive IgE to a number of inhaled allergens and food allergens are found in the majority of patients.
871 3. Positive familial antecedents of atopic diseases are found in 66% of patients. 4. Of subjects with AD, 50%-80% suffer also from asthma and/or rhinitis. The presence of specific IgE or a positive skin test to an allergen still does not mean that the AD lesions are triggered by this particular allergen. The prick test and the determination of specific IgE via the RAST are both known to yield frequent false-positive and false-negative results [25]. A possible explanation for the false-negative results is that the allergen can induce skin lesions by nonIgE-dependent mechanisms. A positive prick test corresponds to a clinically detectable allergy (by a provocation test) in only about 25% of AD patients, although in young children prick tests are frequently negative. The search for specific IgE offers no more diagnostic possibilities than the prick test. These two tests are comparable in specificity and sensitivity. If both RAST and prick test are used together in one patient, the diagnostic precision remains the same as for separate interpretation of each test. The anamnestic features usually contain insufficient information to establish a clear link between exposure to an allergen and the appearance of skin lesions. Parents often report their child to be "allergic" to a particular food, but when a provocation test is carried out, this food seldom seems to have any effect on the eczematous lesions. The opposite is often equally true: clearly positive provocation results are obtained by foods which the parents did not suspect. At the moment, the best method to demonstrate that an allergen triggers AD is the double-blind placebo-controlled provocation test (DBPCPT). In children with severe AD challenged by Sampson and McCaskill 63 children out of 113 (56%) showed positive reactions to food, using the DBPCPT [27]. Milk, eggs, and peanuts were responsible for 72% of the positive DBPCPT. In another study, on 25 children with severe AD, we could demonstrate, by DBPCPT, that foods are able to induce exacerbations of AD in 24 out of 25 of the subjects. In that same study it was also found that food additives, tyramine and acetylsalicylic acid were able to cause exacerbations of AD [32]. Skin biopsies of AD shows epidermal spongiosis and mononuclear cell infiltration of the dermis, suggesting a type IV hypersensitivity reaction. On the other hand, different studies point to the importance of IgE-mediated reactions in AD [26]. The relationship between IgE-mediated reactions and cellular infiltration has to be linked to the occurrence of the late cutaneous reaction (see below) [12]. For some years, it has been shown that IgE-mediated processes are able to induce two types of reactions: immediate reactions, characterized by the release of mast cell mediators, especially histamine, and most frequently appreciated in the skin as a wheal-andflare response, and late reactions characterized by the infiltration of different cells, especially eosinophils and lymphocytes. These late reactions have been described in the bronchi (asthma) [9], nose (rhinitis) [30], eye (conjunctivitis) [4] and skin [13]. At present, it is accepted by many investigators that AD is the natural occurring equivalent of a late cutaneous reaction, initiated
by mast cell degranulation. Theoretically, two types of allergens should be able to induce mast cell degranulafion: inhaled allergens and ingested allergens.
Inhaled allergens In a great number of patients with AD, positive reactions (prick test and specific IgE) can be found to many inhaled allergens. These reactions are not usually directly linked to the skin symptoms; they are merely a manifestation of an atopic constitution (i.e. the capacity to produce IgE against a variety of allergens). There is as yet no clear evidence that inhaled allergens trigger AD directly, after inhalation and IgE induction. There are, however, anecdotal reports of AD induced by inhaled allergens (e.g. after contact with pets or grass pollen). In a study by Platts-Mills et al., it was shown that AD improved by cleaning the patients' bedrooms [23]. On the other hand, it was demonstrated that inhaled allergens, applied epicutaneously by patch test, may penetrate the skin and induce eczematous skin lesions. These skin reactions which are delayed in time (positive 24 h-72 h after patch testing) did not occur in allergic asthma and allergic rhinitis and, therefore, seemed to be specific for AD [1, 5, 8, 11, 20]. Microscopy of the patch test reactions shows many similarities to the clinically involved skin of AD [21]. Therefore, inhaled allergens are believed to be involved only by direct contact in a number of patients with AD who have a concomitant allergy to inhaled allergens, especially to house dust mite. It is consequently reasonable to advise elimination of inhaled allergens (e.g. by removing house dust) in some patients with AD and a house dust mite allergy.
