Abridged from the

Dermatology Foundation

Progress in Dermatology

Editor: Alan N. Moshell , MD.

Atopic Dermatitis: Recent Trends in Pathogenesis and Therapy

Kevin D. Cooper Immunodermatology Unit, Department of Dermatology, Universiry of Michigan Medical School; and Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan, U .S.A.

Emerging concepts in the areas related to the pathogenesis and treatment of atopic dermatitis are reviewed. In particular, recent findings have revealed several key steps in the mainte­nance of a vicious circle of spongiotic dermatitis associated with elevated T -lymphocyte activation, hyperstimulatory Langerhans cells, defective cell-mediated immunity, and B-cell IgE overproduction. The discovery of specific IgE­binding structures on Langerhans cells provides a mechanism for Langerhans cells to capture and present IgE-targeted al­lergens to allergen-specific T cells. Furthermore, certain mi­crobial allergens that tend to preferentially elicit IgE-type responses also elicit a T-cell response dominated by the IgE­inducing lymphokine interleukin 4. Repeated stimulation by activated Langerhans cells appears to induce just such a re­sponse. Abnormal biochemical responsiveness and mediator release by AD monocytes, mast cells, and eosinophils also participate in the sustainment or initiation of such a vicious circle, and contribute directly to the dermatitis as well. De­velopments in the areas of neuropeptides, genetics, microbial superantigens, and cytokine networks in the skin also appear to have promise in providing a rational link between immune defects and the inflammatory events in AD.

Recent a~vances in the pathog,eneSiS of atopic dermatitis are leadmg to novel forms of therapies for this disease, which can have enormous impact, not only on the life of the patient, but also on his or her family. An under­standing of these developments and the underlying

biology is critical to successful physician utilization of our cllrrently available agents and newer agents that are currently under develop-

Reprint requests to: Dr. Kevin D. Cooper, Immunodermatology Unit, Universiry of Michigan, R5548 Kresge IjCampus Box 0530, Ann Arbor, MI48109.

Conventional therapy remains the mainstay of atopic der­matitis management; however, new therapies based upon the above concepts are being tested in clinical trials. Although the difficulty of objectively grading AD lesional activity and the high placebo response of AD patients hampers the inter­pretation of many reports, several types of approaches are coming into focus. The effectiveness of cyclosporinA, which targets T-cell activation and antigen presentation, indicates that additional agents with such activity should be effective, and verifies the criticality of these cells in AD pathogenesis. Therapy with biologic response modifiers, such as interferon gamma or thymopentin, is oriented toward normalization of imbalanced immune responsiveness, rather than direct sup­pression of the immune system. The mechanism of action of and toxicities of Chinese herbal mixtures require further in­vestigation, but may reveal hitherto unconsidered avenues. Other recent therapeutic trials have focused on reduction of trigger factors, such as house dust mite exposure, foods, and the abnormal epidermal lipid barrier to irritation. Key words: IgE/immunology/T lymphocytes/antigens. ] Invest Dermatol 102:128-137, 1994

ment. Many concepts of pathogenesis are currently being explored, as evidenced by the activity in the field of atopic dermatitis; among approximately 4000 publications that are currently available on atopic dermatitis, over 1000 have been published just since 1989. For a treatment of this previolls literature, the reader is referred to several wide-ranging articles that review materials prior to 1989 in greater depth than the current manuscript [1-4].

Abbreviations: ELAM, endothelial leukocyte adhesion molecule; MF­CTCL, mycosis fungoides - rype cutaneous T -cell lymphoma; VIP, vasoac_ tive intestinal peptide; PDE, phosphodiesterase.

Copyright © 1994 Dermatology Foundation, 1560 Sherman Avenue, Evanston, Illinois 60201

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VOL. 102, NO. 1 JANUARY 1994

GENETICS

Atopic dermatitis is clearly a genetic disorder. The inherited abnor­mality appears to be carried in the immune system; atopic dermatitis and antigen-specific IgE reactivity has been transferred into a nona­topic bone-marrow transplantation recipient from an atopic derma­titis donor [6,7). The promise of gene therapy as a future approach for atopic dermatitis is evidenced by the observation that the eczema ofWiskott-Aldrich syndrome cleared following successful engraft­ment of a nonatopic bone marrow (8). However, progress on identi­fyi ng the gene for atopic dermatitis is limited [9,10].

CLINICAL IMMUNOLOGY

Abnormalities in the immune system known to be associated with atopic dermatitis include an increased susceptibility to viral and fungal infections, microbes normally handled by T cel ls generated by the delayed-type hypersensitivity (DTH) arm of the immune system. Consonant with such susceptibility, patients are frequently anergic upon intradermal DTH testing. Because atopic dermatitis patients exhibit generally normal ill lIitro proliferative blood T -cell responses to the same antigens to which they exhibit cutaneous anergy (11), the immune defect appears skin limited, and the pa­tients are not considered to be systemically immunosuppressed . Atopic dermatitis patients are, however, deficient in their ability to engage the mechanisms leading to allergic contact dermatitis, w hich also depends upon the generation of antigen-specific T cells. Thus, in a careful quantitative study, atopic dermatitis patients were definitely shown to exhibit an impaired ability to become contact sensitized to dinitrochlorobenzene (DNCB) (12). Impaired sensiti­zation appears to be proportional to the disease severity at the time of immunization [13] . These findings explain the clinical observa­tions that patients with atopic dermatitis develop contact allergic dermatitis less frequently than nonatopic subjects (14). However, because of their heavy exposure to topical medications, atopic der­matitis patients often do exhibit reactivity to contact allergens. The most common allergens for atopic dermatitis patients include fra­grance-mix, balsam of Peru, and neomycin, which can be compo­nents of these topical agents, as well as nickel [15), so patch testing can be a useful clinical maneuver in discovering trigger factors that can be removed .

