Springer Semin Immunopathol (1992) 13:427-440

Springer Seminars in Immunopathology 9 Springer-Verlag 1992

Immunopathology of atopic dermatitis Donald Y.M. Leung Division of Pediatric Allergy-Immunology,The National Jewish Center for Immunology and Respiratory Medicine, Department of Pediatrics, University of Colorado Health Sciences Center, 1400 Jackson Street, Denver, CO 80206, USA

Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease that frequently occurs in patients with a personal and/or family history of atopy [19, 31]. Its onset usually occurs during infancy or early childhood. Recent studies suggest that approximately 10% of children are affected by AD. During infancy, AD is typically characterized by an erythematous papulovesicular rash, i.e., acute eczematoid lesions, on the face and the extensor surfaces of the extremities. In more severe cases, generalized skin involvement with weeping lesions and impetiginization is often seen. Childhood AD is characterized by an erythematous papular rash involving the flexural surfaces as well as the face and neck. In adults, AD also involves the flexural regions but is characterized by dry, scaly, papular and lichenified lesions, i.e., chronic lesions. In practice, however, patients with chronic AD usually do not clearly segregate into distinct eczematoid reaction patterns. Indeed, adult patients with severe chronic AD are more likely to have a persistent infantile pattern to their skin disease. At all phases of illness, these patients suffer from marked pruritus that is exacerbated by multiple triggers including allergens, infection, reduced humidity, excessive sweating and irritants such as wools, acrylics, soaps or detergents. During the past 10 years, there has been considerable progress in our understanding of the immunologic basis of allergic diseases. The functional distinction between T helper cells on the basis of the cytokines they produce, in particular, the compartmentalization of IL-4 and IL-5 to T helper type 2 (Th2) cells has provided an important immunologic framework to study allergic diseases [42]. This review will describe the immunoregulatory features of AD and the insights they provide into the pathogenesis of this fascinating disease.

Pathologic features of AD The alterations observed by routine histology of AD skin lesions are not specific and can frequently be found in a variety of inflammatory skin disorders, including

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contact dermatitis, acute photoallergic dermatitis and inflammatory pityriasis rosea. The histopathology of AD generally depends on the stage of the dermatitis [29, 40]: acute eczematoid lesions are characterized by intraepidermal vesicles, intercellular edema (spongiosis) of the epidermis, and a dermal perivenular inflammatory cell infiltrate consisting predominantly of lymphocytes, and occasional monocyte-macrophages. Only rare eosinophils, basophils, and neutrophils are present. Mast cells are frequently hypogranulated and present in normal numbers when compared with clinically uninvolved skin or skin from normal control subjects. The endothelial cells of the superficial venular plexus, a site where inflammatory cells egress, are frequently enlarged and contain large nuclei with prominent nucleoli. In chronic lichenified lesions, the epidermis is hyperplastic with elongation of the rete ridges, prominent hyperkeratosis and minimal amounts of spongiosis. There is an increase of Langerhans cells in the epidermis, and macrophages dominate the dermal infiltrate. The number of mast cells are increased in number and are generally fully granulated. Alterations of the superficial venular plexus and deep venules include endothelial cell hypertrophy with enlarged nuclei and prominent nucleoli, and basement membrane thickening. Demyelination and fibrosis of the cutaneous nerves can be seen at all levels of the dermis in the chronic lesion. Using monoclonal antibodies on frozen skin sections, immunohistochemical staining of acute and chronic skin lesions in AD reveal that the lymphocyte infiltrate consists predominantly of T cells bearing the CD3, CD4 and HLA-DR surface antigens with only occasional CD8 + T lymphocytes [30]. There are no natural killer cells or B cells. Increased numbers of Langerhans cells expressing the CD1 surface antigen and HLA-DR surface antigen are present in the dermis and epidermis of chronic lesions to a greater degree than in acute lesions. Langerhans cells as well as macrophages infiltrating into the AD skin lesion have been found to have surface-bound IgE molecules [32]. Intact eosinophils are infrequently observed in the lesional skin of AD. However, Leiferman and co-workers [27] have reported that extracellular major basic protein (MBP) derived from the eosinophil granule can be detected by immunofluorescence in a fibrillar pattern resembling the distribution of elastic fibers throughout the upper dermis. In more than half of AD specimens examined they also found MBP deposition in a granular pattern deeper in the dermis. When involved and uninvolved areas of skin were compared, extracellular MBP deposition was much more extensive in the involved areas. Although the role of MBP in the pathogenesis of AD is unknown, it has been postulated that it may contribute to tissue injury in AD through its cytotoxic properties and its capacity to induce basophil and mast cell degranulation [17].

