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The ACVD task force on canine atopic dermatitis (IX): the controversy surrounding the route of allergen challenge in canine atopic dermatitis
Veterinary Immunology and Immunopathology 81 (2001) 219±225
The ACVD task force on canine atopic dermatitis (IX): the controversy surrounding the route of allergen challenge in canine atopic dermatitis Thierry Olivrya,*, Peter B. Hillb a
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA b Department of Veterinary Clinical Studies, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Hospital for Small Animals, Easter Bush Veterinary Centre, Roslin, Edinburgh EH25 9RG, Scotland, UK
Abstract For decades, the dogma that environmental allergens trigger cutaneous in¯ammation led to the denomination of canine atopic dermatitis as ``allergic inhalant dermatitis''. De®nitive proof for a respiratory route of allergen challenge is lacking, however. Recent observations suggest, in fact, that skin in¯ammation could occur because of epidermal allergenic contact. The aim of this paper is to review the evidence published in favor and against the two suspected routes of allergen provocation. # 2001 Elsevier Science B.V. All rights reserved. Keywords: Allergen; Allergic skin disease; Atopy; Dog
1. Introduction During the last half-century, two theories have emerged to explain the way by which antigens gain access to the skin to trigger cutaneous allergic in¯ammation and symptoms of atopic dermatitis (AD). The ®rst hypothesis proposes allergens to be inhaled, penetrate the respiratory tract and migrate via the circulation to the skin where they trigger dermal mast cells. The second suggests that environmental antigens directly transfer through the stratum corneum and contact antigen-presenting cells in the epidermis, thereby initiating cutaneous in¯ammation. Arguments can be proposed in support, or against, these two theoretical concepts.
*
Corresponding author. Tel.: 1-919-513-6276; fax: 1-919-513-6336. E-mail address: [email protected] (T. Olivry). 0165-2427/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 2 4 2 7 ( 0 1 ) 0 0 3 1 1 - 7
220
T. Olivry, P.B. Hill / Veterinary Immunology and Immunopathology 81 (2001) 219±225
2. Evidence in favor of a respiratory route of allergen challenge Since the early report of an allergic disease in a dog with rhinitis, conjunctivitis and urticaria, it has been considered that environmental aeroallergens could induce pruritus and skin lesions via inhalation (Wittich, 1941). The denomination ``canine allergic inhalant dermatitis'' eventually was coined as a name for aeroallergen-induced skin disease (Anderson, 1973). In one anecdotal report, rhinorrhea, lacrimation, conjunctivitis and asthmatiform symptoms were reproduced with aerosolized ragweed pollens in a dog with spontaneous allergic conjunctivitis and dermatitis (Patterson, 1960). Multiple accounts of allergic rhinitis and asthma additionally have been reported in the canine species during the last three decades (Emala and Hirshman, 1997). These reports con®rm the possible development of allergic symptoms after allergen inhalation. An experimental canine model for allergic asthma was subsequently developed via sensitization of normal dogs with inhaled Ascaris suum allergens (Gold et al., 1972; Patterson et al., 1974). Indeed, increased airway reactivity to nonallergenic stimuli, a feature of human asthma, was described in a group of Basenji±Greyhound (BG) crossbreed dogs that were either natively allergic to Ascaris suum or were sensitized by repeated aerosolized antigenic challenge (Hirshman et al., 1980). These Ascaris-sensitive BG dogs exhibit an antigen-speci®c dose-dependent release of leukocyte-histamine after allergen nebulization (Peters et al., 1982). Similar ®ndings have been reproduced in Beagle dogs which are experimentally sensitized to Ascaris (Turner et al., 1995). These dogs develop acute broncho-constriction, increased bronchial-reactivity to histamine and a pulmonary late-phase reaction after bronchial allergen challenge (Turner et al., 1995). The acute respiratory response is also associated with increased bronchial histamine and prostaglandin D2 (Turner et al., 1995). A recurrent, predominantly pedal, nonseasonal, pruritic dermatitis manifested as licheni®ed plaques and in¯ammatory papules developed in BG crossbred dogs with nonspeci®c and Ascaris-speci®c airway hyper-reactivity and changes in pulmonary mechanics similar to human asthma (Butler et al., 1983). Histologically, skin lesions consisted of epidermal hyperplasia, spongiosis, ®brosis, and a dense, perivascular to diffuse, mixed in®ltrate in the super®cial dermis. The dermatitis appeared to be a manifestation of the atopic state in these dogs, and was considered as an animal model for the study of human AD. The authors also discussed the possibility that these skin lesions could represent a hypersensitivity response to the observed staphylococcal skin colonization (Butler et al., 1983). Whether or not the skin lesions present in BG dogs truly mimic those observed in patients with spontaneous AD remains the matter of controversy. Further, characterization of the skin lesions seen in this experimental canine ``model'' of AD was not described beyond this original report, almost 20 years ago. 3. Evidence not in favor of a respiratory route of allergen challenge It must be kept in mind that there are many de®ciencies in the arguments developed in the preceding paragraphs.