In addition to cell-mediated immune defects of the T cell arm, defects in monocyte and neutrophil chemotaxis and phagocytosis are present [2], and may be implicated in susceptibility to bacterial infection, in particular, Staphylococcus aurellS.

IMMUNOPATHOLOGY

Infiltrating Leukocytes Increased numbers of lymphocytes, monocyte/macrophages, and fully granulated mast cells (16) are present in atopic dermatitis lesions. The lymphocytes within atopic dermatitis lesions are predominantly of the CD4 + helper cell phe­notype, with a mean CD4: CD8 ratio of7: 1 [17]. A subset ofT cells appears to undergo intralesional activation, as evidenced by their expression of IL-2 receptors (CD25) [18,19)' and the majority ex­press HLA-DR (a class II major histocompatibility complex mole­cule), which is another, less labile, marker ofT-cell activation. The CD4 + T lymphocytes are of the memory subset (indicating previous encounter with antigen) [20] and express high levels of the skin-homing Sialyllewisx/ c lectin ligand for the endothelialleuko­cyte adhesion molecule 1 (ELAM-l) [21,22].

EndotheliulIl In addition to histologically evident hypertrophy, endothelial cells in lesional atopic dermatitis skin abnormally ex­press ELAM-l (22) as well as upregulated levels of intercellular adhesion molecule (ICAM-l) [22,23]. Because T cells that express the highest levels of ligands for these endothelial adhesion mole­cules are those that have recently undergone activation, it is possible that T cells in atopic dermatitis may activate in lymphoid organs (i.e., nodes) prior to landing in the skin. A number of mechanisms may be responsible for the enhanced adhesiveness of atopic dermati­tis vasculature for leukocytes: mast cell release of tumor necrosis factor (TNF) can induce ELAM- l [24,25), monocyte or keratino-

ATOPIC DERMATITIS 129

cyte IL-l can induce ELAM-l and ICAM-l [26), and T-cell inter­leukin 4 (IL-4) can potentiate ELAM-l (27). Thus T-cell activation can lead to enhanced adhesiveness of the microvasculature, either directly through lymphokine release, or indirectly through the re­lease of mast cell-degranulating factors [28], which in turn leads to enhanced binding and extravasation of leukocytes into the lesional milieu, and further increasing the likelihood of addi tional T-cell activation.

Keratinocytes Keratinocytes in lesional atopic dermatitis exhibit evidence of cytokine or lymphokine modulation. In some cases ICAM-l can be visualized on epidermal keratinocytes [23,29], al­though not universally [18]' and almost always in the absence of HLA-DR (17), indicating that interferon gamma (IFN-y) is not likely to be the inducing lymphokine. CD36 and CDla, and even IgE, have been observed on atopic dermatitis epidermal keratino­cytes, f~~the~ testimony to tl~e abnormal cytokine milieu of atopic dermatitis sklJ1 [30,31]. Studies on epidermal cytokine production are limited in atopic dermatitis but abnormalities in IL-l (3 2) and IL-8 [33] have been noted.

Shared Features of Atopic DerlIlatitis and Cutaneous T-Cell LYlIlpholIla (CTCL) The high CD4: CD8 ratios in lesional atopic dermatitis can be as high as that in the mycosis fungoides form of CTCL (MF-CTCL) [34,35]. Combined with exocytosis of activated lymphocytes into the epidermis, the distinction of MF­CTCL from active, chronic atopic dermatitis is difficult. The de­gree of spongiosis in relation to the pattern of infiltration and other features is usually sufficient to make the distinction, but spongiosis and epidermotropism can be altered by the presence of topical corti­costeroids, so biopsy of patients withdrawn from steroids is pre­ferred . CTCL can arise in patients with severe atopic dermatitis l36] (unpublished observations), and CTCL can appear as a spongiotic dermatitis in its early stages, so the differential diagnosis can be highly relevant.

Langerhans Cells Lesional skin of atopic dermatitis shares addi­tional abnormal features with CTCL; both exhibit increased num­bers of dermal Langerhans cells [37]' as well as epidermal Lan­gerhans cells of abnormal phenotype, and hyperstimulatory antigen-pres~nting.a.ctivity. Such Langerhans cells abnormally ex­press CDlb (111 addltlon to CDla) and CD36, and are able to induce activation of resting T cells from the same individual in the absence of any added antigen [38,3~] . Thus, the normal compartmentaliza­tion of LC phenotype that 1S maintained in normal skin (epidermal LC-high CDla, absent CDlb, absent CD36; dermal LC-Iow CDla, positive CDlb, absent CD36) [40] is replaced by a single milieu characteristic of atopic dermatitis in which both epidermal and dermal LC express the same phenotype: CDla and CDlb are both expressed simultaneously at high levels, and in concert with positive CD36 expression [38]. Additional evidence for a markedly modulated LC population in lesional atopic dermatitis skin is the abnormal expression of the interpenetrating reticulum cell marker RFD-l, a molecule normally reserved for dendritic antigen­presenting cells of the T-cell area of lymph nodes [19], and the binding of easily detectable levels of 19E on the Langerhans cells surface.

The abnormal status of atopic dermatitis Langerhans cells may be of significance in both the maintenance of the dermatitis and the tilt of the immune system response in atopic dermatitis toward IgE and eosinophil production with concomitant depression of DTH re­sponses (recently reviewed in [41 D. Whereas normal Langerhans cells are unable to activate resting blood CD4+ T cells from the same individual (autologous T cells and LC) in the absence of added antigens [42], atopic dermatitis lesional Langerhans cells are potent activators of autologous resting CD4+ T lymphocytes under such conditions [38]. In part, the reactivity is due to presentation of self peptides, indicating a component of true autoreactivity [43]. The remaining signal could be due to presentation of processed foreign antigen or binding of microbial superantigen, both of which could result in T-cell activation in the lesion by LC themselves. The signal

130 COOPER

C.N.S. Inflammation

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;;GE~ t Leukocyte

Monocyte ... Recruitment

Other Mediators

lPD~/ J

HOM? /

-:I~------'. su:'~gV IL-S?