Role of IgE and allergens in AD Several observations suggest that IgE and allergens contribute to the pathogenesis of this skin disease. Of AD patients 80%-90% have a family history of atopy.

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Serum IgE levels are elevated in 80%-85% of patients with AD [28], and are highest in patients with coexisting allergic rhinitis and/or asthma [23]. A correlation between degree of serum IgE elevation and the severity or extent of skin involvement has also been reported. Approximately 85 % of patients have positive immediate skin tests to a variety of food and inhalant allergens [48]. A relationship, however, between skin test reactivity to implicated allergens and the course of the disease has been difficult to establish. Thus, there has been considerable controversy over the significance of immediate skin test reactivity in AD. Substantial evidence has now, however, accumulated to support the notion that food allergens can exacerbate skin rashes in at least a subset of patients with AD. As early as 1915, Schloss [61] noted that avoidance of specific foods resulted in the improvement of AD. In the 1930's, Walzer demonstrated that food proteins could rapidly cross the gastrointestinal mucosa into the circulation, and induce cutaneous mast cell degranulation within 90 min of food ingestion [75]. In 1978, Bock and May first documented the role of foods in AD using double-blind, placebo-controlled food challenge (DBPCFC). In 5 of 9 patients with a history of eczematous reactions to foods, oral challenge resulted in the appearance of typical lesions within 2 h [4]. Subsequently, Sampson studied a large number of children with AD using DBPCFC [55]. Out of 210 patients, 130 patients had a reaction to at least one food during the DBPCFC. Egg, peanut, milk, soy, wheat and fish accounted for almost 90% of positive food challenges [55, 58]. Of the 235 positive food-induced reactions observed in these 130 patients, 75 % of the reactions involved the skin [54]. These skin reactions developed within 2 h of challenge and were characterized by pruritus, erythema, macular or morbilliform rashes. Urticarial lesions were very uncommon. Although these lesions would resolve within 3 h, some patients developed pruritus and macular reactions 6 to 8 h later. Patients experiencing several such reactions during a week of DBPCFC's often developed typical eczematous skin lesions. The latter observation would suggest that repeated ingestion of foods and the excoriations that result from such exposure contributes to the development of AD skin lesions. Since most patients with AD do not have food allergy, there has also been considerable interest in the potential role of inhalant allergens in this illness. In 1918, Walker first reported several patients who had flaring of their AD on exposure to horse dander or ragweed pollen [74]. In the 1950's, Tuft and coworkers demonstrated that in patients with AD, sweating, pruritus and eczematoid skin lesions developed after inhalation challenge with either Alternaria [68] or ragweed pollen [67]. Further studies have speculated on the role of direct contact by inhalants in the development of AD lesions. In a group of patients sensitized to dust mite, Mitchell and co-workers [41] reported that patch testing of abraded skin with mite extract resulted in an eczematous rash. In a study of 18 patients with AD and immediate hypersensitivity reactions to inhalant allergens, Clark and Adinoff [9] observed positive patch tests on nonabraded skin to: dust mite in 39 % of patients, to weeds in 33%, to animal danders in 44% and to molds in 33% of patients. Avoidance of aeroallergens that elicited an eczematous reaction at patch test sites resulted in marked improvement or resolution of AD in all patients. Environmental rechallenge with incriminated allergens resulted in flares of AD. These studies suggest that aeroallergen contact may play a role in the exacerbation

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of AD in select patients. Further controlled studies are needed, however, before the exact role of inhalant allergens in AD can be established.

