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Chapter 7 Histopathological and Immuno- 7 histopathological Features of Irritant and Allergic Contact

Jean-Marie Lachapelle, Liliane Marot

Contents Among such examples, the following can be 7.1 Introduction: General Considerations . . . . . 107 quoted: 7.2 Histopathological Features of Positive Allergic Patch Test Reactions . . . . 108 í Nummular dermatitis (eczema) versus para- 7.2.1 Epidermal Changes ...... 108 psoriasis en plaques (benign type), psoriasis 7.2.2 Dermal Changes ...... 108 or tinea incognito. 7.3 Histopathological Features í Seborrheic dermatitis versus lupus erythema- of Positive Irritant Patch Test Reactions . . . . 110 tosus or rosacea. 7.3.1 Epidermal Changes ...... 110 í Pompholyx versus pustular psoriasis, palmo- 7.3.2 Dermal Changes ...... 112 plantar pustulosis or bullous pemphigoid. 7.4 Histopathological Criteria for Distinguishing Between Allergic and Irritant Patch Test Reactions in Humans . 112 When an eczematous reaction is involved, the histo- pathological clue in diagnosis is the presence of a 7.5 Comparative Immunohistochemical spongiotic (spongiform) dermatitis, notwithstand- and Immunocytochemical Characteristics of Allergic and Irritant Patch Test Reactions ing its origin: irritant, allergic or endogenous. in Humans ...... 114 In each individual case, the histopathological pic- 7.5.1 Epidermal Langerhans Cells in Irritant ture is dependent on various parameters, which can and Allergic Positive Patch Test Reactions . . . 114 play a confounding role, such as: (1) unknown dura- 7.5.2 Cells of the Infiltrate in Irritant tion of the disease; (2) lesions related to scratching; and Allergic Positive Patch Test Reactions: (3) infections; and (4) lichenification. Clinicians are Immunophenotypic Studies ...... 114 sometimes advised to perform two biopsies instead 7.6 Conclusions ...... 115 of one, in order to focus on different stages of the dis- References ...... 115 ease. A full description of histopathological signs of al- lergic and/or irritant is better achieved by a careful study of positive allergic and/or 7.1 Introduction: General Considerations irritant patch test reactions. This approach has two advantages: (1) the histo- Histopathological features of allergic and/or irritant pathological signs reflect a practical situation, en- contact dermatitis are not described in full detail in countered daily at the patch test clinic; (2) a positive most textbooks of [1–3]. This is because patch test reaction is a clear-cut,unmodified reaction they are not usually involved in the diagnostic proce- – the direct consequence of the application of a sub- dures of both conditions. In most cases, contact der- stance on previously intact skin. matitis is suspected from anamnestic data and clini- The only possible drawback to using patch test re- cal signs [4]. Diagnosis is confirmed by patch testing actions is the role played by occlusion. This might be and/or other tests, with additional information about especially true for allergic reactions, and it is the rea- the responsible agent(s). Nevertheless, in daily prac- son for this description also being based upon open tice, contact dermatitis may be superimposed onto (unoccluded) reactions, the use of which is becoming an underlying skin disease, the diagnosis of which is commoner in many clinics. sometimes difficult. This description will be a “freeze-frame photo- In those circumstances, skin biopsy is highly rec- graph” of the situation at 48, 72 or 96 h; it does not ommended and considered an important tool of dif- take into account the chronology of events, starting ferential diagnosis. at time 0 (with the application of the substance) and 07_105_116* 04.11.2005 15:38 Uhr Seite 108