Spongiotic Dermatitis

with 1 Cell

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=='L. P.ovale? ~

IL-4

IgE ~ ® .~-----.-"" " Eosinophilia

Figure 1. Overview of interacting inflammatory mechanisms in atopic dermatitis. APCs, in particular hyperstimulatory Langerhans cells, present antigens to T cells and induce intralesional T cell activation, lymphokine production, and spongiotic dermatitis. The antigens may be focused on those targeted by IgE (i.e., house dust mite (HOM) or P. Ova/e), because of Fe binding ofIgE on Langerhans ce ll s, or the antigens may be self peptides, or staph super-antigens (Staph Super Ag) . An abnormal balance of neuropeptides in atopic dermatitis skin would appear to favorT -cell activation. Although uncommon in many skin diseases, TH2 cells are present in lesional atopic dermatitis skin. Their production of IL-4 may help promote the hyper IgE of atopic dermatitis, and their putative production of IL-5 may be responsible for eosinophilia in atopic dermatitis. THl cells are also present, but their relative role may be diminished by the overproduction of PGE (selectively inhibitory for THl cells) by abnormal monocytes with elevated cAMP phosphodiesterase. THl cells may also be selectively inhibited by TNF released from mast cells which are easily triggered in atopic dermatitis, possibly in response to T-cell-derived histamine-releas­ing factor (a putative lymphokine). The diminished role ofTHl in AD is theorized to result in less gamma interferon (IFN) inhibition ofTH2 cells, which, in turn, act to inhibit THl expansion and cell-mediated immunity. Lymphokines and cytokines induce endothelial adhesion molecules and leukocyte recruit­ment, further propagating the cycle.

for autoreactive T-cell stimulation by lesional epidermis does not arise from keratinocytes themselves presenting antigen or superan­tigen, because depletion ofleukocytes (leaving all the keratinocytes behind) totally removes the stimulus for T-cell activation [38]. An important concept has recently emerged that CD4 + T cells repeat­edly stimulated with activated (cultured) LC differentiate into T lymphocytes that produce high amounts of IL-4 and negligible IFNy [44,45] . Such Tcells are termed "TH2" and exist in a dynamic opposition with "TH 1" type T cells, which produce IFNy, but little IL-4, IL-5 , or IL-I0 [46] .

Because IL-4 induces IgE synthesis and the expression of recep­tors for IgE on cells, a positive feedback loop might be operative in atopic dermatitis, which is linked to allergic responses. In this con­cept, IgE directed toward certain allergens is passively bound to Langerhans cells, the IgE captures selected allergens (e.g., dust mite or pollens), which are then internalized and processed by the LC for presentation to T lymphocytes, which in turn are influenced to be of the IL-4 (Th2) type, further boosting IgE production. The evidence for this hypothesis is as follows. Langerhans cells and dendritic dermal cells in atopic dermatitis (and other high-IgE states) [47] have detectable levels ofIgE on their surface [48 - 50], particularly in eczematous skin [51]. This appears to occur by absorption of circulating IgE onto a specific receptor for the Fc portion of the IgE molecule (Fc epSilon R I) [52- 541 and via lectin-like IgE-binding molecules [48]. That the surface IgE might skew the type of anti­gens presented by Langerhans cells is evidenced by findings that atopic dermatitis Langerhans cell s could only present house dust mite antigen if the Langerhans cells was surface IgE positive [55], and that Langerhans cells pre-incubated with antigen-specific IgE could present that antigen if it were then available to the Langer­hans cel ls [48] .

lMMUNOREGULATION

T-Cell Subsets: Thl and Th2 In mice, CD4+ T lymphocytes have been classified according to their profile of lymphokines that they release upon activation. Certain strains of mice tend to generate

immune responses dominated by the Thl subset, which produces large amounts of IFNy, along with IL-2, TNF, and other, less spe­cific lymphokines, but Thl cells produce very little IL-4, IL-5, and IL-lO [46,56] . Thl cells mediate DTH responses, and mice who develop strong Th 1 responses handle microbes requiring DTH re­sponses, like Leishmania, quite effectively [57,58] . This feature may be related to the ability ofThl responses to recruit monocytes and activate macrophages at sites of intracellular infections, and to in­duce cytolytic T lymphocytes [59] .

Other strains of mice tend to develop a Th2-dominated response; these mice do not handle Leishmania well, but are very effective at handling intestinal parasites, such as NiJ?postrongyloides, which the Thl-generating mice handle poorly l58,60,61]. Th2 cells, in contrast to Th 1 cells , make large amounts ofIL-4, IL-5, and IL-I0, and very little IFNy [46,62]. IL-4 is a potent inducer of B-cell IgE production, IL-5 induces eosinophilia, and IL-I0 depresses DTH responses, possibly at the antigen-presenting cell level [63,64] . All of these features are manifested in the atopic dermatitis state, but may be useful in dealing with helminths (alternatively, helminths may have evolved to elicit an immune response that allows their survival [59,60]). Both the Th 1 and the Th2 responses tend to be self-amplifying and inhibitory to the recipropical subset, such that IL-4 inhibits THl-type responses and IFNy inhibits Th2-type re­sponses [65 ,66]. In humans, Th2 responses appear to dominate over Thl responses in diseases such as lepromatous leprosy (which ex­plains the poor handling of organisms in these patients) [67], in allergic (lgE-associated) disorders [59]. and in the Sezary syndrome variant of cutaneous T-cell lymphoma [68] . Conversely, diseases with IFNy-producing T cells (Thl-type response) include allergic contact dermatitis [69] , tuberculoid leprosy [67], and psoriasis [70 -72].

Atopic dermatitis patients exhibit reduced abil ity to generate IFNy l73 - 75], a situation that could be improved by blocking the activity oflL-4 in the culture [73] , or by removing monocytes [75] . Atopic dermatitis T cel ls appear particularly responsive to IL-4 [76], possibly related to their elevated levels ofIL-4 receptor mRNA [77] .