Role of infection in AD

Patients with AD have an increased susceptibility to various viral infections of the skin including Herpes simplex (eczema herpeticum), Verruca vulgaris (common warts), Molluscum contagiosum, and rarely Vaccinia [22, 36]. They are also prone to cutaneous infection with superficial dermatophytosis, particularly with Trichophyton rubra. P i t y r o s p o r u m ovale is a lipophilic yeast that colonizes seborrheic areas of the skin. Increased serum IgE levels have been reported to both Trichophytic antigens and to P. ovale in AD patients [25]. The greatest attention, however, has probably focused on the potential role of Staphylococcus aureus colonization and infection to the severity of this skin disease. Leyden and co-workers [37] showed that S. aureus was found in over 90% of their AD lesions. In contrast, the skin of normal subjects harbors this organism only in 5 % of the cases, and its localization is mainly in the nose and intertriginous areas. Using quantitative methods, the density of S. aureus on inflamed AD lesions without clinical superinfection can reach up to 10 7 colonyforming units/cm 2 [20]. Although recurrent staphylococcal pustulosis can be a significant problem in AD, invasive S. aureus infections occur rarely. Clinically, it is also well known that not only patients with impetiginized AD but also patients without superinfection show a better clinical response to combined treatment with anti-staphylococcal antibiotics and topical corticosteroids than to corticosteroids alone. These clinical observations clearly do not definitively demonstrate a cause and effect relationship between colonization or infection with S. aureus and the exacerbation of skin disease. Indeed, it could be argued that the increased presence of bacteria on eczematoid skin lesions is due to decreased local immunity or biochemical changes resulting from severe skin inflammation. The recent observations, however, that staphylococcal enterotoxins (SEs) are potent stimulators of macrophages and T cells provides a new mechanism by which S. aureus could exacerbate skin disease [39]. SEs are prototypic superantigens which stimulate large populations of T cells in a class II MHC-dependent, yet unrestricted manner. Once bound to class II MHC molecules, SEs selectively stimulate T cells expressing particular T cell receptor (TCR) /3 chain-variable (V~) gene segments [39]. Other variable elements (D~, J~, V~, J~) of the TCR contribute little to the recognition of these so called V~-specific superantigens, as they do for conventional antigens. SEs are also potent inducers of IL-1 and TNF-o~ from monocytes. SE-mediated stimulation of monocytes is a consequence of binding and transducing a positive signal through MHC class II antigen on the monocyte cell surface. This process can be blocked by anti-class II antibodies. The capacity of bacterial toxins to bind to MHC class II molecules or stimulate T cells bearing particular TCR V~s provide several mechanisms by which S. aureus could exacerbate AD. First, SEs secreted at the skin surface could

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penetrate inflamed skin and engage HLA-DR on epidermal macrophages or Langerhans cells to stimulate the production of IL-1 and TNF. IL-1 and TNF have potent proinflammatory properties which may contribute to skin inflammation. Second, bacterial toxins could stimulate a high proportion of T cells via their TCR V~ to divide and produce cytokines which modulate tissue inflammation. Finally, we have recently found that a subset of AD patients with frequent staphylococcal infections have circulating IgE directed to SEs, such as toxic-shock syndrome toxin-l, or SEB, which have been identified on their skin [35]. Furthermore, their own basophils release histamine on exposure to the relevant exotoxin but not in response to exotoxins in which there is no IgE response. These findings suggest the possibility that local production of exotoxin at the skin surface could cause IgE-mediated histamine release and thereby trigger the itch-scratch cycle which can exacerbate AD.

Mechanisms of IgE-mediated skin inflammation A number of investigators have been reluctant to accept the concept that IgEmediated mechanisms play a role in the pathogenesis of AD because routine histology of the skin lesion in AD more closely resembles a type IV delayed-type hypersensitivity reaction than a type I immediate hypersensitivity skin reaction [40]. The demonstration that clinically significant allergen-induced reactions are generally characterized by an IgE-dependent biphasic response [13, 64] has provided an explanation for the presence of inflammatory cells in allergic reactions. In cutaneous biphasic reactions, following exposure to allergen, mast cells bearing IgE directed to the relevant allergen become activated and release histamine as well as other mediators, cytokines and leukocyte chemotactic factors into local tissue. This immediate reaction is associated with pruritus, erythema and capillary leakiness. It is generally evident within 15-60 min of allergen challenge, and subsides within 30-90 min after allergen injection. Three to four hours after the immediate reaction begins to subside, there is onset of a late-phase reaction (LPR) characterized initially by the infiltration of eosinophils, neutrophils and mononuclear cells into the inflamed area. Granulocytes reach their maximum cell accumulation at 6-8 h, and by 24-48 h after onset of the reaction the cellular infiltrate consists predominantly of mononuclear cells. The histologic appearance of an IgE-mediated LPR is similar in appearance to a type IV delayed-type hypersensitivity reaction and the eczematoid skin lesion found in AD. Recently, there have several important insights into the immunologic events that accompany allergen-induced LPRs. Using in situ hybridization, Kay and coworkers [24] have demonstrated that the T cell infiltrate in allergen-induced latephase skin reactions contain increased mRNA for IL-3, IL-4, IL-5 and granulocyte/macrophage colony-stimulating factor (GM-CSF) but no mRNA for IFN-7. In this regard, a recent study found that antigen-specific T cells grown from acute AD lesions produced IL-4 but not IFN-3, [69]. These results suggest that the T cells infiltrating into the allergen-induced LPR are equivalent to the

