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Flare factors and atopic dermatitis: The role of allergy
Journnl of Dermatological Science, 1 (1990) 3 1 l-3 18 Elsevier
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DESC 00037
Review Article
Flare factors and atopic dermatitis: * The role of allergy Mark V. Dal11 Universityof Minnesota Medical School, Minneapolis,Minnesota, U.S.A. (Received 24 November
Key words: Atopic dermatitis;
1989; accepted 29 March 1990)
Allergy; IgE; Urticaria;
Late phase reaction
Abstract Atopic dermatitis is a genetically determined eczematous skin disease strongly influenced by environmental conditions called flare factors. Allergic reactions are one such flare factor. These reactions include contact urticaria, allergic contact dermatitis, and late phase reactions. Contact urticaria could induce eczema by eliciting scratching. A late phase reaction may be involved in eczema produced by prolonged epicutaneous applications of antigens in individuals with immediate sensitivity to these antigens. Mechanisms of allergic contact dermatitis might also elicit dermatitis. Environmental allergens may include mold, dust, mite, pollens, foods, danders and bacteria.
Introduction Atopic dermatitis is a chronic or chronically relapsing, severely pruritic eczematous dermatosis. It affects characteristic anatomic areas of the skin surface depending upon the age of the patient. T’he presence of dermatitis predisposes the skin to lichenification from scratching. Atopic dermatitis often occurs in patients with a personal or family history of atopic eczema, allergic rhinitis, or extrinsic asthma. A variety of other abnormalities serve as minor criteria for the diagnosis of the
Correspondence to: Mark V. Dahl, University of Minnesota Medical School, Box 98 UMHC, Minneapolis, MN 55455, U.S.A. Fax: (612)626-3824. * Presented at the Second Clinically Oriented Research Symposium of the Japanese Society for Investigative Dermatology, Kyoto, Japan, on November 10, 1989. 0923-181 l/90/$03.50
0 1990 Elsevier Science Publishers
disease [ 11. The cause is not known, but is presumed to be multifactorial. Although the disease has a genetic basis, the expression of eczema is highly dependent on environmental stimulae called flare factors [2]. These include low humidity, heat, rough or tickling clothes, high counts of bacteria and yeasts on the skin, scratching, emotional tensions and anxiety, sudden changes in skin temperature, rapid elevations of atmospheric pressure, development of upper respiratoy tract infections, contact of skin with strong or weakly irritating chemicals, and superimposed pruritic skin disorders such as scabies, bites, or m&aria. Atopic dermatitis begs to be recognized as an immunologic disease. The genetic basis of atopic dermatitis dictates a series of subtle and not so subtle abnormalities of immune function [3,4]. Patients with atopic dermatitis frequently wheeze
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from allergic extrinsic asthma and sneeze from allergic rhinitis. Yet despite intensive research efforts, the cause of atopic dermatitis remains unknown and immunologic hypotheses about its cause remain wishful guesses. Evidence supporting allergic mechanisms
Patients with atopic dermatitis often have: - A high incidence of elevated serum IgE levels [ 4,5] - Profound elevations of serum IgE, especially among patients with extensive skin disease [4,5,61. - A high incidence of IgG anti-IgE circulating immune complex levels [7] - Associated asthma, allergic rhinitis, and urticaria [ 1] - Multiple positive prick tests to food and environmental allergens [ 81. - Multiple positive radioallergosorbent tests to food and environmental allergens. - Itching and dermatitis after the ingestion of certain foods (different ones for different patients [ 91). - Reduction of itch and improvement of dermatitis after eliminating certain foods (different ones for different patients [lo]) - Frequent peripheral blood eosinophilia (a common finding during allergic reactions). - Elevated serum and urinary histamine levels, implying that mast cells have degranulated, possibly from allergic cause). - Elevated serum and urinary histamine levels (implying that mast cells have degranulated, possibly from allergic cause). - Reduced numbers of peripheral blood T helper and suppressor cells [ 121. In addition, the atopic-like dermatitis of a patient with Wiskott-Aldrich syndrome resolved after the patient received an allogeneic bone marrow transplant from a nonatopic donor [ 131. Treatment with immunosuppressive drugs such as azathioprene, cyclophosphamide, and cyclosporin A improves atopic dermatitis. The transient immunodeficiency which frequently fol-
lows measles may account for improvement of dermatitis observed following this infection [ 141. Immunobiology
Cause and effect relationships between these immunologic perturbations and the dermatitis are speculative. The lymphocytes that infiltrate lesions are predominently activated CD4 + (helper/inducer) cells expressing class II antigens [ 15,16,17]. Other infiltrating mononuclear cells include dermal Langerhans cells, interdigitating reticulum cells, and dermal dendrocytes apparently capable of antigen presentation [ 18,191. Some, but not all, of the dendritic cells express Fc receptors for IgE. Binding of antigen to IgE on the cell surface may somehow stimulate antigen presentation to effector cells [20-241. All of these factors favor enhanced immune responses, especially in tissue fluid containing interleukin-1 released from damaged keratinocytes and antigen that entered the dermis through a leaky epidermal barrier. An hypothesis
An allergic hypothesis for atopic dermatitis or for flaring up atopic dermatitis can be reasonably proposed. Patients with atopic dermatitis (or at least a subgroup of such patients) are genetically prone to produce large amounts of IgE when exposed to certain antigens. These antibodies are produced by B lymphocytes and plasma cells controlled by helper and suppressor T lymphocytes. Dysregulation leads to overproduction of IgE of many specificities. Induction or elicitation of immune responses to specific antigens may be facilitated by enhanced antigen presentation and excessive or dysregulated antigen presenting cells. The IgE produced by these responses circulates and the Fc end binds to mast cell Fc receptors on mast cells in the skin. Bridging of specific antigen across two IgE molecules on the surface of the mast cell cause granule and mediator release into the surrounding dermis, such as histamine, leukotrienes, proteases and other vasoactive and
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pro-inflammatory agents. These tickle cutaneous nerves to cause pruritus and dilate cutaneous blood vessels to cause erythema. Direct damage to the skin by these or other mediators or indirect damage to the epidermis by a late phase reaction or by scratching could produce acute or chronic eczematous dermatitis. Contact allergy as a flare factor There are at least three types of contact allergic reactions: allergic contact dermatitis, contact urticaria, and a novel eczematous reaction mediated by IgE and elicited by prolonged contact of antigen with skin. All three types elicit an inflammatory reaction, albeit by different mechanisms. Allergic contact dermatitis Allergic contact dermatitis is a prototypic eczematous dermatitis mediated by lymphokines produced by activated T lymphocytes responding to specific antigens. The disorder resembles atopic dermatitis in both clinical and histological respects [25]. Clinically there is acute or chronic eczematous dermatitis with notable roughness, scale, erythema, weeping, crusting, and pruritus. Histologically there is spongiosis, exocytosis of inflammatory cells, and a perivascular round cell infiltrate, primarily composed of lymphocytes and histiocytes. Dermatitis develops 4-72 h after exposure to antigen and often the dermatitis lasts several weeks. Although atopic dermatitis does not usually have the severe acute changes of allergic contact dermatitis, it could be an allergic contact dermatitis from reaction to an environmental antigen or even a normal constituent in or on the skin itself. Indeed, the T cells infiltrating lesions of atopic dermatitis express CD4 and class II antigens [ 15,161 similar to lymphocytes mediating allergic contact dermatitis. The subtle global deficit of cell mediated immunity detected in patients with atopic dermatitis by intradermal skin tests, mitogen stimulation, quantitation of T and B cell numbers, and impaired induction and elicitation of allergic contact dermatitis to potent