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continuing for instance every 6 h – until 48 or 72 h. layer. In some but not all cases, it spares the cells of This dynamic view has been achieved in previous re- the sweat duct unit. Hair follicles are usually involved search studies [5]. by the spongiotic process. It has to be emphasized that this description is A more plentiful accumulation of fluid results in useful when expressed in scientific (more than prac- rupture of the intercellular prickles and the forma- tical) terms, to improve our knowledge at the micro- tion of vesicles. Thus, in allergic contact dermatitis, scopic level. In this respect, patch testing has been spongiotic vesiculation can be defined as an intra- used recently as a tool for evaluating the efficacy of epidermal cavity with ragged walls and surrounding topical drugs, such as pimecrolimus [6] or tacroli- spongiosis. There is migration of inflammatory cells mus, [7] versus corticosteroids regarding the out- into the epidermis (exocytosis). These cells, mainly come of allergic positive patch test reactions to nick- lymphocytes and occasionally polymorphonuclear el sulfate in volunteers. The evaluation of results has neutrophils and eosinophils, accumulate in the spon- been based on visual scoring and biometrical meas- giotic vesicles. urements using noninvasive technology, but not on Some vesicles are rounded and tense; they are lo- the evaluation of histopathological parameters. In- cated in the stratum spinosum, whereas others are deed, biopsy is considered an invasive procedure, re- flat and located in the stratum corneum. They finally 7 jected nowadays by most ethical committees. rupture at the surface of the epidermis and vertical A lot of information delivered in the next para- channels of fluid discharge are occasionally seen on graphs comes from our own material, used in former serial sections. These channels are sometimes color- studies, at a time when legal procedures were not as fully described as “Devergie’s eczematous wells.” strictly codified as they are today. Intracellular edema of keratinocytes does occur, with accumulation of glycogen. At the electron microscopic level, dissolution of Core Message interdesmosomal areas, or “microacantholysis,” can be demonstrated; remaining desmosomes show ten- í In clinical practice, when the diagnosis of sion and alignment of tonofilament bundles. allergic and/or irritant contact dermatitis In photoallergic contact dermatitis,a biopsy of the is not clear-cut, skin biopsy is considered photopatch test site, when positive, clearly shows an important tool of differential diagnosis. transforming keratinocytes in sunburn cells. In contrast, biopsies of positive patch tests are not recommended, except for scientific purposes. 7.2.2 Dermal Changes

Papillary blood capillaries are often congested and dilated; dilatation of lymphatic vessels is very con- spicuous in some but not all cases. Dermal edema is 7.2 Histopathological Features of Positive prominent with deposits of acid mucopolysaccha- Allergic Patch Test Reactions rides. A dense mononuclear cell infiltrate is usually present around blood vessels of the lower dermis, The histopathological picture of a positive allergic and even in the subcutaneous tissue. The cells of the patch test reaction (read at 48 h) is a typical example infiltrate migrate from the perivascular spaces to the of a spongiotic dermatitis [3]. Features are very simi- epidermis and are found throughout the dermal tis- lar in all cases. sue, either isolated or grouped in small clumps. It is not uncommon to see a dermal infiltration of inflammatory cells around and within hair sheaths 7.2.1 Epidermal Changes and sebaceous ducts, which show some degree of spongiosis and cellular degeneration. This picture In the epidermis, spongiosis is an almost constant could be partly due to direct penetration of the aller- sign, resulting from the accumulation of fluid around gens through the pilosebaceous unit. individual keratinocytes (exoserosis) and the conse- The infiltrate is of the lymphohistiocytic type, quent stretching of intercellular desmosome com- composed almost exclusively of mononuclear cells, plexes (or “prickles”). varying in form and size. The occurrence of an inti- Spongiosis is focally or evenly distributed along mate contact between the cell surfaces of lympho- the length of the epidermis; it is either limited to the cytes and the cell processes of macrophages was lower layers or extends from the basal to the granular demonstrated many years ago at the ultrastructural 07_105_116* 04.11.2005 15:38 Uhr Seite 109

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Fig. 1. Allergic positive patch test reaction to balsam of Peru (Myroxylon pereirae) at 2 - days: spongiotic vesiculation in epidermis with exocytosis of mononuclear cells and dermal edema. Hematoxy- lin–eosin–saffron stain (×150)

