Fcer11/CD23 Receptor Distribution in Patch Test Reactions to Aeroallergens in Atopic Dermatitis

FceRll/CD23 Receptor Distribution in Patch Test Reactions to Aeroallergens in Atopic Dermatitis

Colin C. Buckley, Carol Ivison, Leonard W. Poulter, and Malcolm H.A. Rustin Departments of Dermatology and Immunology (LWP), The Royal Free Hospital and School of Medicine, London, U.K.

There is increasing evidence that exposure to organic aller The numbers of Langer hans cells were reduced in the epider gens may induce or exacerbate lesional skin in patients with mis :and increased in the dermis in patch test reactions and atopic dermatitis. In this study, patients with atopic dermati lesional skin compared to their controls. Double staining tis were patch tested to 11 common organic allergens and to reve:aled a change in the distribution of CD23 antigen. In control chambers containing 0.4% phenol and 50% glycerin patch test control and non-Iesional biopsies many macro in 0.9% saline. In biopsies from positive patch test reactions, phages and only a few Langerhans cells within the dermal patch test control skin, lesional eczematous and non-lesional infiltrates expressed this antigen. In patch test reaction and skin from atopic individuals, and normal skin from non lesional skin samples, however, the proportion of CD23+ atopic volunteers, the presence and distribution of macro dermal Langerhans cells had increased compared to macro phages (RFD7+), dendritic cells (RFD1 +), and Langerhans phages. Furthermore, in these latter samples an increased cells, and the expression of the low-affinity receptor for IgE proportion of dermal CD 1+ cells expressed the dendritic cell (CD23) were investigated. (RFD 1+) marker. These results show that following antigen In patch test reactions and lesional skin samples, inflamma challenge there are marked similarities between the pheno tory infiltrates of diffusely distributed macrophages type of the cellular infiltrate in patch test reaction and le (RFD7+), dendritic cells (RFD1+), T lymphocytes sion:al skin biopsies, and also demonstrate a changing distri (RFTmix+), and Langerhans cells (CD1+) were seen, the bution of CD23 on antigen-presenting cells.] Invest Dermatol latter being present in both the epidermis and the dermis. 99:184-188,1992

or many years the role of IgE in the pathogenesis of It has been shown that AD can relapse following environmental atopic dermatitis (AD) has been controversial. Approxi Contact with specific allergens, and the dermatosis remits if these mately 80% of patients with AD show an immediate allergens are removed from the patient'S environment [6,10]. The type hypersensitivity reaction to environmental aller aeroallergens in these and other studies [5,7,8,11,12] were identi gens when given intradermally as a skin prick test, to fied by their ability to induce both positive skin prick test reactivity getFher with elevated serum IgE levels with a specificity to these and positive patch test reactions. Delayed patch test reactions oc allergens [1] . Despite this, the cellular characteristics of the eczema curred only to allergens to which the patient reacted when chal tous lesion are repeatedly described as that of a delayed-type hyper lenged in the skin prick test. Significantly, these reactions uni sensitivity reaction, with the T lymphocyte as the predominant cell formly failed to exhibit the clinical or histologic features of an type in the dermal infiltrate [2 - 4] . Epicutaneous patch testing with immediate hypersensitivity reaction when analyzed at 48 h. It has ae roallergens such as house dust mite (Dermatophagoides pterol1Ys therefore been suggested that the skin lesions of AD result from a sinus) produces an eczematous