Food allergens As already mentioned, the strangest stories are told concerning food and AD. At the moment, the gold standard in diagnosing food allergy is the DBPCPT, as both anamnestic features and determination of a IgE-mediated allergy (by prick test or determination of specific IgE) frequently show false-positive and false-negative results [25, 27, 32]. In view of the fact that it is difficult to demonstrate the existance of a food allergy, the following rules and procedure are recommended: 1. Food is important as a triggering factor in children with severe AD (about 10% of all cases). The importance of food in children with mild AD is unknown. 2. Certain foods and food additives can induce AD by various mechanisms, some being IgE-mediated. 3. Prick tests and specific IgE determination are frequently false-positive and false-negative in AD. They may act as a guideline in defining the atopic state, but often they are useless as routine tests. 4. If the clinician relies on the results of prick tests and IgE determination, inadequate modifications of the diet will be prescribed resulting in poor compliance and ineffectiveness.
872 5. Since DBPCPTs are often impossible to perform, a trial diet is justified in some patients with severe AD, unresponsive to a simple standard therapy of lubricants, topical corticosterois and antihistamines. Such a trial diet should be maintained for 4 weeks before reassessment is performed. From our own experience and from the literature, we advise a trial diet which excludes milk, eggs, nuts, and additives [27, 32]. If this diet has a beneficial effect, the clinician will try to determine which foods are responsible for the AD. For this purpose the diet is gradually relaxed, including reintroduction of one food at a time. It should, however, be noted at this point that after avoiding a food for some time its reintroduction into the diet is not always safe and that anaphylactic reactions have been described [10].
Cellular interactions in atopic dermatitis (Fig. 1) The histopathology of AD shows the presence of a lymphocyte infiltrate, being the equivalent of the late skin reaction. In chronic lesions, an increased number of mast cells and Langerhans cells (LC) is found. After intradermal injection of staphylococcal antigens, basophilic infiltration has also been demonstrated in AD [17]. Although patients with AD frequently show elevated blood eosinophil counts, increased numbers of eosinophils are seldom found in the skin lesions. On the other hand, it was demonstratet that AD lesions contain large amounts of eosinophilic major basic protein, suggesting that eosinophils may also play a role in the pathogenesis of AD [19]. Another important cell in the pathogenesis of AD is the LC [24]. In the later 1970s the antigenpresenting function of the LC and its central role in the immune response of the skin-associated lymphoid tissue were recognized definitively. The LC possesses surface receptors for a variety of molecules of the immune system. In fact, they have receptors for complement (C3), for the Fc fragment of IgG, and for interleukin-2. Recently it was discovered that in patients with AD, LCs also express the presence of a receptor for IgE (FcER) [6]. In contrast, normal non-atopic controls do not possess this FcER. It was also found that the receptor on the LC is of the same type as on eosinophils, platelets, and macrophages (FcER-II), but differs structually from the FcER on human B lymphocytes (CD23 positive). An important characteristic of the LC is its ability to produce and release interleukin-1, and to induce T-lymphocyte proliferation by a Allergen
strong antigen presenting capacity [3, 28, 29]. There also exists much evidence that LCs generate, directly or indirectly, an eosinophilic chemotactic factor [7]. In 1986, Peterson et al. were able to demonstrate an inhibitory effect of ECP on lymphocyte profileration in vitro [22]. This observation suggests an inhibitory function of eosinophils upon the allergen-induced lymphocyte response.
Pathogenesis of atopic dermatitis About 20% of patients with AD have normal or low serum IgE levels without a specificity to inhaled or ingested allergens. The clinical characteristics of these patients do not differ from AD patients with elevated serum IgE levels. Therefore, in those patients, IgEmediated reactions may not be responsible for the AD lesions. Thus, other non-IgE-mediated mechanisms, leading to mast cell degranulation, should be involved in the pathogenesis of AD. Analogous to bronchial asthma, but still largely speculative, the basic condition for AD seems to be the existance of a cutaneous hyperreactivity, induced by a number of allergic (food, inhalants) and non-allergic triggers (itching, stress, humidity) (Fig. 2) [9, 32].