Fig. 2. Allergic positive patch test reaction to wool wax alco- hols (lanolin alcohol) at 2 - days: dense perivascular in- filtrate of mononuclear cells. Hematoxylin–eosin–saffron stain (×250)

level. It was emphasized that, in delayed hypersensi- sels is usually more pronounced. At this later stage, a tivity, macrophages were thought to play an impor- few eosinophils can be observed very occasionally. tant role, together with lymphocytes. This view was The role of the mast cell in allergic contact hyper- later confirmed and broadened by the discovery of sensitivity remains controversial. Some studies the role played by Langerhans cells. showing histological evidence of mast cell degranu- Polymorphonuclear neutrophils are usually ab- lation suggest that early mast cell activation occurs sent. Some eosinophils can be found in the edema- [8]. tous tissue of the upper dermis, migrating towards In recent years, Hannuksela’s repeated open appli- the epidermis. cation test (see Sect. 22.10.2) has become popular for The histopathological picture is very similar when confirming the clinical relevance of positive allergic the biopsy is taken 72 h or 96 h after application of patch test reactions [9]. We have taken biopsies from the . The dermal infiltrate around blood ves- positive allergic open test reactions on the volar as- 07_105_116* 04.11.2005 15:38 Uhr Seite 110

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pect of the forearm,or the cubital fossa,48,72,or 96 h different patients, even when it is applied for the after application of the allergen. In all cases, the his- same duration and under the same conditions. There topathological picture was quite similar to that ob- is no general rule in this respect. served in positive allergic patch test reactions. Two additional features can be observed occasion- ally: 7.3.1 Epidermal Changes

Various alterations of epidermal cells can be ob- í In some positive allergic patch test reactions, served. In some cases, these alterations are limited to particularly to azo dyes, purpuric lesions are the superficial layers of the epidermis, the stratum clinically present [10]: in those cases, there is granulosum and the upper part of the stratum spino- an important extravasation of erythrocytes, sum; in others they extend to the dermo-epidermal mainly located around blood capillaries, but junction, invading all layers of the epidermis. At first extending also to interstitial dermal tissue and cells become karyopyknotic and lose their cytoplas- invading epidermis (exocytosis). mic staining properties on hematoxylin and eosin í In some other positive allergic patch test reac- sections. These changes are known as “Bandmann’s tions, e.g., to gold (more often at 96 h than 7 achromasia” [12]. When the irritation process be- 48 h), the infiltrate may be lymphomatoid and comes more severe, complete necrosis (or cytolysis) mimics pseudolymphoma [11]. It is dense, of epidermal cells occurs, leading to the formation of with a few mitotic figures, and subtle nuclear intra- or subepidermal vesicles and bullae.“Chemical atypia. Rarely, the lymphoid cells may be very acantholysis” of epidermal cells can be seen, mainly, bizarre. but not exclusively, with certain irritants, such as cantharidin and trichloroethylene [13]. Polymorpho- nuclear neutrophils accumulate in the damaged epi- dermis, leading to the formation of subcorneal or Core Message intra-epidermal pustules. In some cases, the formation of pustules is prefe- í Histopathological features of positive rentially limited to the hair follicles. Follicular pus- allergic patch test reactions are typical tules are preferentially provoked by some irritants, of a spongiotic dermatitis, similar to such as croton oil (“croton oil effect”), or metal salts that observed in different eczematous such as chromates, and those of mercury and nickel. (exogenous or endogenous) reactions. Pustules due to metals are observed mainly, but not exclusively, in atopics. As already noted many years ago, some irritant reactions do not show any of the

7.3 Histopathological Features of Positive Irritant Patch Test Reactions Table 1. Epidermal lesions observed in relation to certain com- mon irritants