reaction, which also has the dy chronic delayed hypersensitivity reaction involving epidermal Lan namics and histology of a delayed-type hypersensitivity reaction gerhans cells that present antigen to sensitized T lymphocytes [13]. [5-9]. Though the positive patch test reaction and lesional skin in pa tients with AD do not exhibit the clinical or histologic features of a type 1 hypersensitivity reaction, IgE may playa role in presenting aeroallergens. In a recent in vitro study, cell-bound IgE on Langer Manuscript received July 9, 1991; accepted for publication February 27, hans cells was required to initiate T-cell responses to allergens [14]. 1992. Further work has shown that in patients with AD the ratio of This resea rch was supported by grants from The Sir Jules Thorn Charita CD 1- + /IgE+ cells in the epidermis decreases after 1 week of treat ble Trust and The Skin Disease Research Fund. ment with topical corticosteroid, with complete disappearance of Part of this work was presented at the 52nd annual meeting of the Sociery IgE+ cells after 2 weeks [15]. Low-affinity receptors for IgE have for Investigative Dermatology, Seattle, May 1991. been identified on epidermal Langerhans cells as well as on macro Reprint requests to: Dr. C. Buckley, Department of Dermatology, The Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, En phages, Band T lymphocytes, and platelets [16] . This has been gland. observed in biopsies both from patients with AD and non-atopic Abbreviations: individuals [17]. Although the precise function of these receptors in AD: atopic dermatitis AD is unclear, it could be hypothesized that they may playa role in APAAP: alkaline phosphatase - anti alkaline phosphatase the presentation of antigen to activated T lymphocytes. In this FlTC: fluorescein isothiocyanate study, we have investigated CD23 expression on Langerhans cells, MoAb: monoclonal antibody dendritic cells (RFDl +), and macro phages (RFD7+) in both posi RF: The Royal Free Hospital School of Medicine ti"e patch test reactions and non-patch tested lesional skin from TBS: Tris-buffcred saline patients with AD. We also wished to study the relative distribution TRITC: tetramethylrhodamine isothiocyanate

184 VOL. 99, NO.2 AUGUST 1992 CD23 RECEPTORS IN ATOPI C DERMATITIS 185 of these subsets of non-lymphoid immunocompetent cells in the Table I. List of Monoclonal Antibodies Used in the Study positive patch test reaction, patch test control, lesional, and non-le Reactivity in sional biopsies. Name CD Subclass Source Normal Tissues MATERIALS AND METHODS RFDl IgMp RFHSM' Epitope of HLA-DR Patients Fifty-six patients (37 male, 19 female) with atopic der with restricted ex- matitis (age range, 22 - 38 years) diagnosed according to the criteria pression to dendritic of Hanifin and Rajka [18] were studied. Patients had moderate to cells severe dermatitis requiring daily topical corticosteroids. Seven of RFD7 IgGl RFHSM Mature tissue macro- the patients had bronchial as thma and 20 suffered from seasonal phages RFT6 CDl IgGy RFHSM Thymocytes and Lan- allergic rhinitis. .. gerhans cells All patients were skl11 prick test~d on the volar aspect of the RFTmix CDS,8, IgGy RFHSM Pan T lymphocyte non-dominant forearm to the followl11g common mhaled allergens: CDll Cladosporium herbartlm, Alternaria telnlis, Candida albican s, Dermato FceR11 CD23 IgG1y Dakopatts Low-affinity IgE recep- phago ides pteronyssinus, Dermatophago ides jarinae? cat and dog dander, UK Ltd. tor birch and plane tree extracts, rye grass, and ttmothy grass pollens • RFHSM, Royal Free Hospital School of Medicine. (Pharmacia Ltd.), using 1 % histamine as a positive control and 0.4% phenol and 50% glycerin in 0.9% saline as a negative contro!'