VOL. 102. NO.1 JANUARY 1994

Lesional skin of patients with allergic conjunctivitis and atopic der­matitis clearly contain T cells of the Th2 type [55.78-84J. Of particular interest was that a high percentage (10-47%) ofTh2 cell clones grown from lesional atopic dermatitis skin appeared to be specific for a house dust mite antigen [80] or for grass pollens [82]. This phenomenon was also quite pronounced in epicutaneous patch tests to aeroallergens [80 - 83J. In one study the frequency of Derma­tophagoides pteronyssimls- reactive T-cell clones was estimated to be 0.4 - 2.7%. and 42% of the clones were found to be of the Th2 type [85]; in another study. all of the clones were reactive to the inciting aeroallergen. and 70% were of the Th2 type [86]. Why such high percentages of T cells are reactive to these aeroallergens is unclear: antigen-induced enrichment of antigen-specific T cells is the fa­vored hypothesis, but self-antigen cross-reactivity (autoimmune molecular mimicry), or superantigen-like stimulatory properties of the extracts, or a selection due to the cloning procedure must also be held as possibilities.

Despite the clear presence ofTh2-type T cells, the lesional skin of patients with atopic dermatitis also contains IFNy-producing (Th 1-like) T-cell clones [59,79]; their antigen specificity remains un­known. The actual frequency of Th 1 and Th2 cells in lesions, and their relative roles in initiating or maintaining the dermatitis, will be the focus of much work in coming years. However, the identifi­cation ofTh2 cells in atopic dermatitis blood and skin has formed a rational basis for therapeutic intervention with recombinant human IFNy, which should be inhibitory to such cells, in patients with atopic dermatitis [87].

Other T-Cell Abnormalities Depressed DTH and cell-me­diated immunity (CMI) in atopic dermatitis may be related to more than the Th 1 /Th2 imbalance concept, and there may be many more ramifications of Th 1/Th2 imbalance than are currently appre­ciated. Alternatively, a Th 1/Th2 imbalance may be the result of a serious underlying immunoregulatory abnormality. For instance, transforming growth factor beta (TGF/f), a potent immunosuppres­sive cytokine and tissue regulator, favors the activation ofTh2 over Th 1 cells [60]. Depressed CMI could also be related to a shift of the primary site of T-cell activation from the regional lymph node to the skin; dendritic antigen-presenting cells in atopic dermatitis lymph nodes demonstrate abnormal morphology and reduced in­terdigitation with T lymphocytes [88]. However, the sera of atopic dermatitis patients clearly displays evidence of ongoing and signifi­cant T-cell activation in some location by the elevated levels of soluble IL-2 receptors [89,90] and CD8 molecules [91]. The dem­onstration of IL-2 receptor bearing T cells in lesional atopic derma­titis skin [19] strongly suggests that the skin is a major source of the shed IL-2 receptors in the serum of these patients.

Activated lymphocytes spill out of their tissue sites and are detect­able in the blood of patients with atopic dermatitis. In addition to release of activated CD4 + cells [92J, enlarged (activated) B cells and enlarged CD8+ Cllb+ T cells (putative suppressors) are found increased in the blood of patients with AD [93] , indicating selective circulation of these activated lymphocyte subsets. Indeed, some pa­tients have CD8 + T suppressor cells that, upon removal, can be shown to have been restraining the atopic dermatitis patient's CD4 + proliferative response to herpes simplex virus [94].

Despite the evidence of in llivo activated T cells in atopic dermati­tis, blood mononuclear cells of atopic dermatitis patients often ex­hibit slight reductions in their ability to be stimulated in vitro. In addition to the above-mentioned reductions in IFNy production, atopic dermatitis patients release less IL-l [32,95]' TNF [96], and IL-2 [97] , and proliferate less briskly, possibly due to the selective inhibitory effect on CD4+ T cells of prostaglandin E overproduc­tion by atopic dermatitis monocytes [98]. Decreased proliferation by atopic dermatitis T cells may also reflect the tendency of patients with atopic dermatitis to demonstrate reduced lymphocyte counts in general [93]; in at least one case, erythrodermic flares are asso­ciated with CD4+ lymphocytopenia [99] .

Subtle alterations in the proportions of immunoregulatory sub­sets are present in the blood of atopic dermatitis patients that are not

ATOPIC DERMATITIS 131

currently understood. Reduced numbers of lymphocytes bearing the LFA-3 receptor, CD2, have been documented for years, with the most consistent reduction being found within a subset that ex­presses CD8 and Fc receptors for IgG (reviewed in [3] and [1 J) , and that may represent a reduction in a CD2 + natural killer-type cell subset [93,100]. Whether this reduction is due to the extreme sensi­tivity of natural killer cells to topical steroid applications is not yet clear [101].

Alterations in CD4/CD8 ratios are also detectable in atopic der­matitis (reviewed in [1,3,84]), but the ratio can be found to be either elevated or reduced, which I believe relates to how the "small lym­phocytes" are electronically separated from the "large monocytes"; in atopic dermatitis this separation is not distinct as it is in normals, likely because of the above-described selective shifts of normally small lymphocytes into the "monocyte-sized" cell cluster follow­ing enlargement upon activation. Thus, the lymphocyte ratios can be altered by how the cells are chosen for analysis. In a recent study that reported both small and large cell data, the CD4/CD8 ratio was minimally changed among the small lymphocytes and markedly reduced among the large cells, due primarily to an increase in CD8 + CDl1b+ cells and a decrease of CD4+ cells [93J.