The histopathological picture of positive allergic Irritants Epidermal lesions patch test reactions has been shown to be very simi- lar (“monotonous and uniform”) in most cases (see Nonchlorinated organic Achromasia; superficial above). When irritants are applied – under occlusion solvents (i.e., alkanes, necrosis; karyopyknosis; – on the skin, a wide range of different lesions can be such as n-hexane; toluene; very occasional acantholy- xylene; white spirit; sis; subepidermal vesicles seen. This kaleidoscope of lesions concerns mainly turpentine, etc.) and/or bullae epidermal alterations. Various factors play a role in the formation of le- Chlorinated organic Acantholysis ++; karyopyk- solvents (i.e., trichloro- nosis; complete necrosis of sions: (1) the nature of the irritant agent, and conse- ethane; trichloroethylene; epidermal cells; intraepi- quently its mode of deleterious action on the cells,(2) carbon tetrachloride; etc.) dermal vesicles and/or the concentration of the irritant applied on the skin, bullae (3) the ways of penetration of the skin, and (4) the in- Acids, alkalis, surfactants, Achromasia; superficial or dividual reactivity of the skin to a well-defined irri- detergents, aldehydes complete necrosis of epi- tant. dermal cells; subepidermal It is therefore possible that the same irritant vesicles and/or bullae; no acantholysis chemical can produce different types of lesions in 07_105_116* 04.11.2005 15:38 Uhr Seite 111

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Fig. 3. Irritant positive patch test reaction to croton oil at 2 - days: spongiotic vesiculation in epidermis with exocytosis of mononuclear cells. This picture is indistinguishable from an allergic reaction. Masson’s trichrome blue stain (×150)

Fig. 4. Irritant positive patch test reaction to trichloroethylene at 2 days: epidermal necrosis with acantholytic keratino- cytes, exocytosis of inflam- matory cells. Masson’s tri- chrome blue stain (×150)

aforementioned histopathological signs; they are ex- chloric acid. More recently, Willis et al. [14, 15] com- clusively spongiotic (with or without vesicles). pleted an extensive study comparing the action of Such observations can be made: (1) with weak irri- several categories of irritants, using semi-thin sec- tants, (2) with strong irritants, applied on the skin at tion technology. They noted in particular that vari- a low concentration, and (3) in the “excited” (or irri- ous kinds of detergents damaged epidermal cells in table) skin syndrome. different ways when applied at a low concentration. Examples of epidermal lesions classically ob- For instance,the major response to the anionic deter- served with certain categories of irritants are given in gent sodium lauryl sulfate was parakeratosis, indicat- Table 1. ing increased epidermal cell turnover, whilst benzal- Many years ago, ultrastructural studies threw konium chloride, a cationic detergent, caused a dif- some light on the mode of action of certain irritants, ferent type of reaction – spongiosis and exocytosis including croton oil, sodium hydroxide, and hydro- with focal necrotic damage [16]. 07_105_116* 04.11.2005 15:38 Uhr Seite 112

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Fig. 5. Irritant positive patch test reaction to croton oil at 2 - Fig.6. Irritant positive patch test reaction to sodium lauryl sul- days: a follicular pustule is filled with neutrophils and lym- fate at 2 days: the epidermis is partly necrotic with infiltration phoid cells. There is a perivascular infiltrate of mononuclear of mononuclear cells. There is a dermal perivascular infiltrate cells. Masson’s trichrome blue stain (×75) of mononuclear cells. Hematoxylin–eosin stain (×150)

Phototoxic reactions are characterized by the Core Message presence of eosinophilic necrotic keratinocytes (“sunburn cells”). í Histopathological features of positive irritant patch test reactions are varied, 7.3.2 Dermal Changes according to the nature and/or concen- tration of irritant chemicals and to the Dermal changes are also related to the mechanisms individual reactivity of the skin. This involved in the mode of action of each individual ir- “kaleidoscope” of lesions concerns mainly ritant. Dermal edema is absent or slight. Blood capil- epidermal alterations. laries and lymphatics are discretely dilated, but usu- ally to a lesser extent than in positive allergic patch test reactions. In some cases, there is an important inflammatory response distributed around the blood vessels of the 7.4 Histopathological Criteria upper and mid-dermis. It is either homogeneously for Distinguishing Between Allergic mononuclear or mixed (polymorphonuclear neu- and Irritant Patch Test Reactions trophils and lymphocytes/macrophages). Eosino- in Humans phils are absent. In cases of severe irritation, it is usu- al to find pyknotic remnants of neutrophils in the upper part of the dermis. In the preceding paragraphs, the various histopatho- logical signs encountered in allergic and irritant patch test reactions have been reviewed in detail [12, 17–20]. We must remember that this description re- 07_105_116* 04.11.2005 15:38 Uhr Seite 113