Aeroallergen Patch Testing and Skin Biopsies All patients Quantification of the distribution of specific cell rypes was per had not applied topical corticosteroids to the areas to be patch tested formed using an image analyzer to define and measure framed areas for 2 weeks prior to testing and none had received ultra-violet 13 of section (one high-power field [X 400] below the dermo-epider irradiation, PUV A, or treatment with immunosuppressive agents in mal junction) to be counted and point counts made of the positively the previous month. . . . stained cells in at least six areas. The results were expressed as the Epicutaneous patch testl11g was perfor.me? O? all pattents .wah number of cells per unit area. Counts of RFD 1+ cells were) per 8-mm Finn chambers (Epltest Ltd, Helsl11b, Fmland) contalmng formed using a fluorescence microscope and the results expressed as the same allergens in the same concentrations as used for skin prick the number of cells per high-power view (X 400). testing, on clinically normal skin on both sides of the upper back, one side having been prepared by Sellotape stripping 15 times. One Statistical Methods Where appropriate, statistical differences chamber on either side contained diluent as contro!' The patch tests between densities of the cellular infiltrates were determined using were examined at 48 h and the positive patch test reactions were the Wilcoxon sign rank test for paired data; a value of p < 0.05 was graded according to the International Contact Dermatitis Group considered significant. guidelines [19]. . . RESULTS Ten patients consented to have 4-mm .punch bIOpSies from the Sellotape-strippe~ poslt.lve pa.tch test reactlO~ and pat~h test control All patients with AD were skin prick test positive to one or more sites. For companson, SIX pattents With atopic dermatttts who were inhalant allergens. Seventeen patients showed positive patch test skin prick test positive had biop.sies tak~n from non-t a p ~ -stripped reactions to one or more epicutaneously applied allergens. The lesional eczematous and non-leslOnal skl11. Non - tape-stnpped skin commonest reactions were to Dermatophagoides pteronyssinus and biopsies from five age- and sex-matched normal individuals with nO Dermatophagoides jarinae, cat dander, Candida albicans and Cladospor personal or family history of atopy and who were skin prick test ium herbanlm, and rye grass pollen. T en patients reacted to more negative acted as further control samples. Specimens were placed in than one allergen and four patients developed positive patch test embedding compound (Bright Instruments Company Ltd, UK), reactions on both the Sellotape-stripped and non-stripped sides, snap frozen in liquid nitrogen, and stored at -70 ° C. Six-microme whereas no patient reacted on the non-stripped side only (Table II). ter sections were cut, mounted on poly-l-lysine-coated slides, air dried for 30 min, fixed in chloroform: acetone (1 : 1), and stored at -20°C. Table II. Details of Patients who Developed Positive Patch Immunostaining The following panel of monoclonal antibod Test Reactions· ies (MoAb) were used: CDl (Dakopatts, Ltd), which identifies thy mocytes and Langerhans cells; CD23 (Dakopatts) (FceRll), a Pos itive Patch Test Reactions marker for the low-affinity receptors for IgE; RFD1 (Royal Free Hospital School of Medicine [RFJ, London), which labels dendritic Patient Skin Prick Sellotape- an tigen-presenting cells; RFD7, a marker for tissue macrophages; Number/ Age Reactivity Stripped Non-Stripped and RFTmix, which is a pan T-cell marker (Table I). DP,DF,P For the staining of individual cell types, the indirect alkaline 1/ 30 DP,DF DP 2/29 R,T,DP,P R,T phosphatase method was used. The primary antibody diluted in 3/34 B,R,CH,DP,DF,AT,CA B,R Tris-buffered saline (TBS) was added to the reaction and incubated 4/24 CA,C,R,DP,DF CA for 30 min. After washing in TBS for 2 min, a second layer of rabbit 5/22 CH,C,P,R,T,DP CH,C,P anti-mouse immunoglobulin (Dakopatts Ltd.) was applied and in 6/29 DP,CA,AT,B,T DP cubated for 30 min, washed for 2 min, and followed by a third layer 7/32 C,D,DP,DF,CH C,CH of an alkaline phosphatase-mouse anti-alkaline phosphatase corn 8/22 CH,CA,DP,D,C,T C,D C,D plex (AP AAP; Dakopatts) for a further 30 min. Fast red (Sigrna 9/36 DP,CA,AT,R,T DP,R Ltd.) was used as a developer. Sections were counterstained in he 10/26 CA,DP,AT,R,PT DP,AT AT,CA,DF,C,R matoxylin and mounted in phosphate-buffered saline/glycerol 11 /28 CA 12/ 39 DP,DF,B,R,T,D DP,DF,B (9: 1). For controls, the first layer was replaced by TBS. Double 13/30 R,C,DP,DF,T,D R R staining was performed for CD1 /CD23, RFD7/CD23, using 14/ 28 CA,DP,C,PT CA APAAP and peroxidase methods sequentially. Peroxidase staining 15/23 R,C,DP R identified CD23 expression and AP AAP identified RFD7 and CD 1. 