Modulation of the Immune Response by Abnormal Mono­cytes in Atopic Dermatitis The T-cell activation that occurs as a result of hyper stimulatory Langerhans cells in patients with atopic dermatitis appears to be influenced by several factors. A current hypothesis is that the profile of lymphokines produced by the acti­vated T cells is "tilted," resulting in the unique constellation of atopic dermatitis features that eventuate in spongiotic dermatitis, hyperimmunoglobulinemia of IgE, depressed cell-mediated immu­nity, tendency to respiratory allergy, and eosinophilia. Recent work by Hanifin el ai, described below, has begun to shed light on how abnormally functioning monocytes with an impaired ability to rec­ognize immunoregulatory signals can affect the nature of T-cell differentiation.

Peripheral blood mononuclear cells, and particularly monocytes, from patients with atopic dermatitis produce elevated levels of pros­taglandin E2 (PGE2) [75 ,102]. Although normal CD4+ cells do not adjust to external PGE2 by raising their cyclic adenosine mono­phosphate (cAMP) phosphodiesterase, atopic dermatitis CD4 + T cells do, resulting in a marked reduction in atopic dermatitis T-cell cAMP levels [103]. Thus, atopic dermatitis monocyte restriction of atopic dermatitis T-cell IFNy lymphokine secretion appears due to both a disordered level of PGE2 production by atopic dermatitis monocytes and an abnormal response on the part of atopic dermati­tis T cells to the PGE2 [75J .

Because PGE2 can inhibit THl IFNy, but not TH2 IL-4, PGE oversecretion can tip the balance of the immune response in favor of a TH2 response [104] . The ability of a cAMP phosphodiesterase inhibitor with beneficial clinical activity in atopic dermatitis [105] to reduce atopic dermatitis ill I,ilro IgE secretion by blood mononu­clear cells [106] could now be interpreted such that the inhibitor may make atopic dermatitis T-cell IFNy less susceptible to inhibi­tion by atopic dermatitis monocyte PGE2. PGE2 can also act di­rectly on B cells to enhance IgE production [104J. Thus , monocytic series PGE2 overproduction may represent an important factor in the tilt of the atopic dermatitis immune response toward a "TH2-like" immune lymphokine pattern.

Monocytes Monocytes are present in increased numbers in th e lesional skin of atopic dermatitis patients [19,1 07J, and may thereby account for the elevated levels ofPGE series prostaglandins detecta­ble in atopic dermatitis skin [108J . Besides elevated PGE produc­tion, atopic dermatitis monocytes are abnormally primed for super­oxide production [109], additional evidence of ;n ";"0 activation. The abnormal state of atopic dermatitis mOllocytes may be due to the elevated level of activation ofT lymphocytes [19,38,89] and the monocyte response to stimulation by T-cell lymphokines [110]. However, atopic dermatitis monocytes may exist in an abnormal functional state as a consequence of th eir profound elevation of cAMP phosphodiesterase levels [111] and elevated adenyl ate cyclase

132 COOPER

levels [112]. This abnormality is independent of lesional activity and is present even in the cord blood of infants of atopic parents [113], leading to the speculation that this defect in atopic dermatitis monocyte membrane proteins may be linked to the genetic defect(s) responsible for atopic dermatitis susceptibility, and that cAMP phosphodiesterase levels may be useful as a diagnostic test for atopic dermatitis [114] .

Mast Cells/Basophils Evidence has existed for many years that atopic dermatitis patients experience intermittent mast degranula­tion (see previous reviews). cAMP agonists (PGE, adrenergic agents, histamine) in normals exert a down-modulatory tone on mast cell or basophil degranulation; an alteration in responsiveness to such agents due to an elevated level of cAMP phosphodiesterase in atopic cells may playa role in the excessive releasibiliry ofbaso­phils in atopic dermatitis patients [115] and mast cells in atopic dogs l116]. The ability of substance P, a neuropeptide released by cutane­ous nerves, to degranulate cutaneous mast cells [117] provides an­other mechanism for mast cell histamine release that may be highly relevant in explaining the close relationship of psychic stress to cutaneous inflammation in atopic dermatitis.

In addition to the well-appreciated effects of mast cell products on inflammation and itching, the products of mast cells have also been implicated in the epidermal hyperplasia of atopic skin [118]. Furthermore, mast cell release may be a contributing factor in the "tilt" of the atopic dermatitis T-cell response toward Th2 because of their ability to release TNF [24]. TNFa inhibits the growth of Thl IFNy-producing T-cell clones, but not atopic dermatitis skin infiltrating Th2 (IL-4-producing) T-cell clones [81]. Indeed, plasma TNF levels are elevated in the serum of patients with atopic dermatitis, and the levels are tightly correlated with plasma hista­mine [119] .

Eosinophils High eosinophil counts are common in atopic der­matitis [120] . Whether this is due to the concomitant production of IL-5 by Th2 cells .in atopic dermatitis remains to be established. However, the eosinophils are acutely regulated and undergo activa­tion in correlation with disease activity. Eosinophils degenerate in atopic dermatitis skin [121], presumably releasing the polypeptide crystalloid core of the eosinophil granule, termed major basic pro­tein. This/rotein is distributed extensively in atopic dermatitis dermis, an is also capable of degranulating mast cells (reviewed in [1] and [3]). The eosinophil cationic protein is also useful as a marker of eosinophil activity in vivo; eosinophil cationic protein levels are elevated in atopic dermatitis serum [89,122,123], providing further evidence for eosinophil involvement in atopic dermatitis. Interest­ingly, eosinophilia was the most sensitive blood element to treat­ment with IFNy [87,93] and cyc1osporin A [124].

TRIGGER FACTORS

Early recognition of the presence of trigger factors can allow earlier appropriate intervention and less severe exacerbations, and thus are an important part of clinical management. Patients usually learn early in life that wool (lanolin) and harsh detergents are irritating to their skin. A recent study has documented that the skin of atopic dermatitis patients demonstrates a statistically significantly higher increase in skin thickness (by ultrasound) in response to exposure to sodium !auryl sulfate, as compared to controls [125]. Whether this is due to the abnormalities in epidermal lipid metabolism, in particular elevated free arachidonic acid, of patients with atopic dermatitis [126] or abnormally low levels of ceramides in the stratum corneum of atopic dermatitis patients [127] or to defective conversion of linoleic acid [128] remains to be determined. Other contributory factors include various microbes and psychic stress. Under rare cir­cumstance, triggers can include dietary foods, aeroallergens [129], and ultraviolet [130]. Contact urticaria to raw foods [131], or con­tact allergens, i.e., dermatitis, but mainly extrinsic contact irritant dermatitis is responsible for the high incidence of hand dermatitis. Several studies have documented that 80-85% of patients with occupational hand epidermis had coexisting atopy [132,133], a

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finding likely related to the high prevalence of atopy in the general population.