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221
Firstly, the original anecdotal clinical cases described with respiratory signs and skin lesions were published decades before the recognition of many dermatoses that could have complicated the clinical signs of allergy without being directly caused by the allergen challenges (e.g. super®cial pyoderma or Malassezia dermatitis). Secondly, in some of the older references on allergic rhinitis, the authors could have possibly interpreted nasal pruritus as indicative of rhinitis, as the latter diagnosis was supported neither by nasal cytology nor by mucosal biopsy. In fact, nasal pruritus might have represented a focal area of allergen-induced cutaneous in¯ammation. Thirdly, most of the data collected from experimental canine allergic ``models'' came from the investigations targeted at the study of asthma, and these dogs have not been reported to exhibit any skin lesions! Fourthly, dogs with spontaneously arising AD rarely exhibit asthmatiform symptoms nor rhinitis, as would be expected if allergens would trigger disease after inhalation. Indeed, eosinophils, as seen in humans with allergic rhinitis, were not observed in nasal smears of 46 dogs with AD (Willemse, 1984). Additionally, airway resistance to intranasal allergen exposure was detected only in three out of these 46 atopic dogs (Willemse, 1984). A worsening of the skin lesions was not described after intranasal provocation with offending allergens. Similarly, eight dogs were challenged, by intranasal aerosol nebulization, with allergens causing skin wheal-and-¯are after intradermal injection (Helton-Rhodes et al., 1987). Six out of eight dogs exhibited an increase in serum histamine 10 min after nasal allergen challenge (Helton-Rhodes et al., 1987). This provocation test was accompanied by a mild increase in nasal secretion in two out of four dogs. One patient experienced anaphylactic shock. In spite of these respiratory symptoms, a worsening of the skin lesions was not reported in any of the dogs, however (Helton-Rhodes et al., 1987). It must be kept in mind that the dogs in this study had not been reported to exhibit rhinitis prior to intranasal challenge. Therefore, the results from this experiment merely support that aerosolization of allergens can cause symptoms of nasal in¯ammation but this route of challenge might not represent a ``physiologic'' route of provocation. 4. Evidence in favor of an epidermal route of allergen challenge In canine AD, an epidermal route of allergen contact has been hypothesized based on a combination of clinical and histological observations. In dogs with AD, clinical lesions affect most commonly ventral hairless areas (axillae, inguinal region, interdigital areas) similarly to the lesions seen in allergic contact dermatitis (Scott, 1981). Moreover, lesions seen around the eyes could be due to selftrauma associated with pruritus caused by allergic conjunctivitis. Similarly, lesions in ¯exure areas (e.g. anterior elbows) or zones of friction (e.g. axillae) might re¯ect a chronic abrasion of the epidermal barrier, thus facilitating the rubbing of allergens on the epidermis (see ACVD task force section XIV in this issue). Microscopic examination of lesional skin biopsy specimens permits three observations consistent with the hypothesis of an allergen challenge occurring in the super®cial epidermis.
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Fig. 1. Clusters of epidermal Langerhans' cells (arrowhead) often can be seen in lesional skin of dogs with AD (immunoperoxidase method, monoclonal antibody 9H11, directed against canine CD1c, 400) (Olivry et al., 1996).