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murine T helper type 2 (Th2) subset. In contrast, type IV contact-sensitivity reactions are associated with the infiltration of IL-2- and IFN-3,-secreting T helper type 1 (Thl) cells. These observations may account for the observation that keratinocytes in type IV skin reactions, but not in AD lesions, express HLA-DR surface antigen [2]. It has also been demonstrated that LPRs are associated with the release of cytokines such as IL-1 and TNF [3]. These cytokines have been demonstrated to play an important role in the induction of leukocyte adhesion molecules [11]. In this regard, we and others have found that the AD lesion (Leung, Pober and Cotron, unpublished observations) and the LPR are associated with the induction of leukocyte adhesion molecules such as ELAM-1 and ICAM-1 [26, 34]. More importantly, the induction of LPRs can be blocked by neutralizing antibodies to IL-1 and TNF. Thus, the release of such cytokines may represent an important regulatory event in the local accumulation of inflammatory cells at the site of allergic reactions. In at least one subset of AD patients, several observations support the concept that IgE-mediated LPRs have an important role in the pathogenesis of food induced AD. First, immediate hypersensitivity skin reactions are invariably found to the food which induces the positive food challenge [58]. Second, patients with negative immediate skin testing generally have negative PCDBFC [56]. Third, patients experiencing a positive food challenge have been found to have a significant rise in their plasma histamine level, whereas those patients having no symptoms to a food antigen or placebo have no change in plasma histamine [57] . Fourth, skin biopsies done in patients with AD prior to food challenges have demonstrated the absence of cutaneous eosinophils in uninvolved skin sites [55]. Several hours following positive food challenges, eosinophils can be observed infiltrating into areas of erythema. The observation that eosinophilic MBP is deposited in the skin lesions of patients with chronic AD suggests that mast cell degranulation from chronic exposure to allergens may also contribute to the pathogenesis of AD [27]. The elaboration of histamine-releasing factors by infiltrating mononuclear cells may also serve to sustain the mast cell activation and secretion of mediators into the skin [38]. IgE molecules may also participate in a number of mechanisms other than direct IgE allergen activation of mast cells. For example, histamine-releasing factors secreted by activated lymphocytes and monocytes have been reported to induce the degranulation of mast cells and basophils by binding to surface-bound IgE molecules [38]. In a study by Sampson and co-workers [59], basophils from children with AD and food hypersensitivity were found to have high spontaneous basophil histamine release. Their peripheral blood mononuclear cells (PBMC) also secreted high levels of histamine-releasing factors. After these children were placed on food-elimination diets, their increased production of histamine-releasing factor and elevated spontaneous basophil histamine release dropped to normal levels. They were also observed to have concomitant clearing of their skin rash. Langerhans cells and macrophages infiltrating into the AD skin lesion bear IgE antibody on their cell surface [32], presumably due to increased local production of IL-4 resulting in the expression of CD23 [71]. In other settings, allergens have been demonstrated to activate such cells in an IgE-dependent manner with