senitizers like dinitrochlorbenzene might be a result of bodily attempts to downregulate the persisting specific allergic reaction in the skin, or to downregulate cell mediated immunity in general [26,27]. Suppressor T cells could blunt both an allergic reaction specifically and cell-mediated reactions globally. Excessive IgE production could also blunt the reaction by eliciting edema via mast cell mediators that washes the antigen away. Despite searches both in the clinic and the laboratory, a relevant antigen eliciting a delayed hypersensitivity response in all patients has not been found. Although numerous antigens elicit wheal and flair reactions mediated by IgE in most patients, patients with atopic dermatitis typically have no propensity to develop allergic contact dermatitis. Occasionally a patient does develop allergic contact dermatitis to a chemical such as a preservative in a therapeutic cream. In these cases, allergic contact dermatitis is best viewed as a flare factor to the unrelated atopic dermatitis. Contact urticaria Contact urticaria is an erythematous wheal and flair reaction mediated by histamine and other mast cell products. An antigen on the skin surface penetrates the epidermal barrier, combines with specific IgE on the mast cell surface, and triggers mediator release [28]. Contact urticaria is a positive prick test without the prick; a positive scratch test without the scratch. The reaction occurs within an hour and usually occurs within seconds or minutes, reaches a peak within a few more minutes, and resolves within the day leaving no residual sign. A pink erythema develops and may be studded with small papular wheals. If eczema is present, these may be difficult to see. Contact urticariais pruritic, but its itch is the kind that does not evoke uncontrolled scratching. The reaction can be suppressed with antihistamines or sympathomimetic agents. A large number of food, dander, cosmetic, and airborne antigens are known that can produce contact urticaria [28]. Although many patients with atopic dermatitis have relevant specific IgE
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antibodies in their plasma and on mast cells, contact urticaria is rarely recognized by patients and even more rarely recognized by physicians. The urtications usually occur in areas of eczema where the epidermis allows better antigen penetration. These areas are already red and itchy. Patients attribute the itch to irritation from the food or antigen, and they attribute the redness and swelling to irritation or the resulting fit of scratching. Physicians rarely see contact urticaria, since the erythema and edema are gone when the patient visits the physician hours to days later. Contact urticaria per se acts as a flare factor because it elicits scratching which elicits eczema. Late phase reactions
Dermatitis may be a consequence of a late phase reaction. This reaction, like contact urticaria, involves mast cells [29,30]. Erythema, induration, and annoying pruritis develop several hours after injection of antigen or mast cell degranulators such as compound 48/80. These reactions reach maximum intensity after about eight hours and often disappear within a day, but may persist for 72 h or more. The initial inliltration of neutrophils, basophils, and eosinophils is replaced by lymphocytes and macrophages. The reaction is mediated by mast cell products including inflammatory factor of anaphylaxis (IF-A), a peptide released slowly from the proteoglycan matrix of the mast cell granule [31]. Leukotriene B4, 12-hydroxyeicosatetranoic acid (12-HETE), platelet activating factor, eosinophil chemotactic factor of anaphylaxis (ECF-A) and neutrophil chemotactic factor of anaphylaxis (NCF-A) may also play some role [32,33]. In contrast to atopic dermatitis, no spongiosis develops. Mitchell [34] elicited an eczematous reaction by abrading the skin of volunteers and applying antigen epicutaneously in a closed patch test system. If the volunteer had previously had a wheal and flare reaction to the chemical by prick test, then he or she developed eczematous dermatitis at the test site. Other volunteers did not. The reaction was specific to specific antigens; that is,
some antigens caused dermatitis is some individuals but not in others and different antigens caused reactions in different subjects, but all reactions occurred only in subjects who developed wheal reactions to the antigen after prick tests. Reitamo et al. [ 351 in a similar study, applied chambers with antigens from birch pollen and house dust mite to patients with atopic dermatitis. Delayed eczematous reactions developed in some but not all patients. Biopsy showed spongiosis and an inflamatory infiltrate consisting primarily of activated T helper cells and Langerhans cells. These eczematous reactions bear pathophysiologic mechanisms similar to the late phase reaction and link type I allergy to atopic dermatitis. On abraided skin, prolonged epicutaneous exposure to antigen produces an eczematous dermatitis from an IgE medicated immune reaction even in the absence of scratching. Apparently the initial urticarial response disappears and is replaced by an eczematous dermatitis when enough antigen and IgE drive the reaction under appropriate conditions for hours or days, especially when the antigen is presented topically. Atopic dermatitis produced by a modified late phase reaction might also explain why patients with atopic dermatitis continue to have dermatitis even after antigens are removed. When a late phase reaction occurs in the respiratory tract, it produces airway wheezing. The respiratory tract then becomes hypersensitive to a variety of other stimulae. Patients with asthma wheeze after inhaling histamine or methacholine in the clinic or after inhaling cold air or chemical fumes in the environment. In the skin, a similar phenomenon might occur to explain provocation of eczema by xerosis, sweating, rough clothes, or marginal irritants such as soaps. Mechanistically, chronic antigen-independent stimulation of dermatitis may be due to recruitment of basophils to the area by the original allergic reaction and self perpetuation of basophil and mast cell mediator release by neutrophils and neutrophil-derived histamine releasing factor (HRA-N) [31]. IgE might also mediate other forms of cellmediated immune reactions. Ray et al. [36] in-
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jetted mice with monoclonal IgE directed against determinants on dinitrofluorobenzene (DNFB). Subsequent challenge with DNFB elicited a delayed reaction in BALB/C mice but not in nude mice. This reaction was indistinguishable from the reaction that occured in mice sensitized by epicutaneous application of DNFB, but did not occur in BALB/C mice induced with monoclonal IgA-antiDNFB antibody. Another link between cell-mediated immunity and IgE may be on the surfaces of Langerhans cells. Many, but not all, Langerhans cells in the dermis of patients with atopic dermatitis have both Fc receptors for IgE and IgE itself on their surfaces [20-241. Antigen-specific IgE could act as a receptor for antigen to trigger an antigen processing/presenting sequence eliciting a T lymphocyte immune response. This is speculative because no function for these receptors has been found to date. Antigens