Firstly, epidermal antigen-presenting Langerhans cells (LC) are seen in clusters (Fig. 1) and in higher numbers in lesional atopic skin compared to clinically normal atopic or normal control canine skin (Day, 1996; Olivry et al., 1996). Moreover, in lesional atopic canine skin, epidermal LC exhibit membrane-bound IgE (Olivry et al., 1996). In humans with AD, it is suspected that LC-bound IgE are responsible for allergen capture and presentation (Mudde et al., 1990). This concept is corroborated by the recent demonstration that IgE-positive LC are required for the elicitation of positive aeroallergen epicutaneous patch tests in human patients with AD (Langeveld-Wildschut et al., 2000). Gamma-delta T-cells are the lymphocytes specialized in epithelial skin and mucosal immunity (Bluestone et al., 1995). These cells have been implicated recently in the pathogenesis of human allergic asthma (Spinozzi et al., 1995, 1996; Zuany-Amorim et al., 1998). In lesional atopic canine skin, epitheliotropic lymphocytes commonly express the gamma-delta T-cell receptor (Fig. 2) (Olivry et al., 1997). This observation is a ®nding quite unique among canine skin diseases (Cannon et al., 1998). This hyperplasia of T-lymphocytes involved in epithelial defense suggests that antigenic stimulation probably occurs in the epidermis in canine AD. Finally, intact and degranulated eosinophils can be seen below the stratum corneum of lesional (Fig. 3), but not clinically unaffected, atopic canine skin (Olivry et al., 1997). This ®nding is similar to that seen after epicutaneous allergen patch testing in humans affected with AD (Bruynzeel-Koomen et al., 1988). Similarly, eosinophil microabcesses and a mixed eosinophilic, neutrophilic and lymphocytic dermatitis were elicited via
T. Olivry, P.B. Hill / Veterinary Immunology and Immunopathology 81 (2001) 219±225
223
Fig. 2. In atopic canine skin, epitheliotropic lymphocytes commonly express the gamma-delta T-cell receptors (immunoperoxidase method, monoclonal antibody 8H1, directed against canine gamma-delta T-cell receptor, bar 50 mm) (Olivry et al., 1997).
epicutaneous patch testing with house dust mite and grass pollen allergens in three out of 11 dogs with AD (Frank and McEntee, 1995). Because positive reactions to epicutaneous challenge were also seen in two out of 10 control dogs, it is not known at present whether or not patch testing could be a valuable tool to model cutaneous atopic in¯ammation in
Fig. 3. Microabscesses-containing eosinophils (arrowhead) are present below the stratum corneum in the lesional skin of a dog with AD (hematoxylin and eosin, bar 50 mm) (Olivry et al., 1997).
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the canine species. Recent unpublished observations suggest that genetically predisposed Beagle dogs can develop both allergen-speci®c IgE and macroscopic dermatitis following an epicutaneous sensitization with Dermatophagoides farinae house dust mites.1 Moreover, the epicutaneous application of Dermatophagoides or ¯ea saliva in sensitized dogs results in the development of macroscopic and microscopic reactions similar to those of spontaneously occurring canine AD.2 These recent studies give further credence to the natural occurrence of an epicutaneous (i.e. epidermal) route of allergen contact in canine AD. 5. Conclusions All the studies described herein contribute to the confusion regarding the route of allergen challenge in canine AD. Even though a de®nitive proof for a causative pathway has not been ®rmly established at this time, critical evaluation of the literature suggests that, for now, an epidermal allergen challenge is more plausible than that of a respiratory one. For this reason, it is logical to recommend that the