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Table 2. Distinctive histopathological criteria between allergic and irritant patch test reactions in humans (modified from [8])

Allergic reactions Irritant reactions

Epidermis Spongiosis + to +++ + or – Exocytosis + to +++ +++ Vesicles + (spongiotic) + (rarely spongiotic) Formation of bullae Facultative (spongiotic) Facultative (rarely spongiotic) Pustules – + or – Necrosis of epidermal cells – + to +++ Acantholysis of epidermal cells – + or – Distribution of the infiltrate in epidermis Focal [21] Diffuse [21] Dermis Perivascular infiltrate Mononuclear Mononuclear or mixed (mononuclear + neutrophils) Eosinophilic leucocytes + or – – Dilatation of lymphatic vessels + or – – Dilatation of blood capillaries + or – + or – Edema + or – Very unusual

fers to “typical” cases: irritant (without allergic com- dermatitis, many difficulties remain in making such ponent) or allergic (without irritant component). a differentiation [21]. Comparative signs are presented in Table 2. These When considering all these potential criteria of distinctive criteria are of limited value in practice for differential diagnosis,it is worth saying that spongio- many reasons: (1) most criteria are present in irritant sis is in bulk a more consistent feature in allergic as well as in allergic positive patch test reactions; (2) than in irritant reactions.Vestergaard et al. [22] have other criteria are predominant either in irritant or in recently conducted a human study comparing aller- allergic reactions, but they lack specificity; (3) most gic and irritant reactions. Biopsy samples were taken also have irritant properties. Even when al- at a very early stage (6–8 h) after applying (1) an irri- lergens are patch tested at a concentration below the tant (benzalkonium chloride) and (2) an allergen level of clinical irritancy to avoid “mixed” pictures, it (that is colophony or quaternium-15) to individuals is just possible that subclinically, at the microscopic with known to one of these allergens, selected level, they might show a mixed picture of irritation because they rarely give rise to unspecific or irritant and allergy. reactions. The significant finding was that focal In practice, when a positive patch test reaction is spongiosis was present only in allergic reactions. clinically doubtful (irritant versus allergic), the help It is likely that the aggregation of monocytes/mac- from a biopsy is minimal, due to the differential bias rophages and proliferating T-cells, along with their explained above. chemical mediators, is responsible for the epidermal Avnstorp et al. [21] conducted a semi-quantitative spongiosis in allergic contact dermatitis [23]. histopathological study of individual morphological In conclusion, though conventional histopatholo- parameters in allergic and irritant patch test reac- gy of positive patch test reactions can provide some tions. Their conclusions were as follows: statistical useful information, it is of little help in separating al- analysis by correlation of 17 selected variables gives a lergic from irritant or mixed reactions. Drawing such diagnostic specificity of 87% and a sensitivity of 81% a conclusion at the end of this section might appear for allergic reactions. For irritant reactions, the spec- to be negative, since a different view has prevailed for ificity is 100% and the sensitivity 46%. By multiple decades in so many European contact dermatitis regressive analysis, an index was calculated for the clinics. Nevertheless, it is based on a careful review of differentiation of allergic and irritant reactions. If the literature and a reappraisal of our own material. this index were to be used in cases of allergic patch It coincides with the views of the basic scientists and test reactions, all would also be reported as allergic must be considered by practicing dermatologists as reactions while half of the irritant reactions would be reflecting reality. reported as allergic. Although this study has shed some light on the problem of the histopathological differentiation between allergic and irritant contact 07_105_116* 04.11.2005 15:38 Uhr Seite 114

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Core Message that allergic and irritant patch test reactions cannot be differentiated reliably by counting LC, in spite of the small differences observed [27]. Moreover, lym- í Histopathological differential diagnosis phocyte/LC apposition is observed in both types of between allergic and irritant patch test re- reaction [28, 29]. The presence of human leukocyte actions is clearly explained in Table 2. antigen (HLA) DR antigens on keratinocytes in aller- gic reactions may reflect an immunological response [30].