Many antigens could be relevant. Some could be delivered to the skin via the blood, while others could penetrate through intact or eczematous skin. The antigens could be foods, house dust mites, animal hairs, molds, pollens, bacteria, foreign proteins or other exogenous substances. They could also be endogenous substances such as a component of dander or sweat. The skin of patients with atopic dermatitis is heavily colonized with bacteria, especially Staphylococcus aureus [ 37-391. Acute exudative lesions carry about 10,000,000 bacteria on each square centimeter. Even the clinically uninvolved skin may carry large numbers (10,000 bacteria/sq.cm) of S. Aureus. These bacteria lie within the stratum corneum, on it, and on the crusted weepings and excoriations that litter it. Surface bacteria are only millimeters away from dermal mast cells. Some patients with atopic dermatitis have high levels of antistaphylococcal IgE which can mediate mast cell degranulation [ 40,4 11. Even in the absence of these specific antibodies, staphylo-
coccal protein A can probably trigger mediator release by interacting with the F(ab’)2 region of nonspecific IgE and/or IgG to provoke eczema [42,43]. Protein A can also cause delayed reactions when injected intradermally [ 441. Similarly, high serum IgE levels to Pityrosporon orbiculare are found in some patients with atopic dermatitis, especially among patients suffering from head and neck dermatitis [45]. During natural decomposition of stratum corneum proteins, monosaccharide-lysine residues are formed which can be allergenic [ 461. The major proteins have approximate molecular weights of 10,000 and 13,000 kDa [47]. Patients with atopic dermatitis react to patch tests with mixtures of pooled human danders as well as their own [47-5 13. Uehara and Ofugi [ 521 found 61 of 98 patients with atopic dermatitis reacted to scalp danders applied as patch tests. Only one of 31 normal subjects responded similarly. Reactions lasted for several days and the histology showed eczema. Intradermal tests were also positive at 48 h. Mold extracts frequently produce positive prick test results in patients with atopic dermatitis, even in those with no coexisting respiratory allergy [8,53]. These molds include species of altemaria, hormodendrum, penicillium, rhizopus, mucor, and aspergillus. Skin test reactions to molds may be delayed and persist for up to two weeks. House dust includes molds, but also includes the house dust mite Dermatophagoidespteronysinus or D.farinae [47]. Mite feces are also allergenic [54]. Gondo et al. [55] applied ointments containing ferritin-labelled and unlabeled crude mite antigens to scratched skin of a patient with atopic dermatitis and high levels of IgE antibodies to mite antigens. Both immediate urticarial and delayed eczematous reactions were elicited. Norris et al. [56] applied solutions of house dust mite antigens to eczematous and normal skin of patients with atopic dermatitis in a double blind study. One third of subjects with positive prick tests to house dust mite showed ‘marked or moderate deterioration after 5 days’ on both
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mildly involved and uninvolved skin. Apparently mite antigens can cause eczematous reactions when applied to the skin of at least some atopic patients. Contact with foods frequently elicits contact urticaria, especially in atopic patients with hand eczema. Aggravation of hand dermatitis by contact with food is well documented [ 57-601. Fish, fruits, meats, grains, spices, and vegetables have all been implicated. Provocation of atopic dermatitis by ingestion of foods is more controversial [lo]. Appropriate double-blind challenge studies are difficult to do because the taste of foods is difficult to disguise. Nonetheless, Sampson and Jolie’s [ 91 double-blind study not only found foods which exacerbated dermatitis, but also showed increased plasma histamine levels in these subjects but not in normal subjects or atopic subjects without prick test allergy to the foods in question. Some investigators suggest the response of skin to allergen avoidance diets is slow and may require four to six months. Patients with food hypersensitivity have high rates of spontaneous histamine release from basophils. This response returns only slowly toward normal when antigen is eliminated [61]. Summary
There are other nonimmunologic hypotheses which can explain many of the above and other findings. Szentivanyi [62] suggested that cells behave abnormally as though their betaadrenergic receptors are blocked, and Grewe et al. [ 631 noted elevated phosphodiesterase levels in leukocytes from patients even when in remission. These abnormalities suggest perturbed cell function leading to abnormal vascular responses, decreased itch thresholds, low thresholds for mast cell degranulation, unrestrained IL-l production, and disregulation of humor-al and cellmediated immunologic responses. Scratching may eczematize skin. Patients with atopic dermatitis who are unable to scratch or neurologically unable to sense itch see their dermatitis improve and disappear. Conversely,
patients with scabies, dermatitis herpetiformis, and other severely pruritic non-eczematous skin diseases frequently develop patchy eczema between lesions from scratching and mediator release [ 641. The high counts of bacteria on the skin may be due to plasma leakage to the surface from spongiosis, weeping, or excoriation. Elevated serum levels of IgE and immune disregulation may be a consequence of the continuous insult of the skin surface by digging fingernails or abrasive appliances and the resulting inoculation of various chemicals into the dermis. There are other compelling hypotheses too. There is also the possibility that atopic dermatitis is more than one disease, so, for example, that patients with normal IgE levels really have something else. Whatever causes atopic dermatitis, allergic reactions can cause it to appear or flare in at least some patients. Allergy may simply be one of many flare factors aggravating atopic dermatitis, but it is also possible allergy is somehow its cause. References 1 Hanifin JM, Rajka G: Diagnostic features of atopic dermatitis. Acta Derm Venerol 92 (suppl): 44-47, 1981. 2 Dahl MV: Atopic dermatitis: the concept offlare factors. S Med J 70: 453-455, 1977. 3 Cooper KD: Mechanisms of atopic dermatitis, in Immune Mechanbms of Cutaneous D&ease. Edited by DA Norris. Marcel Dekker Inc, New York, 1989, pp 247-276. 4 Ogawa M, Berger PA, McIntyre OR, Clendenning WE: IgE in atopic dermatitis. Arch Dermatol 103: 575-580, 1971. 5 Stone SP, Mulle SA, Gleich GJ: IgE levels in atopic dermatitis. Arch Dermatol 108: 806-811, 1973. 6 Uehara M: Heterogeneity of serum IgE levels in atopic dermatitis. Acta Derm Venerol (Stockholm) 66: 404-408, 1986. 7 Swainson JA, Wilson PB, Dore P, Pumphrey RSH: Evidence for circulating immune complexes containing IgE in patients with atopic dermatitis. Int Arch Allergy Appl Immuno178: 995-999, 1986. 8 Rajka G: Atopic Dermatitis. WB Saunders Co Ltd, London, 1975. 9 Sampson HA, Jolie PL: Increase plasma histamine concentrations after food challenge in children with atopic dermatitis. N Engl J Med 311: 372-376, 1984. 10 Atherton DJ: Diet and atopic eczema. Clin Allergy 18: 215-228, 1988.