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the formation of leukotrienes, PAF, IL-1, and TNF [6, 14, 54]. Patients with AD possess circulating autoantibodies to IgE which can also activate macrophages bearing IgE ([47] and Leung, unpublished observations). IL-1 and TNF are known to activate vascular endothelium and initiate leukocyte recruitment via the induction of endothelial leukocyte adhesion molecules [ 11]. The activation of IgE-bearing Langerhans cells (IgE+LC) and macrophages by allergens and autoantibodies to IgE could, thus, contribute to the skin inflammation associated with AD. Although IgE+LC and macrophages have been found in other inflammatory skin diseases such as psoriasis, these other skin conditions are not been associated with the production of allergen-specific IgE. Thus, the expression of IgE+LC in these inflammatory skin conditions may not have the same pathogenic consequences as in AD. Recently, Mudde and co-workers [43] have also investigated the role of IgE+LC from AD in antigen presentation. IgE+LC were found to be as effective as IgE-LC in the stimulation of T cells responding to Candida albicans. However, IgE+LC but not IgE-LC were capable of presenting house dust allergen to T cells. These results suggest that cell-bound IgE on LC may facilitate binding of allergens to LCs prior to their processing and antigen presentation. The critical role of LCs in the activation of T cells in AD is further supported by a recent report that CD1 +CD36 + LC are responsible for increased autologous T lymphocyte reactivity to lesional epidermal cells in patients with AD [66].

The role of T cells in AD

There has been considerable interest in the possibility that abnormalities of T cell function may contribute to the elevated serum IgE levels and eczematoid rashes observed in AD. This concept is supported by the observation that patients with primary T cell immunodeficiency disorders such as DiGeorge syndrome and Wiskott-Aldrich syndrome [7] frequently have elevated serum IgE levels and eczematoid skin lesions indistinguishable from AD. In the case of Wiskott-Aldrich syndrome, clearing of the skin rash and normalization of serum IgE levels occur following successful bone marrow transplantation [60]. Nonatopic recipients who have received bone marrow transplants from atopic donors have subsequently been shown to develop positive immediate skin tests and atopic symptoms following successful engraftment [1]. These data suggest that atopic eczema is not due to a constitutive skin defect but rather the dysfunction of a bone marrow-derived cell. Studies dating back to the early 1970's, in rodents, have demonstrated that T cells play a critical role in the development of IgE responses [45]. The critical events, however, involved in the induction of IgE synthesis in humans have only recently been identified. The induction of IgE synthesis in human B cells requires at least two signals: the first signal is delivered by IL-4 which acts as an IgE-isotype switch factor causing the transcription of 1.7-kb IgE germ-line mRNA transcripts but not 2.2-kb productive IgE mRNA transcripts [16]. The second signal can be delivered by a variety of B cell activators which can induce the expression of productive 2.2-kb IgE mRNA transcripts when co-stimulated with IL-4. This is

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followed by the synthesis and secretion of IgE antibody. To date, a variety of second signals that synergize with IL-4 to induce IgE synthesis have been identified. These include: signals delivered by T cells via the T cell receptor and/or surface molecules which act on B cells in a non-cognate interaction, EBV infection, monoclonal antibodies to the CD40 surface antigen on B cells, and hydrocortisone [70]. IL-4-dependent IgE synthesis is subsequently amplified by other cytokines such as IL-5, a B cell growth factor, and IL-6, a B cell differentiation factor. Of potential interest, from a therapeutic viewpoint, are reports that IFN-3, suppresses IgE synthesis in vivo and in vitro by B cells from experimental animals and humans [21, 63, 70]. Furthermore, it has been reported that the capacity of human and mouse T cell clones to induce IgE synthesis is directly correlated with the ratio of secreted IL-4 to IFN-7 [46]. IFN-3/has also been reported to inhibit the capacity of IL-4 to induce CD23 (low-affinity IgE receptor) on B cells [12]. The mechanisms of functional antagonism between IFN-3, and IL-4 are poorly understood. It has, however, been clearly demonstrated, particularly in mice, that these interleukins are produced by different T helper (Th) cell subpopulations. Thl cells produce IL-2 and IFN-3,, whereas Th2 cells produce IL-4 and IL-5 [42]. Furthermore, the addition of IL-4 to lymphocytes undergoing activation in vitro results in down-regulation of IFN-3, production with concomitant enhancement of IgE synthesis [72]. These observations may explain the functional antagonism between IL-4 and IFN-3,. More importantly, it suggests that highly atopic patients have a dysregulation of IL-4 and IFN-3, production, possibly resulting from a high frequency of Th2 cells. Several clinical observations suggest that patients with AD have cellular defects in their immune system [28]. Their propensity to develop cutaneous viral infections and dermatophytosis suggests an underlying T cell defect. Patients with AD have also been reported to have a reduced incidence of contact sensitization as well as decreased sensitization to poison ivy. More recently it has been reported that patients with AD have decreased contact sensitization to dinitrochlorobenzene [49] than normal subjects. These clinical observations are supported by a number of laboratory observations that suggest an underlying immunoregulatory abnormality in AD. These include studies which demonstrate that PBMC from AD patients contain decreased CD8 + suppressor/cytotoxic T cell number and function [30]. The latter may partially account for the increased frequency of viral infections in AD. The relative lack of suppressor T cell activity in AD is associated with evidence of concomitant cellular activation. In this regard, elevated serum levels of soluble IL-2 receptor are frequently elevated in symptomatic patients [10]. B cells and monocytes from AD patients express increased levels of the CD23 (low-affinity IgE receptor) surface antigen. Furthermore, peripheral blood B cells from AD patients spontaneously produce high levels of IgE. Since IL-4 plays an important role in the induction of IgE synthesis and CD23 expression on B cells and monocytes, these observations suggest that AD is associated with increased secretion of IL-4 in vivo. Indeed, several investigators have reported that the increased spontaneous production of IgE in vitro by lymphocytes from AD patients can be inhibited by the addition of anti-IL-4 [53, 73]. Furthermore, T cells from atopic individuals have been reported to secrete increased amounts of IL-4 [53].