House Dust Mites There seems to be no question that patients with atopic dermatitis have a high frequency of IgE antibodies that detect house dust mite antigens and that the skin and blood of at least some patients also harbor T cells that can recognize house dust mite antigens when presented by appropriate antigen-presenting cells (recently reviewed in [84]). These findings generally occur in patients who demonstrate a positive epicutaneous "patch" test to dust mite antigens. Because dust Inites are ubiquitous, it is attractive to postulate that either aeroallergens or epicutaneous exposure can initiate immunologic events that exacerbate the dermatitis. In fact, there is a positive correlation between the magnitude of exposure to dust mites and the frequency of disease [134]. However, although dust mites are known to have a more favorable growth rate under damp conditions than dry conditions, the association was indepen­dent of the presence of domestic humidity. Thus, these authors hypothesize that the association between high densities of mites and atopic dermatitis may be related to differences in lipid composition of the shed squames on which the mites feed, or perhaps on the amount of squame available [134] .

A cornerstone of the work implicating dust mite antigens as a trigger in atopic dermatitis has been the development of an epicu­taneous patch test to detect a subset of patients with atopic dermati­tis that have such reactivity. In many instances investigators use tape stripped or somewhat abraded skin to obtain positive reactions. The lack of standardized preparations and methods of application is the likely cause of variations in the literature with regard to the fre­quency of atopic dermatitis patients with positive tests. In one re­cent study, the authors varied both the type of allergen and the state of the skin being patch tested; they found positive patch tests in 40 - 50% of atopic dermatitis patients and favored a simple applica­tion on healthy appearing skin [135]. In another comparative study, non-specific reactions due to tape stripping, fixation tape, or patch­test occlusion were observed in up to 80%, with specific reactions occurring in only 30% of atopic dermatitis patients. Almost all of these reactions occurred in patients with extremely high serum IgEs [136]. Careful use of this test is therefore required. However, the immunoreactivity that occurs after initiation of such a test has re­vealed significant useful information. Presentation of house dust antigen via specific IgE bound to Langerhans cells has been demon­strated, as described above [55], and an antibody to house dust mite antigen has even been used to visualize the antigen in positive patch tests by immunoelectron microscopy in epidermal and dermal Lan­gerhans cells [137].

In addition to dust mites, other airborne allergens, such as tree and grass pollens, have been used in occlusive chamber-scarification patch tests to elicit contact sensitivity -like delayed-in-time re­sponses in patients with atopic dermatitis. Although such special testing may be able to elicit atopic dermatitis -like cutaneous in­flammation under these controlled circumstances, it still is ex­tremely unusual for allergen desensitization to provide any benefit for the dermatitis of atopic dermatitis. Another ubiquitous antigen, which has been found to elicit reactions in patients with atopic dermatitis under chamber-scarification patch tests is PityrosponlPl/ ova Ie. Large molecular weight antigenic substances from P. ollale (greater than 60 kD) have been found to induce lymphocyte prolif­eration in atopic dermatitis patients with positive patch test to P. ovale extracts [138]. IgE antibodies against P . ol/ale were found in two of three atopic dermatitis patients, particularly in those with lesions predominantly in the seborrheic areas, the area of highest prevalence of P. ol/ale [139] in young adults . Whether this commOn lipophilic yeast is truly pathogenic, or whether these findings merely reflect the propensity of atopic dermatitis patients to develop IgE-dominated responses to microbial and aeroallergens is currently unclear.

The mechanism by which Staphylococcus aureus can trigger atopic dermatitis flares might be one of several things. Staphylococcal cell

VOL. 102, NO.1 JANUARY 1994

wall products (teichoic acid and peptidoglycan), as well as a staphy­lococcal secreted superantigen, entero-toxin B, can stimulate pe­ripheral blood lymphocytes , and, particularly in combination with IL-4, can lead to a pronounced increase in IgE synthesis and FeIgE receptor expression [140]. Staphylococcal superantigens also have the capacity to activate large classes of T cells, regardless of their antigen specificity, because they are able to bridge the linkage be­tween the class II major histocompatibility complex molecule on the antigen-presenting cell and the T-cell receptor without having to be processed and presented by the antigen-presenting cell. In this scenario, staphylococcal superantigens released into the epidermis would find a way onto class II major histocompatibility complex­positive Langerhans cells or dermal DR + cells, and could thereby cause a marked stimulation of several classes of T cells that have been non-specifically recruited into the lesion. This hypothesis is consistent with our findings that Langerhans cells exclusively carry the autostimulatory signal for autologous T lymphocytes in atopic dermatitis [38]. However, this cannot be the entire source of stimu­lation, because a significant component of the T-cell response to self antigen-presenting cells can be removed by removing autoreactive T cells that respond to blood antigen-presenting ' cells [43] .