terminology ``allergic inhalant dermatitis'' is to be discontinued. Conversely, the fact that inhaled or ingested allergens also could contribute to the exacerbation of canine AD skin lesions cannot be ruled-out, however. Future studies should be aimed at investigating, by means of aerosolization or cutaneous provocation, whether and how canine AD lesions can be provoked by environmental allergens. References Anderson, W., 1973. Canine allergic inhalant dermatitis. Published by author, Blue Island, IL. Bluestone, J.A., Khattri, R., Sciammas, R., Sperling, A.I., 1995. TCR gamma-delta cells: a specialized T-cell subset in the immune system. Ann. Rev. Cell. Dev. Biol. 11, 307±353. Bruynzeel-Koomen, C.A.F.M., van Wichen, D.F., Spry, C.J.F., Venge, P., Bruynzeel, P.L.B., 1988. Active participation of eosinophils in patch test reactions to inhalant allergens in patients with atopic dermatitis. Br. J. Dermatol. 118, 229±238. Butler, J.M., Peters, J.E., Hirshman, C.A., White, C.R., Margolin, L.B., Hanifin, J.M., 1983. Pruritic dermatitis in asthmatic Basenji±Greyhound dogs: a model for human atopic dermatitis. J. Am. Acad. Dermatol. 8, 33±38. Cannon, A.G., Olivry, T., Ihrke, P.J., Naydan, D.K., Moore, P.F., 1998. Gamma-delta T cells in normal and diseased canine skin. In: Kwochka, K.W., Willemse, T., vonTscharner, C. (Eds.), Advances in Veterinary Dermatology, Vol. 3. Butterworths/Heinemann, Oxford, UK, pp. 137±143. Day, M.J., 1996. Expression of major histocompatibility complex class II molecules by dermal inflammatory cells, epidermal Langerhans cells and keratinocytes in canine dermatological disease. J. Comp. Pathol. 115, 317±326. 1
McCall, C., Geoly, F., Clarke, K.B., 2001. Transdermal allergen exposure of genetically high IgE Beagle puppies elicits allergen-specific IgE and dermatitis at the site of exposure. In: Proc. Ann. Meeting of Amer. Acad. Vet. Dermatol. Amer. Coll. Vet. Dermatol., Norfolk, VA, p. 37. 2 Olivry, T., Geoly, F., Dunston, S.M., Clarke, K.B., McCall, C.A., 2001. Histological and immunohistochemical characterization of ``atopy patch tests'' in IgE hyperresponsive Beagle dogs: a pilot study. In: Proc. Ann. Meeting of Amer. Acad. Vet. Dermatol. Amer. Coll. Vet. Dermatol., Norfolk, VA, p. 38.
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Emala, C., Hirshman, C.A., 1997. Canine models of asthma and hyperresponsiveness. In: Allergy and Allergic Diseases, Vol. 2. Blackwell Science, Oxford, UK, pp. 1103±1110. Frank, L.A., McEntee, M.F., 1995. Demonstration of aeroallergen contact sensitivity in dogs. J. Vet. Allergy Clin. Immunol. 3, 75±78. Gold, W.M., Kessler, G.F., Yu, D.Y.C., Frick, O.L., 1972. Pulmonary physiologic abnormalities in experimental asthma in dogs. J. Appl. Physiol. 33, 496±501. Helton-Rhodes, K., Kerdel, F., Soter, N.A., Chinnici, R., 1987. Investigation into the immunopathogenesis of canine atopy. Semin. Vet. Med. Surg. Small Anim. 2, 199±201. Hirshman, C.A., Malley, A., Downes, H., 1980. Basenji±Greyhound dog model of asthma: reactivity to Ascaris suum, citric acid, and metacholine. J. Appl. Physiol. 49, 953±957. Langeveld-Wildschut, E.G., Bruijnzeel, P.L.B., Mudde, G.C., Versluis, C., van Leperen-van Dijk, A.G., Bihari, I.C., Knol, E.F., Thepen, T., Bruijnzeel-Koomen, C.A.F.M., van Reijsen, F.C., 2000. Clinical and immunologic variables in skin of patients with atopic eczema and either positive or negative atopy patch test reactions. J. Allergy Clin. Immunol. 105, 1008±1016. Mudde, G.C., van Reijsen, F.C., Boland, G.J., De Gast, G.C., Bruijnzeel, P.L.B., Bruijnzeel-Kommen, C.A.F.M., 1990. Allergen presentation by epidermal Langerhans' cells from patients with atopic dermatitis is mediated by IgE. Immunology 69, 335±341. Olivry, T., Moore, P.F., Affolter, V.K., Naydan, D.K., 1996. Langerhans cell hyperplasia and IgE expression in canine atopic dermatitis. Arch. Dermatol. Res. 288, 579±585. Olivry, T., Naydan, D.K., Moore, P.F., 1997. Characterization of the cutaneous inflammatory infiltrate in canine atopic dermatitis. Am. J. Dermatopathol. 