7.5 Comparative Immunohistochemical 7.5.2 Cells of the Infiltrate in Irritant and and Immunocytochemical Allergic Positive Patch Test Reactions: Characteristics of Allergic Immunophenotypic Studies and Irritant Patch Test Reactions in Humans Early human studies showed little evidence of diffe- 7 rential release between allergic and irritant An explosion of knowledge concerning the mecha- contact dermatitis. nisms involved in contact dermatitis has been taking This strongly suggests that, although initiating place over the past 10 years; the discovery of the key events vary considerably, the cascade mechanisms role played by the Langerhans cell and the ability to responsible for the induction and release of regulat- identify subpopulations of lymphocytes by the use of ing mediators are similar [31, 32]. Clearly, most, if not monoclonal antibodies must be considered as major all, pro-inflammatory phenomena can be caused advances. This has raised the question as to whether both by irritants and allergens. Therefore, they do the use of new immunocytopathological techniques not unambiguously discriminate between irritants might help in distinguishing between irritant and al- and contact allergens [33]. lergic patch test reactions. In the various studies conducted so far, the com- position of the infiltrates is similar in allergic and ir- ritant reactions, and consists of T lymphocytes of 7.5.1 Epidermal Langerhans Cells helper/inducer types in association with T-cell acces- in Irritant and Allergic Positive sory cells, that is, LC and HLA-DR-positive macro- Patch Test Reactions phages. Probably, true differences between these types of compounds depend on whether or not allergen-spe- Semi-quantitative studies related to the number of cific T-cells become involved [33]. Thus, only after

Langerhans cells (LC; CD1 or T6 dendritic cells) in specific T-cell triggering might distinctive features the epidermis in positive irritant and allergic patch be observed, e.g., local release of certain chemokines, test reactions have been conducted. These studies such as CXCL10 (IP-10) and CXCL11 (I-TAC/IP9) [34]. have revealed a statistically significant decrease in LC The latter chemokines are produced by interferon- 48 or 72 h after the application of various types of γ-activated keratinocytes and T lymphocytes [35]. irritants: sodium lauryl sulfate, mercuric chloride, benzalkonium chloride, croton oil, or dithranol. Core Message There was also a significant reduction in dendritic length. These changes in density were unrelated to the intensity of the inflammatory response [24]. í New immunocytopathological techniques Similar studies in positive allergic patch test reac- are of no real help in distinguishing tions show an early transitory increase in LC in the between irritant and allergic patch test first few hours [25] following the application of aller- reactions, since there is little evidence gens, though a similar response occurs at the sites of of differential cytokine release. petrolatum application [25]. This phenomenon may Clearly, most, if not all, of pro-inflamma- therefore lack specificity. Later on, at 24, 48, or 72 h tory phenomena can be caused by both after application of the allergen, the number of LC is irritants and allergens. Therefore, they unchanged or decreases when compared with nor- do not discriminate between irritants mal skin.It may also be reduced at the site of negative and contact allergens. patch test reactions [26]. Current studies indicate 07_105_116* 04.11.2005 15:38 Uhr Seite 115