317 11 Colver GB, Symons JA: Soluble interleukin-2 receptors in atopic dermatitis. Br Med J 298: 1426-1428, 1989. 12 Braathen LR: T-cell subsets in patients with mild and severe atopic dermatitis. Acta Dermatovenerol 114 (suppl): 133-136, 1985. 13 Saurat JH: Eczema in primary immune deficiencies. Clues to the pathogenesis of atopic dermatitis with special reference to the Wiskott-Aldrich syndrome. Acta Derm Venerol (Suppl) 114: 125-128, 1985. 14 Boner AL, Valletta EA, Bellanti JA: Improvement of atopic dermatitis following natural measles virus infection. Four case reports. Ann Allergy 55: 511-519, 1985. 15 Leung DY, Bhan AK, Schneeberger EE, Geha RS: Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies. J Allergy Clin Immunol 71: 47-56, 1983. 16 Lever R, Turbitt M, Sanderson A, MacKie R: Immunophenotyping of the cutaneous infiltrate and of the mononuclear cells in peripheral blood in patients with atopic dermatitis. J Invest Dermatol 89: 4-7, 1987. 17 Zachary CB, Allen MH, MacDonald DM: In situ quantification of T lymphocyte subsets and Langerhans cells in the intlammatory infiltrate of atopic dermatitis. Br J Dermatol 112: 149-156, 1985. 18 Zachary CB, Poulter LW, MacDonald DM: Cell mediated immune responses in atopic dermatitis: the relevance of antigen processing cells. Br J Dermatol 113 (Suppl): 10-16, 1985. 19 Alegre VA, MacDonald DM, Poulter LW: The simultaneous presence of Langerhans cells and interdigitating reticulum cell antigenic markers on inflammatory dendritic cells. Clin Exp Immunol 64: 330-333, 1986. 20 Bruynzeel-Koomen C, van Wichen DF, Toonstra J, Barrens L, Bruynzeel PLB: The presence of IgE molecules on epidermal Langerhans cells in patients with atopic dermatitis. Arch Derm Res 278: 199-205, 1986. 21 Leung DYM, Schneeberger EE, Siraganian RP, Geha RS, Bhan AK: The presence of IgE on macrophages and dendritic cells infiltrating into the skin lesion of atopic dermatitis. Clin Immunol Immunopathol 42: 328-337, 1987. 22 Bieber T, Dannenberg B, Prinz JC, Rieber EP, Stoltz W, Braun-Falco 0, Ring J: Occurrence of IgE-bearing epidermal Langerhans cells in atopic eczema: a study of the time course of the lesions and with regard to the IgE serum level. J Invest Dermatol 93: 215-219, 1989. 23 Tigalinowa M, Braathen LR, Lea T: IgE on Langerhans cells in the skin of patients with atopic dermatitis and birch allergy. Allergy 43: 464-468, 1988. 24 Bruynzeel-Koomen C, van der Donk EM, Bruynzeel PL, Capron M, de Gast GC, Mudde GC: Associated expression of CD 1 antigen and Fc receptor for IgE on epidermal Langerhans cells from patients with atopic dermatitis. Clin Exp Immunol 74: 137-142, 1988. 25 Prose PH: Pathologic changes in eczema, J Pediat 66: 178-199, 1965.
26 Uehara M, Sawai T: A longitudinal study of contact sensitivity in patients with atopic dermatitis. Arch Dermatol 125: 366-368, 1989. 27 Clark RAF: Cell-mediated and IgE mediated immune responses in atopic dermatitis. Arch Dermatol 125: 413-416, 1989. 28 Odom RB, Maibach HI: Contact Urticaria: a different and cause of contact dermatitis, in DermatolotoxicoZogy Pharmacology.Edited by FN Marzulli, HI Maibach. John Wiley and Sons, New York, 1977, pp 441-453 29 Sampson HA: Late phase response to food in atopic dermatitis. Hosp Prac 22: 111-118, 121-122, 127-128, 1987. 30 Pienkowski MM, Adkinson NF, Plaut M, Norman PS, Lichtenstein LM: Prostaglandin D2 and histamine during the immediate and the late-phase components of allergic cutaneous responses. J Allergy Clin Immuno182: 95-100, 1988. 31 Oertel HL, Kaliner M: The biologic activity of mast cell granules: III. Purification of inflammatory factors of anaphylaxis (IF-A) responsible for causing late phase reactions. J Immunol 127: 1398-1402, 1981. 32 Zweiman B: Mediators of allergic inflammation in the skin. Clin Allergy 18: 419-433, 1988. 33 Kaliner MA: The late-phase reaction and its clinical implications. Hosp Prac 22: 73-83, 1987. 34 Mitchell EB, Chapman MD, Pope F, Crow J, Jouhal S, Platts-Mills T: Basophils in allergen-induced patch test sites in atopic dermatitis. Lancet 1: 127-129, 1982. 35 Reitamo S, Visa K, Kahonen K, Kayhko K, Stubb S, Salo 0: Eczematous reactions in atopic patients caused by epicutaneous testing with inhalant allergens. Br J Dermatol 114: 303-309, 1986. 36 Ray MC, Tharp MD, Sullivan TJ, Tigelaar RE: Contact hypersensitivity reactions to dinitrofluorobenzene mediated by monoclonal IgE antiDNP antibodies. J Immunol 131: 1096-1102, 1983. 37 Leyden JJ, Marples RR, Kligman AM: Staphylococcus aureus in lesions of atopic dermatitis. Br J Dermatol90: 525-530, 1974. 38 Aly R, Maibach HI, Shinefield HR: Microbial flora of atopic dermatitis. Arch Dermatol 113: 780-782, 1977. 39 Dahl MV: Stuphyloccus uureus and atopic dermatitis. Arch Dermatol 119: 840-846, 1983. 40 Abramson JS, Dahl MV, Walsh G, Douglas SD, Quie PG: Antistaphylococcal IgE in patients with atopic dermatitis, J Am Acad Dermatol 7: 105-l 10, 1982. 41 Friedman SJ, Schroeder AL, Homberger HA: IgE antibodies to Staphylococcus aureus. Arch Dermatol 121: 869-872, 1985. 42 White M, Noble WC: Skin response to Protein A. Proc Royal Sot Edinburgh: 79B: 43, 1980. 43 White MI, Noble WC: The cutaneous reaction to staphyloccocal protein A in normal subjects and patients with atopic dermatitis and psoriasis. Br J Dermatol 113: 179-183, 1985.