16/31 DP,DF,R,AT,D DP,DF Double immunofluorescence was performed using a mixture of 17/27 AT,DP,C,B DP DP class-specific second layers conjugated with fluorescein isothio • AT, Allemaria let",is; B, birch; C, cat dander; CA , Ca "dida albicallS; CH, Cladospor- cyanate (FITe) and tetramethylrhodamine (TRITe) to identify ill'" It .rba",,,,; D, dog dander; DF, Dennatopltagoidesjari"ae; DP, Dermatopltago ides plerotl- RFDt+/CD23+ and RFDt+/CDt+ cells. yssitllls; PT, plane tree; R, rye grass; T, timothy grass. 186 BUCKLEY ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

20 12 2a c'" Normal Controls a 18 o u 40 16 ~ Non·Lcsional Skin o Non·Lcsional Skin 0 ~ 10 Z '"c: .,. 16 e • Lesional Skin .!!! 3 .\2 14 [ ::;; ~ 14 0- X 8 2- .!!! 30 0 III i'!'" 12 ~ ~

100 a. b. netic and functional links seem to exist between Langerhans cells o Non ·Lcsional Skin o Palch Test Control and dermal dendritic cells, suggesting inter-differentiation between ~ lcsional Skin rn Patch Test Positivo them dependent upon biologic stimuli and other factors [25]. It is eo noteworthy that within the epidermis of patch test reaction and 1:'" lesional skin samples, very few CD1+ RFD1 + cells were identified, 'in o whereas the reverse was true in the dermis. All patients in this study ~ 60 r.::: produced immediate hypersensitivity reactions to specific antigens o U when skin prick tested. When these same all ergens were applied epicutaneously the morphology of the reactions observed at 48 h, ~" i ~ ~ were eczematous with erythema, papules, and sometimes vesicles, rather than showing urticarial lesions typical of the type 1 reaction. Gondo [20] has shown that with repeated challenge with the house dust mite antigen, a type IV eczematous reaction is produced 24- ;:;:; ,-, .....::1..:. :1. ::1...... :1 ~o 20 n I.';.!.'I.I. :m 1m 48 h after an initial type 1 response. This difference in clinical ~~~~~~~p-~~~~L-~~~~~ lesions is reflected in the histology of the patch test reaction at 48 h, CD1+ MaCfophagcs Dendfl hc Cells CD1+ Macrophages Dendritic Cetls which suggests a delayed T -cell- mediated reaction. This would be (RFD7+) (RFD1+) (RFD7+) (RFD1+) consistent with an IgE-mediated "late-phase" response and recent Figure 3. The percentage of Langerhans cells (CDl+), macrophages studies of allergen-induced mast cell activation have shown that the (RFD7+), and dendritic ce ll s (RFDl+) that are CD23+ within the dermis terminal stages ofIgE-mediated hypersensitivity reactions are char of (aJ non-lesional compared to lesional atopic skin, and (bJ positive patch acterized by infiltration of monocytes and lymphocytes [26,27]. It test reactions compared to patch test control samples. seems likely, therefore, that it is the patch test reaction and not the immediate prick test reaction that reflects the clinical lesions seen in AD. Immunoelectron microscopic studies have shown house-dust an tigen attached to IgE+ dendritic cells in patch test-positive sites Double staining with the dendritic cell marker (RFD1) and CDl [28], although it is unclear as to whether the antigen binds to IgE or MoAb revealed very few positive cells in the epidermis. In contrast, not. Mudde et al [29] have highlighted the importance of IgE+ it was observed that the dendritic cell (RFDl +) antigen emerged on Langerhans cell in antigen presentation. In their in vitro studies, a a significant proportion of Langerhans cells in the dermis of patch T-cell response to house-dust mite antigen was only observed in the test reaction (60%) and les ional skin (70%) samples, compared to presence of IgE+ Langerhans cells from patients with AD. IgE 44% in control skin (p < 0.05). negative Langerhans cell or Langerhans cells from normal controls were unable to present house-dust mite antigen. Furthermore, the DISCUSSION presence of IgE on Langerhans cells correlated with the clinical This study confirms previous reports that the patch test reaction to activity of the disease and Langerhans cells from patients with AD aeroallergens and the lesional skin in patients with AD exhibit char in clinical remission became IgE negative [30]. acteristic features of a delayed type IV hypersensitivity reaction. It Recently, low-affinity IgE receptors (Fc.R11/CD23) have been goes further in revealing 1) the distribution of immunocompetent demonstrated on Langerhans cells in patients with AD [14]. This cells in patch tested and lesional skin; 2) similarities in