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7.6 Conclusions duced by irritants in man. In: Frosch PJ, Dooms-Goossens A,Lachapelle JM,Rycroft RJ,Scheper RJ (eds) Current top- ics in contact dermatitis. Springer, Berlin Heidelberg New In spite of certain differences in the histopathologi- York, pp 42–45 cal lesions observed in allergic and irritant patch test 16. Willis CM, Stephens CJM,Wilkinson JD (1993) Differential reactions, there is as yet no reliable diagnostic tool patterns of epidermal leukocyte infiltration in patch test reactions to structurally unrelated chemical irritants. J In- (either morphological or immunophenotypic) to vest Dermatol 101 : 364–370 “label” specifically each type of reaction. 17. Medenica M, Rostenberg A (1971) A comparative light and electron microscopic study of primary irritant contact dermatitis and allergic contact dermatitis. J Invest Derma- tol 56 : 259–271 References 18. Lachapelle JM (1972) Comparative study of 3H-thymidine labelling of the dermal infiltrate of skin allergic and irri- 1. Wilkinson SM, Beck MH (2004) Contact dermatitis: irri- tant patch test reactions in man.Br J Dermatol 87 : 460–465 tant. In: Burns DA, Breathnach SM, Cox N, Griffiths CE 19. Grosshans E, Lachapelle JM (1982) Comparative histo- and (eds) Rook’s textbook of dermatology, 7th edn, Chap. 19. cytopathology of allergic and irritant patch test reactions Blackwell Science, Oxford in Man. In: Foussereau J, Benezra C, Maibach H (eds) Oc- 2. Beck MH, Wilkinson SM (2004) Contact dermatitis: aller- cupational contact dermatitis. Clinical and chemical as- gic. In: Burns DA, Breathnach SM, Cox N, Griffiths CE pects. Munksgaard, Copenhagen, pp 63–69 (eds) Rook’s textbook of dermatology, 7th edn, Chap. 20. 20. Nater JP, Hoedemaeker PHJ (1976) Histopathological dif- Blackwell Science, Oxford ferences between irritant and allergic patch test reactions 3. Belsito DV (2003) Allergic contact dermatitis. In: Freed- in man. Contact Dermatitis 2 : 247–253 berg IM (ed) Fitzpatrick’s dermatology in general medi- 21. Avnstorp C, Balslev E, Thomsen HK (1989) The occurrence cine, 6th edn, Chap. 120. McGraw-Hill, New York, pp of different morphological parameters in allergic and irri- 1164–1180 tant patch test reactions. In: Frosch PJ, Dooms-Goossens 4. Rietschel RL, Conde-Salazar L, Goossens A, Veien NK A,Lachapelle JM,Rycroft RJ,Scheper RJ (eds) Current top- (1999) Atlas of contact dermatitis. Dunitz, London ics in contact dermatitis. Springer, Berlin Heidelberg New 5. Kerl H, Burg G, Braun-Falco O (1974) Quantitative and York, pp 38–41 qualitative dynamics of the epidermal and cellular inflam- 22. Vestergaard L, Clemmensen OJ, Sorensen FB,Andersen KE matory reaction in primary toxic and allergic dinitroch- (1999) Histological distinction between early allergic and lorobenzene contact dermatitis in guinea pigs. Arch Der- irritant patch test reactions: follicular spongiosis may be matol Forsch 249 : 207–226 characteristic of early allergic contact dermatitis. Contact 6. Queille-Roussel C, Graeber M, Thurston M, Lachapelle JM, Dermatitis 41 : 207–210 Decroix J, de Cuyper C, Ortonne JP (2000) SDZ ASM 981 is 23. Belsito DV (1999) The molecular basis of allergic contact the first non-steroid that suppresses established nickel dermatitis. In: Dyall-Smith D, Marks R (eds) Dermatology contact dermatitis elicited by allergen challenge. Contact at the millennium. The Proceedings of the 19th World Dermatitis 42 : 349–350 Congress of Dermatology. Parthenon, New York, pp 7. Alomar A, Puig L, Gallardo CM,Valenzuela N (2003) Topi- 217–223 cal tacrolimus 0.1% ointment (Protopic®) reverses nickel 24. Ferguson J, Gibbs JH, Beck JS (1985) Lymphocyte subsets