318 44 Marone G, Tamburni M, Giudizi MG, Bragiotti R, Almerigogna F, Romagnani S: Activation of human basophils by StaphylococcusAureus Cowen I. II. Alternative F(ab’)-mediated mechanism. Agents Actions 16: 359-362, 1985. 45 Schrenker T, Kalveram KJ, Horstein OP, Hauch HD, Baurle G: Specific IgE antibodies against Pityrosporon orbicularein patients with atopic dermatitis. Z Hautkr 64: 478-479, 1989. 46 Berrens L: The Chemistry of Atopic Allergens. Monographs in Allergy. Vo17, Basel, Karger, 1971. 47 Yu B, Sawai T, Uehara M: Immediate hypersensitivity skin reactions to human dander in atopic dermatitis: Partial purification and characterization of human dander antigens. Arch Dermatol 124: 1530-1533, 1988. 48 Voorhorst R: The human dander atopy: I. The protoype of auto-atopy. Ann Allergy 39: 205-212, 1977. 49 Simon FA: Allergy to human dander in infantile eczema, Progress in Allergy. Vo12, Basal, Karger, 1944. 50 Kaaglund-Jorgensen 0: Case of Besnier’s prurigo with hypersensitivity to human dander. Acta Derm Venerol (Stockholm) 32: 417-418, 1952. 51 Young E, Bruynzeel-Koomen C, Berrens L: Delayed type hypersensitivity in atopic dermatitis. Acta Derm Venerol 114 (suppl): 77-81, 1985. 52 Uehara M, Ofuji S: Patch test reations to human dander in atopic dermatitis. Arch Dermatol 112: 951-954, 1976. 53 Bruynzeel-Koomen CA: Inhalant allergens as contactants in atopic dermatitis. J. Dermato (Tokyo) 14: 524-532, 1987. 54 Tovey ER, Chapman MD, Platts-Mills TAE: Mite feces
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DESC 00037
Review Article
Flare factors and atopic dermatitis: * The role of allergy Mark V. Dal11 Universityof Minnesota Medical School, Minneapolis,Minnesota, U.S.A. (Received 24 November
Key words: Atopic dermatitis;
1989; accepted 29 March 1990)
Allergy; IgE; Urticaria;
Late phase reaction
Abstract Atopic dermatitis is a genetically determined eczematous skin disease strongly influenced by environmental conditions called flare factors. Allergic reactions are one such flare factor. These reactions include contact urticaria, allergic contact dermatitis, and late phase reactions. Contact urticaria could induce eczema by eliciting scratching. A late phase reaction may be involved in eczema produced by prolonged epicutaneous applications of antigens in individuals with immediate sensitivity to these antigens. Mechanisms of allergic contact dermatitis might also elicit dermatitis. Environmental allergens may include mold, dust, mite, pollens, foods, danders and bacteria.
Introduction Atopic dermatitis is a chronic or chronically relapsing, severely pruritic eczematous dermatosis. It affects characteristic anatomic areas of the skin surface depending upon the age of the patient. T’he presence of dermatitis predisposes the skin to lichenification from scratching. Atopic dermatitis often occurs in patients with a personal or family history of atopic eczema, allergic rhinitis, or extrinsic asthma. A variety of other abnormalities serve as minor criteria for the diagnosis of the
Correspondence to: Mark V. Dahl, University of Minnesota Medical School, Box 98 UMHC, Minneapolis, MN 55455, U.S.A. Fax: (612)626-3824. * Presented at the Second Clinically Oriented Research Symposium of the Japanese Society for Investigative Dermatology, Kyoto, Japan, on November 10, 1989. 0923-181 l/90/$03.50
0 1990 Elsevier Science Publishers
disease [ 11. The cause is not known, but is presumed to be multifactorial. Although the disease has a genetic basis, the expression of eczema is highly dependent on environmental stimulae called flare factors [2]. These include low humidity, heat, rough or tickling clothes, high counts of bacteria and yeasts on the skin, scratching, emotional tensions and anxiety, sudden changes in skin temperature, rapid elevations of atmospheric pressure, development of upper respiratoy tract infections, contact of skin with strong or weakly irritating chemicals, and superimposed pruritic skin disorders such as scabies, bites, or m&aria. Atopic dermatitis begs to be recognized as an immunologic disease. The genetic basis of atopic dermatitis dictates a series of subtle and not so subtle abnormalities of immune function [3,4]. Patients with atopic dermatitis frequently wheeze
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from allergic extrinsic asthma and sneeze from allergic rhinitis. Yet despite intensive research efforts, the cause of atopic dermatitis remains unknown and immunologic hypotheses about its cause remain wishful guesses. Evidence supporting allergic mechanisms
Patients with atopic dermatitis often have: - A high incidence of elevated serum IgE levels [ 4,5] - Profound elevations of serum IgE, especially among patients with extensive skin disease [4,5,61. - A high incidence of IgG anti-IgE circulating immune complex levels [7] - Associated asthma, allergic rhinitis, and urticaria [ 1] - Multiple positive prick tests to food and environmental allergens [ 81. - Multiple positive radioallergosorbent tests to food and environmental allergens. - Itching and dermatitis after the ingestion of certain foods (different ones for different patients [ 91). - Reduction of itch and improvement of dermatitis after eliminating certain foods (different ones for different patients [lo]) - Frequent peripheral blood eosinophilia (a common finding during allergic reactions). - Elevated serum and urinary histamine levels, implying that mast cells have degranulated, possibly from allergic cause). - Elevated serum and urinary histamine levels (implying that mast cells have degranulated, possibly from allergic cause). - Reduced numbers of peripheral blood T helper and suppressor cells [ 121. In addition, the atopic-like dermatitis of a patient with Wiskott-Aldrich syndrome resolved after the patient received an allogeneic bone marrow transplant from a nonatopic donor [ 131. Treatment with immunosuppressive drugs such as azathioprene, cyclophosphamide, and cyclosporin A improves atopic dermatitis. The transient immunodeficiency which frequently fol-
lows measles may account for improvement of dermatitis observed following this infection [ 141. Immunobiology