the pheno antigen is not specific for AD and has been identified in non-atopic type of the dermal infiltrate in the patch test reaction and lesional skin [16]. In this study, we have confirmed that the CD23 antigen is skin; 3) a difference between the normal non-atopic skin and the expressed, albeit weakly, in non-atopic individuals. W e observed non-lesional skin in patients with atopic dermatitis; and 4) a shift in greater numbers of CD23+ cells in patch test- reaction samples the expression of CD23 from tissue macrophages to dendritic cells compared to lesional skin sections and it is possible that this increase within the dermis. is a consequence ofSellotape stripping. Sellotape stripping is known Patch test reactions studied by other investigato~s have shown a to cause a reduction in the number of Langer hans cells in guinea pigs dermal cellular infiltrate of T lymphocytes and CD1+ cells [31] without altering the degree of contact sensitivity to DNCB. In [3,6,7,20]. We have demonstrated increased numbers of Langer contrast, we observed that the numbers of LC were actually in hans cells, macrophages, and lymphocytes in the dermis of patch creased in patch test control compared to non-Iesional skin, sug test rea:::tions. Because the patch test samples were obtained from gesting that the effect ofSellotape stripping was minimal, at least in Sellotape-stripped skin, a direct comparison with samples taken terms of the numbers of inflammatory cells within the sections. from non-stripped skin is not valid. Despite this, however, it is Indeed, we found no significant difference between the non-Ie interesting that lesional skin samples contained similar increases sional skin (non-stripped) and patch test control skin (stripped) for over their controls in the number of these cell subsets observed in the numbers of cell subsets studied (data not shown) although there patch test reactions compared to patch test controls. The reduced was a significantly greater number of CD23+ cells in the patch tes t numbers of Langerhans cells in the epidermis with increased num control samples. bers in the dermis of both lesional and patch test reaction biopsies are In patch test control skin from patients with AD, CD23 was identical to those reported in allergic contact dermatitis [21]. Macro found mainly on tissue macrophages (RFD7+) and only a small phages were diffusely distributed throughout the dennis whereas proportion of Langerhans cells and dendritic cells (RFDl +) were the Langerhans cells and lymphocytes were principally located peri CD23+. The situation was reversed in lesional skin and patch test vascularly in the upper dermis. These results are consistent with the reaction samples, for which less than 10% of macrophages immunohistochemical profile of a delayed hypersensitivity reaction (RFD7+) and up to 80% of Langer hans cells (CD1+) were positive [22]. lending weight to the argument that suggests that the clinical for CD23 (Fig 3). Thus our data offer evidence that there is a shift in lesion in AD is a T-cell-mediated hypersensitivity reaction. CD23 expression from tissue macrophages to dendritic cells in both Another finding from this study is the emergence in the dermis of patch test reaction and lesional skin of patients with AD. both lesional skin and patch test reaction samples of Langerhans It is also significant that> 60% of dermal Langerhans cells ex cells that also express the dendritic cell marker (RFD1). Normal pressed the dendritic cell marker (RFD1), whereas few epidermal skin contains few detectable dendritic cells [23], and Langerhans Langerhans cells were positive. RFD1 positivity has been shown to cells are largely confined to the epidermis. In lesional skin of in flam be specifically associated with cell s presenting antigen [32-34]. matory dermatoses including AD, both Langerhans cells and den Langerhans cells are not constitutively RFD 1+ but become strongly dritic cells are found in abundance within the dermis, the latter positive when activated [35]. Results reported here therefore su g being occasionall y observed in the epidermis [24]. Close histoge- gest that antigen presentation by Langerhans cells (CD1+) occurs 188 BUCKLEY ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY predominantly within the dermis rather .than in the epidermis. It is epidermal Langerhans cells that react with anti-CD23 monoclonal possible that the presence of antigen wI~hlI1 the epIdermIs of pa antibody. Br] DermatoI124:533-537, 1991 tients with AD results in an upregulatlon 111 the expressIon of CD23 18. 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