Mechanism of the cellular interactions in atopic dermatitis Allergens can reach the skin after being ingested or after epicutaneous application. The allergen binds to IgE molecules on mast cells in the dermis and induces an immediate skin reaction, characterized by the release of mast cell mediators, especially histamine. On the other hand, it can be assumed that mast cell degranulation can also be induced by non-allergic triggers. The immediate reaction is most frequently appreciated as a wheal-andflare response. Mast cells also release an eosinophilic chemotactic factor, initiating the late skin reaction which constitutes of an infiltration and activation of eosinophils. On the other hand, epidermal LCs in patients with IgE (allergens)
Non-allergic triggers
Dermal hgperreaetivitg
/
Mast cell activation
\ /
Early skin reaction Mast cells (IgE)
Late skin reaction
Langerhans cells (IgE)
Increase in dermal hgperreaetivitg
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Eosinophils 4 9 T-lymphocytes Fig. 1. Cellularinteractionsin atopic dermatitis
Symptoms provoked by minimal non-specific stimuli Fig. 2. Hypotheticalmodel of atopic dermatitis
873 A D also b e a r I g E molecules and therefore, part of the allergen m a y bind to allergen specific I g E on LCs. A f t e r binding of allergens to epidermal LCs two processes m a y be initiated. Firstly, since the L C has a strong antigen presenting capacity, a T - l y m p h o c y t e proliferative response m a y be i n d u c e d in the dermis. Secondly, eosinophilic infiltration and activation m a y be induced by an eosinophil chemotactic factor. F u r t h e r m o r e , activated T - l y m p h o c y t e s m a y attract eosinophils by the relase o f a l y m p h o k i n e which m a y act as an eosinophil chemotactic factor. A c t i v a t e d eosinophils b e c o m e degranulated, and deposit their granular contents, including m a j o r basic protein and eosinophilic cationic protein. All these events lead to a i n f l a m m a t o r y state in which mast cells, lymphocytes, L C , and eosinophils are involved. T h e complicated interplay of these ceils, including secretion of different mediators, makes up the clinical manifestations of A D . A l t h o u g h m a n y of these cellular interactions n e e d further study, several observations already suggest that A D is the equivalent of bronchial asthma, b o t h diseases being the result of an intense local inflamm a t o r y reaction. T h e r e f o r e , it seems logical to assume that s y m p t o m a t i c t r e a t m e n t of these diseases should be focussed towards these i n f l a m m a t o r y processes.
References 1. Adinoff AD, Tellez P, Clark RAF (1988) Atopic dermatitis and aeroallergen contact sensitivity. J Allergy Clin Immunol 81 : 736-742 2. Agosti JM, Sprenger JD, Lum LG, Witherspoon RP, Fisher LD, Storb R, Henderson WR Jr (1988) Transfer of allergenspecific IgE-mediated hypersensitivity with allogenic bone marrow transplantation. N Engl J Med 319 : 1623-1628 3. Bjercke S, Elg6 J, Braathen L, Thorsby E (1984) Enriched epidermal Langerhans cells are potent antigen-presenting cells for T cells. J Invest Dermatol 83 : 286-289 4. Bonini S, Adriani E, Bonini S, De Petrillo G, Loggi GG, Adabbo A, Pani M, Balsano F (1989) Allergy and asthma: distinguishing the causes from the triggers. An eye model for the study of inflammatory events following allergen challenge. Eur Respir J [Suppl 2] 6:497s-501s 5. Bruynzeel-Koomen CAFM, Bruynzeel PLB (1988) A role for IgE in patch test reactions to inhalant allergens in patients with atopic dermatitis. Allergy 43 : 15-21 6. Bruynzeel-Koomen C, Van der Donk EMM, Bruynzeel PLB, Capron