Cause and effect relationships between these immunologic perturbations and the dermatitis are speculative. The lymphocytes that infiltrate lesions are predominently activated CD4 + (helper/inducer) cells expressing class II antigens [ 15,16,17]. Other infiltrating mononuclear cells include dermal Langerhans cells, interdigitating reticulum cells, and dermal dendrocytes apparently capable of antigen presentation [ 18,191. Some, but not all, of the dendritic cells express Fc receptors for IgE. Binding of antigen to IgE on the cell surface may somehow stimulate antigen presentation to effector cells [20-241. All of these factors favor enhanced immune responses, especially in tissue fluid containing interleukin-1 released from damaged keratinocytes and antigen that entered the dermis through a leaky epidermal barrier. An hypothesis
An allergic hypothesis for atopic dermatitis or for flaring up atopic dermatitis can be reasonably proposed. Patients with atopic dermatitis (or at least a subgroup of such patients) are genetically prone to produce large amounts of IgE when exposed to certain antigens. These antibodies are produced by B lymphocytes and plasma cells controlled by helper and suppressor T lymphocytes. Dysregulation leads to overproduction of IgE of many specificities. Induction or elicitation of immune responses to specific antigens may be facilitated by enhanced antigen presentation and excessive or dysregulated antigen presenting cells. The IgE produced by these responses circulates and the Fc end binds to mast cell Fc receptors on mast cells in the skin. Bridging of specific antigen across two IgE molecules on the surface of the mast cell cause granule and mediator release into the surrounding dermis, such as histamine, leukotrienes, proteases and other vasoactive and
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pro-inflammatory agents. These tickle cutaneous nerves to cause pruritus and dilate cutaneous blood vessels to cause erythema. Direct damage to the skin by these or other mediators or indirect damage to the epidermis by a late phase reaction or by scratching could produce acute or chronic eczematous dermatitis. Contact allergy as a flare factor There are at least three types of contact allergic reactions: allergic contact dermatitis, contact urticaria, and a novel eczematous reaction mediated by IgE and elicited by prolonged contact of antigen with skin. All three types elicit an inflammatory reaction, albeit by different mechanisms. Allergic contact dermatitis Allergic contact dermatitis is a prototypic eczematous dermatitis mediated by lymphokines produced by activated T lymphocytes responding to specific antigens. The disorder resembles atopic dermatitis in both clinical and histological respects [25]. Clinically there is acute or chronic eczematous dermatitis with notable roughness, scale, erythema, weeping, crusting, and pruritus. Histologically there is spongiosis, exocytosis of inflammatory cells, and a perivascular round cell infiltrate, primarily composed of lymphocytes and histiocytes. Dermatitis develops 4-72 h after exposure to antigen and often the dermatitis lasts several weeks. Although atopic dermatitis does not usually have the severe acute changes of allergic contact dermatitis, it could be an allergic contact dermatitis from reaction to an environmental antigen or even a normal constituent in or on the skin itself. Indeed, the T cells infiltrating lesions of atopic dermatitis express CD4 and class II antigens [ 15,161 similar to lymphocytes mediating allergic contact dermatitis. The subtle global deficit of cell mediated immunity detected in patients with atopic dermatitis by intradermal skin tests, mitogen stimulation, quantitation of T and B cell numbers, and impaired induction and elicitation of allergic contact dermatitis to potent
senitizers like dinitrochlorbenzene might be a result of bodily attempts to downregulate the persisting specific allergic reaction in the skin, or to downregulate cell mediated immunity in general [26,27]. Suppressor T cells could blunt both an allergic reaction specifically and cell-mediated reactions globally. Excessive IgE production could also blunt the reaction by eliciting edema via mast cell mediators that washes the antigen away. Despite searches both in the clinic and the laboratory, a relevant antigen eliciting a delayed hypersensitivity response in all patients has not been found. Although numerous antigens elicit wheal and flair reactions mediated by IgE in most patients, patients with atopic dermatitis typically have no propensity to develop allergic contact dermatitis. Occasionally a patient does develop allergic contact dermatitis to a chemical such as a preservative in a therapeutic cream. In these cases, allergic contact dermatitis is best viewed as a flare factor to the unrelated atopic dermatitis. Contact urticaria Contact urticaria is an erythematous wheal and flair reaction mediated by histamine and other mast cell products. An antigen on the skin surface penetrates the epidermal barrier, combines with specific IgE on the mast cell surface, and triggers mediator release [28]. Contact urticaria is a positive prick test without the prick; a positive scratch test without the scratch. The reaction occurs within an hour and usually occurs within seconds or minutes, reaches a peak within a few more minutes, and resolves within the day leaving no residual sign. A pink erythema develops and may be studded with small papular wheals. If eczema is present, these may be difficult to see. Contact urticariais pruritic, but its itch is the kind that does not evoke uncontrolled scratching. The reaction can be suppressed with antihistamines or sympathomimetic agents. A large number of food, dander, cosmetic, and airborne antigens are known that can produce contact urticaria [28]. Although many patients with atopic dermatitis have relevant specific IgE
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antibodies in their plasma and on mast cells, contact urticaria is rarely recognized by patients and even more rarely recognized by physicians. The urtications usually occur in areas of eczema where the epidermis allows better antigen penetration. These areas are already red and itchy. Patients attribute the itch to irritation from the food or antigen, and they attribute the redness and swelling to irritation or the resulting fit of scratching. Physicians rarely see contact urticaria, since the erythema and edema are gone when the patient visits the physician hours to days later. Contact urticaria per se acts as a flare factor because it elicits scratching which elicits eczema. Late phase reactions