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PBMC from AD patients have also been found to have a decreased capacity to produce IFN-3, in response to a number of stimuli [50, 53]. A significant correlation has been reported between IFN--y generation in vitro and IgE serum concentrations in vivo in AD [50]. Since IL-4 and IFN--y have pleiotrophic effects on the immune system, the combined effects of elevated IL-4 synthesis and defective production of IFN- 7 may affect not only the synthesis of IgE, but also antigenpresenting cell and cytotoxic/suppressor T cell activation, as well as anti-viral activity. These abnormalities could then contribute to the complex clinical picture seen in AD. A critical question in this scenario is why patients with AD fail to terminate the normal chain of cellular responses initiated by allergen. Two possibilities are: (a) these patients are continuously being exposed to food and aeroallergens, and thus, are repeatedly triggering allergic responses, and (b) some patients with AD may have a regulatory T cell defect involving the production of cytokines required to terminate immune responses. In this regard, the observation that patients with severe AD are deficient in their capacity to produce IFN- 7 may be relevant because, as noted above, IFN-'y has been found to inhibit IgE synthesis and CD23 expression. Furthermore, it has been found that IFN-3, inhibits T cell proliferation of murine IL-4 producing Th2 cells [15]. Since T cells infiltrating into the AD lesion appear to be the human equivalent of Th2 cells [69], the lack of IFN--y production may contribute to the increased IgE synthesis and sustained T cell activation observed in AD. Further studies, however, are needed before any firm conclusions can be made.

Effects of immunomodulatory therapy on AD Since AD is associated with abnormalities in immune regulation, therapy directed toward correction of their immune dysfunction represents a potential approach in the treatment of this chronic illness. The clinical and immunologic response to such therapy may also provide important insights into the critical events involved in the pathogenesis of this skin disease. In this regard, thymopentin, a synthetic pentapeptide which promotes differentiation of thymocytes and effector T cell function, has been found in a double-blind placebo-controlled study of 100 patients to cause significant relief of pruritus and erythema due to AD [33]. The critical role that cytokines play in the pathogenesis of AD is suggested by the observation that cyclosporine effectively inhibits the skin inflammation associated with this disease [65]. As already discussed, IFN-3, suppresses IgE responses and has pleiotropic effects on immune effector cell function. In an open label study, Boguniewicz et al. [5] reported that 23 patients with chronic AD had a marked reduction in clinical severity following therapy with recombinant(r) IFN-3,. A significant inhibition of spontaneous IgE synthesis by circulating lymphocytes was also noted in patients receiving rIFN-'y therapy. More recently, in a multi-center, randomized, placebo-controlled, double-blind trial of 83 patients, rIFN-7-treated patients had a more significant decrease in skin severity as compared to the

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Table 1. Immunologic features of atopic dermatitis 9 9 9 9 9 9 9 9