M, De Gast GC, Mudde GC (1988) Associated expression of CD1 antigen and Fc receptor for IgE on epidermal Langerhans cells from patients with atopic dermatitis. Clin Exp Immunol 74:137-142 7. Bruynzeel-Koomen CAF, Van Wichen DF, Spry CJF, Venge P, Bruynzeel PLB (1988) Active participation of eosinophils in patch test reactions to inhalant allergens in patients with atopic dermatitis. Br J Dermatol 118 : 229-238 8. Carswell F, Thompson S (1986) Does natural sensitisation in eczema occur through the skin? Lancet II : 1315 9. Cockcroft DW (1983) Mechanism of perennial allergic asthma. Lancet II : 253-255
10. David TJ (1984) Anaphylactic shock during elimination diets for severe atopic eczema. Arch Dis Child 59 : 983-986 11. Desager K, Van Bever HP, Stevens WJ (1987) Contact sensitivity to aeroallergens in children with atopic dermatitis (AD) demonstrated by patch test. J Allergy Clin hnmunol 79:236 (abs 446) 12. Dolovich J, Hargreave FE, Chalmers R, Shier KJ, Gauldie J, Bienenstock J (1973) Late cutaneous allergic responses in isolated IgE-dependent reactions. J Allergy Clin Immunol 52: 38-46 13. Frew AJ, Kay AB (1988) The pattern of human late-phase skin reactions to extracts of aeroallergens. J Allergy Clin Immunol 81 : 1117-1121 14. Hanifin JM (1984) Atopic dermatitis. J Allergy Clin Immunol 73 : 211-222 15. Hanifln JM (1987) Epidemiology of atopic dermatitis. Monogr Allergy 21 : 116-131 16. Hanifin JM, Lobitz WC (1977) Newer concepts of atopic dermatitis. Arch Dermatol 113 : 663-670 17. Hdnocq E, Gaillard J (1981) Cutaneous basophil hypersensitivity in atopic dermatitis. Clin Allergy 11:13-20 18. Larsen FS, Holm NV, Henningsen K (1986) Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 15 : 487-494 19. Leiferman KM, Ackerman SJ, Sampson HA, Haugen HS, Venecie PY, Gleich GJ (1985) Dermal deposition of eosinphilgranule major basic protein in atopic dermatitis. N Engl J Med 313:282-285 20. Mitchell EB, Crow J, Chapman MD, et al (1982) Basophils in allergen-induced patch test sites in atopic dermatitis. Lancet I : 127-130 21. Mitchell EB, Crow J, Platts-Mills TAE (1986) Increase in skin mast cells following chronic house dust mite exposure. Br J Dermatol 114:65-73 22. Peterson CGB, Skoog V, Venge P (1986) Human eosinophil cationic proteins (ECP and EPX) and their suppressive effects on lymphocyte proliferation. Immunobiology 171 : 1-13 23. Platts-Mills TAE, Mitchell EB, Rowntree S, Chapman MD, Wilkins S (1983) The role of dust mite antigens in atopic dermatitis. Clin Exp Dermatol 8 : 233-243 24. Ruco LP, Uccini S, Baroni CD (1989) The Langerhans' cells. Allergy 44 [Suppl 9] : 27-30 25. Sampson HA (1983) Role of immediate food hypersensitivity in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 71 : 473-480 26. Sampson HA (1989) Role of immediate hypersensitivity in the pathogenesis of atopic dermatitis. Allergy 44 [Suppl 9] : 52-58 27. Sampson HA, McCaskill CC (1985) Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 107: 669-675 28. Sauder DN, Dinarello CA, Morhenn VB (1984) Langerhans' cell production of Interleukin-1. J Invest Dermatol 82:605607 29. Silberberg-Sinakin I, Gilgi I, Baer RL, Thorbecke GJ (1980) Langerhans' cells: role in contact hypersensitivity and relationship to lymphoid dendritic cells and to macrophages. Immunol Rev 53 : 203-232 30. Simons FER (1988) Allergic rhinitis: recent advances. Pediatr Clin North Am 35 : 1053-1074 31. Taylor B, Wadsworth M, Wadsworth J, Peckham C (1984) Changes in the reported prevalence of childhood eczema since the 1939-45 war. Lancet II : 1255-1257 32. Van Bever HP, Docx M, Stevens WJ (1989) Food and food additives in severe atopic dermatitis. Allergy 44 : 588-594