19, 477±486. Patterson, R., 1960. Investigations of spontaneous hypersensitivity of the dog. J. Allergy 31, 351±363. Patterson, R., Mellies, C.J., Kelly, J.F., Harris, K.E., 1974. Airway response of dogs with ragweed and Ascaris hypersensitivity. Chest 65, 488±492. Peters, J.E., Hirshman, C.A., Malley, A., 1982. The Basenji±Greyhound dog model of asthma: leukocyte histamine release, serum IgE, and airway response to inhaled antigen. J. Immunol. 129, 1245±1249. Scott, D.W., 1981. Observations on canine atopy. J. Am. Anim. Hosp. Assn. 17, 91±100. Spinozzi, F., Agea, E., Bistoni, O., Forenza, N., Monaco, A., Falini, B., Bassotti, G., De Benedictis, F., Grignani, F., Bertotto, A., 1995. Local expansion of allergen-specific CD30()Th2-type gamma-delta T cells in bronchial asthma. Mol. Med. 1, 821±826. Spinozzi, F., Agea, E., Bistoni, O., Forenza, N., Monaco, A., Bassotti, G., Nicoletti, I., Riccardi, C., Grignani, F., Bertotto, A., 1996. Increased allergen-specific, steroid-sensitive gamma-delta T cells in bronchoalveolar lavage fluid from patients with asthma. Ann. Int. Med. 124, 223±227. Turner, N.C., Fuller, R.W., Jackson, D.M., 1995. Eicosanoid release in allergen-induced broncho-constriction in dogs: Its relationship to airways hyperreactivity and pulmonary inflammation. J. Lipid Mediat. Cell 11, 93±102. Willemse, A., 1984. Canine atopic disease: investigations of eosinophils and the nasal mucosa. Am. J. Vet. Res. 45, 1867±1869. Wittich, F.W., 1941. Spontaneous allergy (atopy) in the lower animal Ð seasonal hay fever (fall type) in a dog. J. Allergy 12, 247±251. Zuany-Amorim, C., Ruffie, C., Haile, S., Vargaftig, B.B., Pereira, P., Pretolani, M., 1998. Requirement for gamma-delta T cells in allergic airway inflammation. Science 280, 1265±1267.
The ACVD task force on canine atopic dermatitis (IX): the controversy surrounding the route of allergen challenge in canine atopic dermatitis Thierry Olivrya,*, Peter B. Hillb a
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA b Department of Veterinary Clinical Studies, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Hospital for Small Animals, Easter Bush Veterinary Centre, Roslin, Edinburgh EH25 9RG, Scotland, UK
Abstract For decades, the dogma that environmental allergens trigger cutaneous in¯ammation led to the denomination of canine atopic dermatitis as ``allergic inhalant dermatitis''. De®nitive proof for a respiratory route of allergen challenge is lacking, however. Recent observations suggest, in fact, that skin in¯ammation could occur because of epidermal allergenic contact. The aim of this paper is to review the evidence published in favor and against the two suspected routes of allergen provocation. # 2001 Elsevier Science B.V. All rights reserved. Keywords: Allergen; Allergic skin disease; Atopy; Dog
1. Introduction During the last half-century, two theories have emerged to explain the way by which antigens gain access to the skin to trigger cutaneous allergic in¯ammation and symptoms of atopic dermatitis (AD). The ®rst hypothesis proposes allergens to be inhaled, penetrate the respiratory tract and migrate via the circulation to the skin where they trigger dermal mast cells. The second suggests that environmental antigens directly transfer through the stratum corneum and contact antigen-presenting cells in the epidermis, thereby initiating cutaneous in¯ammation. Arguments can be proposed in support, or against, these two theoretical concepts.