Foods In a highly selected group of patients, patients with food allergies and atopic dermatitis who follow an appropriate avoidance diet can have substantial clinical improvement [141] and lose their food hypersensitivities [142]. In certain patients in whom a careful history clearly implicates certain foods, ingestion of a food allergen during challenge can lead to a pruritic, morbilliform rash, which can become eczematous after a series of positive challenges over the course of several days [143]. How large food proteins in the diet could induce reactivity in the skin is not clear, but it has been postulated that increased intestinal permeability allows penetration of certain of these antigens such that the food antigens could be processed by antigen-presenting cells similarly to the in vitro model in which food antigens can stimulate atopic dermatitis peripheral blood mononuclear cells to produce high levels ofIL-2 [144]. Expo­sure of carefully identified patients to the offending foods causes their peripheral blood basophils to spontaneously release histamine, which in turn appears dependent upon elevated production of a histamine-releasing factor from mononuclear cells [28]. Interest­ingly, avoidance of the specific food can result in decreased levels of blood histamine-releasing factor and actual histamine release from atopic dermatitis basophils [28]. More generalized food-avoidance diets do not have a good response/risk ratio; an elemental diet has been tried in children with widespread atopic dermatitis and, al­though some clinical benefit was obtainable, the patients required prolonged hospitalization and experienced a fall in body weight and serum albumin, and, in addition, experienced a significant risk of anaphylactic shock in over 10% of the cases [145]. Highly restricted (few foods) diets are extremely arduous, although beneficial for some children, but the long-term outcome does not appear to be affected by compliance or non-compliance for such a diet [146] . A large follow-up cohort of 736 patients was recently evaluated at 7, 11 , and 14 years of age to determine the effect of cow's milk. Children with an atopic family history ran the same risk of subse­quent atopic disease whether they were fed formula or breast milk alone, as compared to cow's milk [147].

Neurocutaneous Alterations As reagents for detecting and measuring neuropeptides have become available, it is becoming possible to visualize and quantitate these neuropeptides and the nerves that carry them. A number of abnormalities in atopic derma­titis are already becoming apparent. For instance, somatostatin-im­munoreactive nerves, easily visualized in normal skin, were not found in the skin of patients with atopic dermatitis [148]. By con­trast, neuropeptide Y - positive dendritic cells in the epidermis are present in lesional atopic dermatitis skin, but not in controls [148]. Also in atopic dermatitis there was an increase in nerve fibers re­vealed by anti-neura l filament antibody and anti-neuron specific protein 9.5 antibody, but a reduction in adrenergic-innervated fibers

ATOPIC DERMATITIS 133

(neuropeptide Y and tyrosine hydroxylase). Markers of sensory nerve fibers (calcitonin gene-related peptide and substance P) also showed a somewhat increased density of fibers [149].

The total skin content of neuropeptides is beginning to be ex­plored. Two groups have found elevated vasoactive intestinal poly­peptide (VIP) in lesional skin of atopic dermatitis [150,151], and in one study this was associated also with a reduction in the level of substance P [152]' Because VIP and substance P are somewhat in dynamic opposition with regard to their immunomodulatory ef­fects, an imbalance of VIP over substance P may participate in the impaired immunologic responses of atopic dermatitis skin. In con­trast to substance P, which is stimulatory for lymphocyte prolifera­tion and monocyte cytokine production, VIP is inhibitory to lym­phocyte proliferation and natural killer cell activity [152] . It is tempting to speculate that the observed imbalances in the neurocu­taneous innervation in atopic dermatitis are related to abnormal vasoactive cutaneous responses in atopic dermatitis [153,154] and the increased itch responses that patients with atopic dermatitis exhibit for agents such as wool fibers [155] , and even a TH1/TH2 imbalance [156].

THERAPY

Objective Assessment of Atopic Dermatitis A critical ad­vance in the study of atopic dermatitis occurred upon the adoption of standardized diagnostic criteria. A similar effort is now needed to standardize the quantitative clinical assessment tools avai lable for assessing whether atopic dermatitis patients improve with a specific therapy. Many clinical trials a.re riddled with subjectivity, because quantitative assessments of severity and pruritis almost invariably allow subjective patient perceptions to influence the physician's assessments, whether intended or unintended. In addition, the mar­gins of atopic dermatitis lesions are not distinct, like those of psoria­sis, so that an accurate quantitation possibly of total body surface involvement is very difficult , because patients have spongiosis even in apparently uninvolved skin and exhibit variable degrees of xerosis blending into frank scaling, which is also modified by the number of hours since bathing or moisturizing. The problem is further com­pounded by the extremely high placebo response in studies of pa­tients with atopic dermatitis, which can mask the detection of a partially effective therapy, or falsely give the impression that an ineffective approach has a response rate. There is also a problem of "subsets," that is, there appear to be therapies in which a percentage of atopic dermatitis patients receive a great deal of benefit, whereas others experience little benefit.

A workshop on the subject outlined quantifiable signs and symp­toms, issues regarding target site selection, and recommendations for systemic and topical steroid washout periods [157J. Other au­thors have recommended weighting the extent of disease by the distribution of severe and mild changes, either as a modification of the psoriasis a.rea and severity index [158], or using a simplified and rapid point-counting technique [159] . Methods involving portable data loggers for the continuous recording of itch [155] have been developed, and actigraphic watches are avai lable to monitor scratching. Ultrasound has been used to quantitate the degree of skin edema. Others have argued that simple, rapid assessments are as accurate as elaborate grading methods [160]. For the purpose of determining whether equally severe patients are entered into both the placebo and active therapy arm of a trial, a system for estimating the lifelong severity of a patient's AD has been proposed [161 J.

Recent Advances in Therapy

UV: Although PUVA [162] and UVB alone provide a response rate, studies have revealed that addition of UV A to the UVB (UV AB) provided a detectably improved therapeutic response [163,164]. Interestingly, UVB is also effective at reducing Staph aureus colonization. Subsequent studies have demonstrated the su­periority of short-wave UVA (UVAII) [165J and, in particular, long-wave UV A (UVAI) [1 66] over UVB. The ability oflong-wave UVA (UVAI) to selectively reduce and transiently inactivate Lan-

134 COOPER

gerhans cells without inducing infiltration of inflammatory macro­phages into the skin [167,168] may be a factor in the improved performance of UVAI over UVB in AD.