Increased IgE production Immediate skin test reactivity to allergens Cutaneous infections Increased basophil histamine release Decreased CD8 suppressor/cytotoxicnumber and function Increased expression of CD23 on mononuclear cells Increased production of IL-4 Decreased production of IFN-3,

placebo-treated group [62]. During this trial, patients treated with rlFN-~/were also noted to have a more significant reduction in their mean circulating total eosinophil count than patients treated with placebo. The immunologic mechanism(s) by which rlFN--y reduces skin inflammation, IgE synthesis and eosinophil counts in AD are presently unknown. However, if AD is associated with the overexpansion of circulating and skin infiltrating IL-4and IL-5-producing Th2 cells, one reasonable hypothesis may be that rlFN-3/is acting to reduce the proliferation of such cells, and thus direct the expansion of IFN-3,-producing Thl cells. Indeed, studies with murine T cell clones indicate that rlFN-~f can selectively inhibit Th2 proliferation more than Thl proliferation [15]. Furthermore, we have recently observed that PBMC from patients with AD produce increased levels of IL-4, and express increased levels of IL-4 receptor [5 I]. Treatment of AD PBMC in vitro with rlFN-'y decreases the production of IL-4 and IL-4 receptor expression [51].

Conclusions In summary, AD is a chronic inflammatory skin disease associated with increased IgE production, eosinophilia, increased mast cell number and increased expression of the CD23 low-affinity IgE receptor on mononuclear cells. The basis of these immunologic defects appear to be the result of increased numbers of IL-4-, IL-5-producing Th2 cells. This results in an overstimulation of their IL-4-IL-4 receptor pathway that is accompanied by a relative deficiency oflFN-3~ production. The acute manifestations of AD occur as the result of mast cell degranulation that can be triggered by a variety o f stimuli including allergens, bacterial toxins or histamine-releasing factors secreted by activated T cells and macrophages. Mast cells release not only histamine which contributes to the acute sensation of pruritus but also cytokines and chemotactic factors which induce leukocyte adhesion molecules and attract inflammatory cells into the local tissue sites [3, 8, 26, 34]. The chronic manifestations of AD are probably the result of sustained cellular activation. The cellular infiltrate in the chronic lesion of AD consists primarily of T cells and macrophages [29]. T lymphocytes play two important roles in allergic responses: First, as already discussed they play a critical role in the regulation of IgE responses. Second, there is increasing evidence that they may play

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an i m p o r t a n t role in the control o f the i n f l a m m a t o r y response. This is o r c h e s t r a t e d through o r g a n i z a t i o n o f the c e l l u l a r c o m p o s i t i o n o f the i n f l a m m a t o r y cell infiltrate by the release o f v a r i o u s c y t o k i n e s . The release o f I L - 3 , I L - 5 , and G M - C S F have p r o n o u n c e d effects on the differentiation and activation o f e o s i n o p h i l s [52]. IL-3 p r o m o t e s the g r o w t h o f m u c o s a l m a s t cells and stimulates b a s o p h i l and mast cell h i s t a m i n e release. I L - 4 p r o m o t e s the g r o w t h o f m u r i n e m a s t cells [ 18] and induces the e x p r e s s i o n o f C D 2 3 on m a c r o p h a g e s [71]. T h e release o f c y t o k i n e s m a y , thus, account for the o b s e r v a t i o n o f i n c r e a s e d mast cell n u m b e r in c h r o n i c e c z e m a t o i d lesions. T a k e n together, these o b s e r v a t i o n s suggest that the A D skin lesion is c h a r a c t e r i z e d b y the infiltration o f i n f l a m m a t o r y cells w h i c h differ f r o m those infiltrating into a t y p e IV c o n t a c t - s e n s i t i v i t y reaction. T h e sustained i m m u n e activation, w h i c h results in c h r o n i c A D , m a y be the result o f an u n d e r l y i n g T cell defect, e . g . , d e c r e a s e d IFN-3, p r o d u c t i o n following the activation o f l y m p h o c y t e s with a v a r i e t y o f stimuli. T r e a t m e n t o f patients withh rIFN-3, d o w n regulates the I L - 4 - I L - 4 r e c e p t o r p a t h w a y w h i c h is o v e r s t i m u l a t e d in this disease. It is i m p o r t a n t to note, h o w e v e r , that although m a n y i m m u n o p a t h o l o g i c features o f A D have r e c e n t l y been e l u c i d a t e d , the f u n d a m e n t a l e t i o l o g y o f these a b n o r malities r e m a i n s to be u n r a v e l e d .

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