contact dermatitis elicited by allergen challenge to a simi- and Langerhans cells in allergic and irritant patch test re- lar degree to mometasone furoate 0.1% with greater sup- actions: histometric studies. Contact Dermatitis 13 : pression of late erythema. Contact Dermatitis 49 : 185–188 166–174 8. Angelini G, Vena GA, Filotico R, Tursi A (1990) Mast cell 25. Christensen OB, Daniels TE, Maibach HI (1986) Expres- participation in allergic contact sensitivity. Contact Der- sion of OKT6 antigen by Langerhans cells in patch test re- matitis 23 : 239 actions. Contact Dermatitis 14 : 26–31 9. Hannuksela M, Salo H (1986) The repeated open applica- 26. Brasch J, Mielke V,Kÿnne N,Weber-Matthiesen V,Bruhn S, tion test (ROAT). Contact Dermatitis 14 : 221–227 Sterry W (1990) Immigration of cells and composition of 10. Lazarov A, Cordoba M (2000) Purpuric contact dermatitis cell infiltrates in patch test reactions. Contact Dermatitis in patients with allergic reaction to textile dyes and resins. 23 : 238 J Eur Acad Dermatol Venereol 14 : 101–105 27. Kanerva L, Ranki A, Lauharanta J (1984) Lymphocytes and 11. Fleming C, Burden D, Fallowfield M et al (1997) Lymphom- Langerhans cells in patch tests.An immuno-histochemical atoid contact reaction to gold earrings. Contact Dermatitis and electron microscopic study. Contact Dermatitis 11 : 37 : 298–299 150–155 12. Lachapelle JM (1973) Comparative histopathology of aller- 28. Willis CM,Young E, Brandon DR,Wilkinson JD (1986) Im- gic and irritant patch test reactions in man. Current con- munopathological and ultrastructural findings in human cepts and new prospects. Arch Belg Dermatol 28 : 83–92 allergic and irritant contact dermatitis. Br J Dermatol 115 : 13. Mahmoud G, Lachapelle JM (1985) Evaluation 305–316 expérimentale de l’efficacité de crèmes barrière et de gels 29. Illis CM, Wilkinson JD (1990) Changes in the morphology antisolvants dans la prévention de l’irritation cutanée and density of epidermal Langerhans cells (CD1 + cells) in provoquée par des solvants organiques. Cah Med Trav 22 : irritant contact dermatitis. Contact Dermatitis 23 : 239 163–168 30. Scheynius A, Fischer T (1986) Phenotypic difference 14. Willis CM, Stephens CJM, Wilkinson JD (1989) Epidermal between allergic and irritant patch test reactions in man. damage induced by irritants in man: a light and electron Contact Dermatitis 14 : 297–302 microscopic study. J Invest Dermatol 93 : 695–699 31. Hoeffaker S, Caubo M, Van’t Erve EH (1995) In vivo cyto- 15. Willis CM, Stephens CJM, Wilkinson JD (1989) Prelimi- kine profiles in allergic and irritant contact dermatitis. nary findings on the patterns of epidermal damage in- Contact Dermatitis 33 : 258–266 07_105_116* 04.11.2005 15:38 Uhr Seite 116

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32. Ulfgren AK, Klareskog L, Lindberg M (2000) An immuno- tivating chemokines IP-10, MIG and IP-9 are expressed in histochemical analysis of cytokine expression in allergic allergic but not in irritant patch test reactions. J Invest and irritant contact dermatitis. Acta Derm Venereol Dermatol 113 : 574–578 (Stockh) 80 : 167–170 35. Tensen CP,Flier J, van der Raaij-Helmer EM, Sampat-Sard- 33. Rustemeyer T (2004) Immunological aspects of environ- joepersad S, van den Schors RC, Leurs R, Scheper RJ, Boor- mental and occupational contact , Thela Thesis, sma DM, Willemze R (1999) Human IP-9: a keratinocyte Amsterdam derived high affinity CXC-chemokine ligand for the IP- 34. Flier J, Boorsma DM, Bruynzeel DP, van Beek PJ, Stoof TJ, 10/Mig receptor (CXCR3). J Invest Dermatol 112 : 716–722 Scheper RJ, Willemze R, Tensen CP (1999) The CXCR3 ac-

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