Cyclosporil1 A: Systemic immunosuppression with corticosteroids is clearly effective in atopic dermatitis, but oral or parenteral corti­costeroids should be limited to brief courses of therapy in extremely severe situations, due to the significant long-term toxicity and de­pendency associated with steroid use in atopic dermatitis. However, other forms of systemic immunosuppression are being developed for atopic dermatitis. Oral cyclosporin A, at a dose of 5 mg/kg/d, was highly effective in reducing disease extent and severity scores, and in improving itch and sleep scores in a double-blind crossover study of atopic dermatitis [158] . Although patients experienced nausea, abdominal discomfort, and paresthesias, and elevations of bilirubin and worsening of renal function were reported, the ad­verse effects were considered more tolerable than placebo [158], indicating high patient acceptance, despite the use of a maximal dose level. This study validates earlier open trials and case reports of the effectiveness of oral cyclosporin A for atopic dermatitis [169-171]. By contrast, topical cyclosporin A application does not appear to be particularly effective for atopic dermatitis [172,173]. Despite the efficacy of cyclosporin A in atopic dermatitis, such therapy does not appear to reduce either intracutaneous skin tests or patch tests to dust mite antigens [170), reducing the likelihood that cyclosporin A is acting primarily to stabilize mast cells, and consistent with the potent ability of cyclosporin A to block Langerhans cell antigen­presenting activity and T-cell activation in the skin [174]. Indeed, cyclosporin A therapy of atopic dermatitis patients results in a po­tent inhibition of the hyperstimulatory Langerhans cells present in lesional atopic dermatitis skin [175], and in a reduction of activated T cells, Langerhans cells bearing IgE, and macrophages [18].

1I1te1eroll Gamma: In addition to the application of immunosup­pressant agents to atopic dermatitis, several agents have been re­cently utilized that·have an immunomodulatory effect, rather than strictly suppressive capacity. Recombinant interferon gamma has been administered to patients with atopic dermatitis in a double­blind, placebo-controlled trial of atopic dermatitis, and found to be statistically significantly superior to placebo [87] . We found clinical benefit to be accompanied by a reduction in eosinophil count, al­though no reduction in serum IgE was noted [87]. Eosinophils were not the only blood element to be reduced, however; reductions in the overall white blood cell count, in particular those with clinical benefit, were also observed [93]. These findings confirm a phase I open erial, which also suggested that atopic dermatitis patients ben­efitted from IFNy therapy [176] . Although it was originally hy­pothesized that IFNy would be of benefit for atopic dermatitis via its ability to down regulate Th2 responses, there was no reduction in spontaneous IgE production [176].

Thymoperltil1 : In a similar recently reported double-blind clinical trial, thymopentin, the active pentapeptide of a thymic hormone with immunostimulatory potential, gave significantly better clini­cal improvement than placebo in severity and pruritus at 6 weeks of treatment [177]. A smaller trial of thymopentin had also demon­strated a beneficial effect of the agent, in contrast to placebo [178]. Like IFNy, the agent was well tolerated, despite that subcutaneous injections are required (because both these agents are proteins and therefore cannot be administered orally). In the IFNy trial, patients self-administered the medication, and the concept was well ac­cepted by the patients, including children.

Mixtures of Chi"ese Herbal Extracts: Two recent controlled trials of traditional Chinese herbal mixtures were performed, one in chil­dren and one in adults. Highly significant reductions in erythema and surface changes were found in the experimental group in the adult study [179]. Children also seemed to benefit, but the unpalata­bility of the concoction limited its applicability [180]. However, over 1 00 active compounds are present in these mixtures, and ad­ministration, which is often via enema, can be associated with hepa­toxicity. Whether potent immunosuppressive, anti-inflammatory,

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

antibiotic, or sedative activities of these plants are responsible is currently under active investigation.

Dieta ry Lipids: Dietary modifications involving supplementation with n-3 fatty acids (including eicosapentanoic acid) slightly fa­vored the experimental group over the control group [179]. How­ever, ingestion of oil of evening primrose extract (which contains the deficient linoleic and gamma-linoleic acids), demonstrated no difference from a control group taking olive oil, or from a group ingesting a combination of primrose oil and fish oil (eicosapentan­oic acid) (181,182]' Although studies have been performed that exhibited a beneficial effect of primrose oil on atopic dermatitis [183], a lack of effect of primrose oil was also found by others [181,182] .

House Dust Mites: Hyposensitization with dust mite allergen was unsuccessful in improving atopic dermatitis [184]. Attempts to re­duce mite levels in the home and to obtain clinical benefit with this approach have been elusive [185 ,186]' including the use of natamy­cin, which kills the aspergillus on which mites feed. Vacuum clean­ing, neither alone or in combination with natamyacin, were able to reduce mite numbers sufficiently to provide clinical benefit [186]' Patients were able to obtain benefit from mite reduction only in a hospital setting in which a room was specially treated to reduce mite density to less than three mites per meter squared. In this study, night-time admission to the mite free room gave 11 of 13 atopic dermatitis patients relief from itching and dermatitis within 2 - 3 weeks.

Mast Cells/Phosphodiesterase: From a mast-cell- stabilizing point of view, reports of activity of ketotifin in atopic dermatitis continue to appear, and even topical cromolyn applied to lesions of young chil­dren improved the dermatitis [188]. Phosphodiesterase inhibition would also be expected to provide some mast cell stabilization, but papaverine (which has limited phosphodiesterase activity) was found to be ineffective [189,190]. However, the development of phosphodiesterase inhibitors specific for the cAMP phosphodiester­ase elevated in atopic dermatitis monocytes continues to be a valid option, and candidates with promising in vitro activity have been identified (105].

CONCLUSION

The activity of investigators in studying patients with atopic derma­titis in part reflects an optimism that newer concepts in immuno­biology can be utilized to better understand atopic dermatitis pathomechanisms. This enthusiasm, combined with the rapid de­velopment of new classes of immunosuppressives, immunomodula­tors, and light sources, makes it likely that significant strides will be made in the coming decades in the understanding and treatment of atopic dermatitis.

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