Dermatitis may be a consequence of a late phase reaction. This reaction, like contact urticaria, involves mast cells [29,30]. Erythema, induration, and annoying pruritis develop several hours after injection of antigen or mast cell degranulators such as compound 48/80. These reactions reach maximum intensity after about eight hours and often disappear within a day, but may persist for 72 h or more. The initial inliltration of neutrophils, basophils, and eosinophils is replaced by lymphocytes and macrophages. The reaction is mediated by mast cell products including inflammatory factor of anaphylaxis (IF-A), a peptide released slowly from the proteoglycan matrix of the mast cell granule [31]. Leukotriene B4, 12-hydroxyeicosatetranoic acid (12-HETE), platelet activating factor, eosinophil chemotactic factor of anaphylaxis (ECF-A) and neutrophil chemotactic factor of anaphylaxis (NCF-A) may also play some role [32,33]. In contrast to atopic dermatitis, no spongiosis develops. Mitchell [34] elicited an eczematous reaction by abrading the skin of volunteers and applying antigen epicutaneously in a closed patch test system. If the volunteer had previously had a wheal and flare reaction to the chemical by prick test, then he or she developed eczematous dermatitis at the test site. Other volunteers did not. The reaction was specific to specific antigens; that is,
some antigens caused dermatitis is some individuals but not in others and different antigens caused reactions in different subjects, but all reactions occurred only in subjects who developed wheal reactions to the antigen after prick tests. Reitamo et al. [ 351 in a similar study, applied chambers with antigens from birch pollen and house dust mite to patients with atopic dermatitis. Delayed eczematous reactions developed in some but not all patients. Biopsy showed spongiosis and an inflamatory infiltrate consisting primarily of activated T helper cells and Langerhans cells. These eczematous reactions bear pathophysiologic mechanisms similar to the late phase reaction and link type I allergy to atopic dermatitis. On abraided skin, prolonged epicutaneous exposure to antigen produces an eczematous dermatitis from an IgE medicated immune reaction even in the absence of scratching. Apparently the initial urticarial response disappears and is replaced by an eczematous dermatitis when enough antigen and IgE drive the reaction under appropriate conditions for hours or days, especially when the antigen is presented topically. Atopic dermatitis produced by a modified late phase reaction might also explain why patients with atopic dermatitis continue to have dermatitis even after antigens are removed. When a late phase reaction occurs in the respiratory tract, it produces airway wheezing. The respiratory tract then becomes hypersensitive to a variety of other stimulae. Patients with asthma wheeze after inhaling histamine or methacholine in the clinic or after inhaling cold air or chemical fumes in the environment. In the skin, a similar phenomenon might occur to explain provocation of eczema by xerosis, sweating, rough clothes, or marginal irritants such as soaps. Mechanistically, chronic antigen-independent stimulation of dermatitis may be due to recruitment of basophils to the area by the original allergic reaction and self perpetuation of basophil and mast cell mediator release by neutrophils and neutrophil-derived histamine releasing factor (HRA-N) [31]. IgE might also mediate other forms of cellmediated immune reactions. Ray et al. [36] in-
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jetted mice with monoclonal IgE directed against determinants on dinitrofluorobenzene (DNFB). Subsequent challenge with DNFB elicited a delayed reaction in BALB/C mice but not in nude mice. This reaction was indistinguishable from the reaction that occured in mice sensitized by epicutaneous application of DNFB, but did not occur in BALB/C mice induced with monoclonal IgA-antiDNFB antibody. Another link between cell-mediated immunity and IgE may be on the surfaces of Langerhans cells. Many, but not all, Langerhans cells in the dermis of patients with atopic dermatitis have both Fc receptors for IgE and IgE itself on their surfaces [20-241. Antigen-specific IgE could act as a receptor for antigen to trigger an antigen processing/presenting sequence eliciting a T lymphocyte immune response. This is speculative because no function for these receptors has been found to date. Antigens
Many antigens could be relevant. Some could be delivered to the skin via the blood, while others could penetrate through intact or eczematous skin. The antigens could be foods, house dust mites, animal hairs, molds, pollens, bacteria, foreign proteins or other exogenous substances. They could also be endogenous substances such as a component of dander or sweat. The skin of patients with atopic dermatitis is heavily colonized with bacteria, especially Staphylococcus aureus [ 37-391. Acute exudative lesions carry about 10,000,000 bacteria on each square centimeter. Even the clinically uninvolved skin may carry large numbers (10,000 bacteria/sq.cm) of S. Aureus. These bacteria lie within the stratum corneum, on it, and on the crusted weepings and excoriations that litter it. Surface bacteria are only millimeters away from dermal mast cells. Some patients with atopic dermatitis have high levels of antistaphylococcal IgE which can mediate mast cell degranulation [ 40,4 11. Even in the absence of these specific antibodies, staphylo-
coccal protein A can probably trigger mediator release by interacting with the F(ab’)2 region of nonspecific IgE and/or IgG to provoke eczema [42,43]. Protein A can also cause delayed reactions when injected intradermally [ 441. Similarly, high serum IgE levels to Pityrosporon orbiculare are found in some patients with atopic dermatitis, especially among patients suffering from head and neck dermatitis [45]. During natural decomposition of stratum corneum proteins, monosaccharide-lysine residues are formed which can be allergenic [ 461. The major proteins have approximate molecular weights of 10,000 and 13,000 kDa [47]. Patients with atopic dermatitis react to patch tests with mixtures of pooled human danders as well as their own [47-5 13. Uehara and Ofugi [ 521 found 61 of 98 patients with atopic dermatitis reacted to scalp danders applied as patch tests. Only one of 31 normal subjects responded similarly. Reactions lasted for several days and the histology showed eczema. Intradermal tests were also positive at 48 h. Mold extracts frequently produce positive prick test results in patients with atopic dermatitis, even in those with no coexisting respiratory allergy [8,53]. These molds include species of altemaria, hormodendrum, penicillium, rhizopus, mucor, and aspergillus. Skin test reactions to molds may be delayed and persist for up to two weeks. House dust includes molds, but also includes the house dust mite Dermatophagoidespteronysinus or D.farinae [47]. Mite feces are also allergenic [54]. Gondo et al. [55] applied ointments containing ferritin-labelled and unlabeled crude mite antigens to scratched skin of a patient with atopic dermatitis and high levels of IgE antibodies to mite antigens. Both immediate urticarial and delayed eczematous reactions were elicited. Norris et al. [56] applied solutions of house dust mite antigens to eczematous and normal skin of patients with atopic dermatitis in a double blind study. One third of subjects with positive prick tests to house dust mite showed ‘marked or moderate deterioration after 5 days’ on both