*
Corresponding author. Tel.: 1-919-513-6276; fax: 1-919-513-6336. E-mail address: [email protected] (T. Olivry). 0165-2427/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 2 4 2 7 ( 0 1 ) 0 0 3 1 1 - 7
220
T. Olivry, P.B. Hill / Veterinary Immunology and Immunopathology 81 (2001) 219±225
2. Evidence in favor of a respiratory route of allergen challenge Since the early report of an allergic disease in a dog with rhinitis, conjunctivitis and urticaria, it has been considered that environmental aeroallergens could induce pruritus and skin lesions via inhalation (Wittich, 1941). The denomination ``canine allergic inhalant dermatitis'' eventually was coined as a name for aeroallergen-induced skin disease (Anderson, 1973). In one anecdotal report, rhinorrhea, lacrimation, conjunctivitis and asthmatiform symptoms were reproduced with aerosolized ragweed pollens in a dog with spontaneous allergic conjunctivitis and dermatitis (Patterson, 1960). Multiple accounts of allergic rhinitis and asthma additionally have been reported in the canine species during the last three decades (Emala and Hirshman, 1997). These reports con®rm the possible development of allergic symptoms after allergen inhalation. An experimental canine model for allergic asthma was subsequently developed via sensitization of normal dogs with inhaled Ascaris suum allergens (Gold et al., 1972; Patterson et al., 1974). Indeed, increased airway reactivity to nonallergenic stimuli, a feature of human asthma, was described in a group of Basenji±Greyhound (BG) crossbreed dogs that were either natively allergic to Ascaris suum or were sensitized by repeated aerosolized antigenic challenge (Hirshman et al., 1980). These Ascaris-sensitive BG dogs exhibit an antigen-speci®c dose-dependent release of leukocyte-histamine after allergen nebulization (Peters et al., 1982). Similar ®ndings have been reproduced in Beagle dogs which are experimentally sensitized to Ascaris (Turner et al., 1995). These dogs develop acute broncho-constriction, increased bronchial-reactivity to histamine and a pulmonary late-phase reaction after bronchial allergen challenge (Turner et al., 1995). The acute respiratory response is also associated with increased bronchial histamine and prostaglandin D2 (Turner et al., 1995). A recurrent, predominantly pedal, nonseasonal, pruritic dermatitis manifested as licheni®ed plaques and in¯ammatory papules developed in BG crossbred dogs with nonspeci®c and Ascaris-speci®c airway hyper-reactivity and changes in pulmonary mechanics similar to human asthma (Butler et al., 1983). Histologically, skin lesions consisted of epidermal hyperplasia, spongiosis, ®brosis, and a dense, perivascular to diffuse, mixed in®ltrate in the super®cial dermis. The dermatitis appeared to be a manifestation of the atopic state in these dogs, and was considered as an animal model for the study of human AD. The authors also discussed the possibility that these skin lesions could represent a hypersensitivity response to the observed staphylococcal skin colonization (Butler et al., 1983). Whether or not the skin lesions present in BG dogs truly mimic those observed in patients with spontaneous AD remains the matter of controversy. Further, characterization of the skin lesions seen in this experimental canine ``model'' of AD was not described beyond this original report, almost 20 years ago. 3. Evidence not in favor of a respiratory route of allergen challenge It must be kept in mind that there are many de®ciencies in the arguments developed in the preceding paragraphs.
T. Olivry, P.B. Hill / Veterinary Immunology and Immunopathology 81 (2001) 219±225
221
Firstly, the original anecdotal clinical cases described with respiratory signs and skin lesions were published decades before the recognition of many dermatoses that could have complicated the clinical signs of allergy without being directly caused by the allergen challenges (e.g. super®cial pyoderma or Malassezia dermatitis). Secondly, in some of the older references on allergic rhinitis, the authors could have possibly interpreted nasal pruritus as indicative of rhinitis, as the latter diagnosis was supported neither by nasal cytology nor by mucosal biopsy. In fact, nasal pruritus might have represented a focal area of allergen-induced cutaneous in¯ammation. Thirdly, most of the data collected from experimental canine allergic ``models'' came from the investigations targeted at the study of asthma, and these dogs have not been reported to exhibit any skin lesions! Fourthly, dogs with spontaneously arising AD rarely exhibit asthmatiform symptoms nor rhinitis, as would be expected if allergens would trigger disease after inhalation. Indeed, eosinophils, as seen in humans with allergic rhinitis, were not observed in nasal smears of 46 dogs with AD (Willemse, 1984). Additionally, airway resistance to