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mildly involved and uninvolved skin. Apparently mite antigens can cause eczematous reactions when applied to the skin of at least some atopic patients. Contact with foods frequently elicits contact urticaria, especially in atopic patients with hand eczema. Aggravation of hand dermatitis by contact with food is well documented [ 57-601. Fish, fruits, meats, grains, spices, and vegetables have all been implicated. Provocation of atopic dermatitis by ingestion of foods is more controversial [lo]. Appropriate double-blind challenge studies are difficult to do because the taste of foods is difficult to disguise. Nonetheless, Sampson and Jolie’s [ 91 double-blind study not only found foods which exacerbated dermatitis, but also showed increased plasma histamine levels in these subjects but not in normal subjects or atopic subjects without prick test allergy to the foods in question. Some investigators suggest the response of skin to allergen avoidance diets is slow and may require four to six months. Patients with food hypersensitivity have high rates of spontaneous histamine release from basophils. This response returns only slowly toward normal when antigen is eliminated [61]. Summary
There are other nonimmunologic hypotheses which can explain many of the above and other findings. Szentivanyi [62] suggested that cells behave abnormally as though their betaadrenergic receptors are blocked, and Grewe et al. [ 631 noted elevated phosphodiesterase levels in leukocytes from patients even when in remission. These abnormalities suggest perturbed cell function leading to abnormal vascular responses, decreased itch thresholds, low thresholds for mast cell degranulation, unrestrained IL-l production, and disregulation of humor-al and cellmediated immunologic responses. Scratching may eczematize skin. Patients with atopic dermatitis who are unable to scratch or neurologically unable to sense itch see their dermatitis improve and disappear. Conversely,
patients with scabies, dermatitis herpetiformis, and other severely pruritic non-eczematous skin diseases frequently develop patchy eczema between lesions from scratching and mediator release [ 641. The high counts of bacteria on the skin may be due to plasma leakage to the surface from spongiosis, weeping, or excoriation. Elevated serum levels of IgE and immune disregulation may be a consequence of the continuous insult of the skin surface by digging fingernails or abrasive appliances and the resulting inoculation of various chemicals into the dermis. There are other compelling hypotheses too. There is also the possibility that atopic dermatitis is more than one disease, so, for example, that patients with normal IgE levels really have something else. Whatever causes atopic dermatitis, allergic reactions can cause it to appear or flare in at least some patients. Allergy may simply be one of many flare factors aggravating atopic dermatitis, but it is also possible allergy is somehow its cause. References 1 Hanifin JM, Rajka G: Diagnostic features of atopic dermatitis. Acta Derm Venerol 92 (suppl): 44-47, 1981. 2 Dahl MV: Atopic dermatitis: the concept offlare factors. S Med J 70: 453-455, 1977. 3 Cooper KD: Mechanisms of atopic dermatitis, in Immune Mechanbms of Cutaneous D&ease. Edited by DA Norris. Marcel Dekker Inc, New York, 1989, pp 247-276. 4 Ogawa M, Berger PA, McIntyre OR, Clendenning WE: IgE in atopic dermatitis. Arch Dermatol 103: 575-580, 1971. 5 Stone SP, Mulle SA, Gleich GJ: IgE levels in atopic dermatitis. Arch Dermatol 108: 806-811, 1973. 6 Uehara M: Heterogeneity of serum IgE levels in atopic dermatitis. Acta Derm Venerol (Stockholm) 66: 404-408, 1986. 7 Swainson JA, Wilson PB, Dore P, Pumphrey RSH: Evidence for circulating immune complexes containing IgE in patients with atopic dermatitis. Int Arch Allergy Appl Immuno178: 995-999, 1986. 8 Rajka G: Atopic Dermatitis. WB Saunders Co Ltd, London, 1975. 9 Sampson HA, Jolie PL: Increase plasma histamine concentrations after food challenge in children with atopic dermatitis. N Engl J Med 311: 372-376, 1984. 10 Atherton DJ: Diet and atopic eczema. Clin Allergy 18: 215-228, 1988.
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are the major source of house dust allergens. Nature 289: 592-593, 1981. Gondo A, Saeki N, Tokuda Y: Challenge reactions in atopic dermatitis after percutaneous entry ofmite antigen. Br J Dermatol 115: 485-493, 1986. Norris P, Schontield 0, Camp R: A study of the role of house dust mite in atopic dermatitis. Br J Dermatol 118: 435-440, 1988. Cronin E: Dermatitis in food handlers. Adv Dermato14: 113-123, 1989. Niinimaki A: Scratch-chamber tests in food handler dermatitis. Contact Derm 16: 1l-20, 1981. Rystedt I: Work-related hand eczema in atopics. Contact Derm 12: 164-171, 1985. Peltonen L, Wickstrom G, Vaahtoranta M: Occupational dermatoses in the food industry. Dermatosen 33: 166-169, 1985. Sampson HA, Broadbent KR, Bemhisel-Broadbent J: Spontaneous release of histamine from basophils and histamine releasing factor in patients with atopic dermatitis and food hypersensitivity. New Engl J Med 321: 228-232, 1989. Szentivanyi A: The biochemical pharmacology of adrenergic reactions as related to the pathogenesis of bronchial asthma. Annals of Allergy 24: 253-254, 1966. Grewe Sr, Chan SC, Hanitin JM: Elevated leukocyte cyclic AMP-phosphodiesterase in atopic disease: a possible mechanism for CAMP-agonist hyporesponsiveness. J Allergy Clin Immunol 70: 452-457, 1982. Nishioka K et al.: Histamine release by scratching inflamed skin. J Dermatol (Tokyo) 14: 284-285, 1987.