intranasal allergen exposure was detected only in three out of these 46 atopic dogs (Willemse, 1984). A worsening of the skin lesions was not described after intranasal provocation with offending allergens. Similarly, eight dogs were challenged, by intranasal aerosol nebulization, with allergens causing skin wheal-and-¯are after intradermal injection (Helton-Rhodes et al., 1987). Six out of eight dogs exhibited an increase in serum histamine 10 min after nasal allergen challenge (Helton-Rhodes et al., 1987). This provocation test was accompanied by a mild increase in nasal secretion in two out of four dogs. One patient experienced anaphylactic shock. In spite of these respiratory symptoms, a worsening of the skin lesions was not reported in any of the dogs, however (Helton-Rhodes et al., 1987). It must be kept in mind that the dogs in this study had not been reported to exhibit rhinitis prior to intranasal challenge. Therefore, the results from this experiment merely support that aerosolization of allergens can cause symptoms of nasal in¯ammation but this route of challenge might not represent a ``physiologic'' route of provocation. 4. Evidence in favor of an epidermal route of allergen challenge In canine AD, an epidermal route of allergen contact has been hypothesized based on a combination of clinical and histological observations. In dogs with AD, clinical lesions affect most commonly ventral hairless areas (axillae, inguinal region, interdigital areas) similarly to the lesions seen in allergic contact dermatitis (Scott, 1981). Moreover, lesions seen around the eyes could be due to selftrauma associated with pruritus caused by allergic conjunctivitis. Similarly, lesions in ¯exure areas (e.g. anterior elbows) or zones of friction (e.g. axillae) might re¯ect a chronic abrasion of the epidermal barrier, thus facilitating the rubbing of allergens on the epidermis (see ACVD task force section XIV in this issue). Microscopic examination of lesional skin biopsy specimens permits three observations consistent with the hypothesis of an allergen challenge occurring in the super®cial epidermis.
222
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Fig. 1. Clusters of epidermal Langerhans' cells (arrowhead) often can be seen in lesional skin of dogs with AD (immunoperoxidase method, monoclonal antibody 9H11, directed against canine CD1c, 400) (Olivry et al., 1996).
Firstly, epidermal antigen-presenting Langerhans cells (LC) are seen in clusters (Fig. 1) and in higher numbers in lesional atopic skin compared to clinically normal atopic or normal control canine skin (Day, 1996; Olivry et al., 1996). Moreover, in lesional atopic canine skin, epidermal LC exhibit membrane-bound IgE (Olivry et al., 1996). In humans with AD, it is suspected that LC-bound IgE are responsible for allergen capture and presentation (Mudde et al., 1990). This concept is corroborated by the recent demonstration that IgE-positive LC are required for the elicitation of positive aeroallergen epicutaneous patch tests in human patients with AD (Langeveld-Wildschut et al., 2000). Gamma-delta T-cells are the lymphocytes specialized in epithelial skin and mucosal immunity (Bluestone et al., 1995). These cells have been implicated recently in the pathogenesis of human allergic asthma (Spinozzi et al., 1995, 1996; Zuany-Amorim et al., 1998). In lesional atopic canine skin, epitheliotropic lymphocytes commonly express the gamma-delta T-cell receptor (Fig. 2) (Olivry et al., 1997). This observation is a ®nding quite unique among canine skin diseases (Cannon et al., 1998). This hyperplasia of T-lymphocytes involved in epithelial defense suggests that antigenic stimulation probably occurs in the epidermis in canine AD. Finally, intact and degranulated eosinophils can be seen below the stratum corneum of lesional (Fig. 3), but not clinically unaffected, atopic canine skin (Olivry et al., 1997). This ®nding is similar to that seen after epicutaneous allergen patch testing in humans affected with AD (Bruynzeel-Koomen et al., 1988). Similarly, eosinophil microabcesses and a mixed eosinophilic, neutrophilic and lymphocytic dermatitis were elicited via
T. Olivry, P.B. Hill / Veterinary Immunology and Immunopathology 81 (2001) 219±225
223
Fig. 2. In atopic canine skin, epitheliotropic lymphocytes commonly express the gamma-delta T-cell receptors (immunoperoxidase method, monoclonal antibody 8H1, directed against canine gamma-delta T-cell receptor, bar 50 mm) (Olivry et al., 1997).
epicutaneous patch testing with house dust mite and grass pollen allergens in three out of 11 dogs with AD (Frank and McEntee, 1995). Because positive reactions to epicutaneous challenge were also seen in two out of 10 control dogs, it is not known at present whether or not patch testing could be a valuable tool to model cutaneous atopic in¯ammation in
Fig. 3. Microabscesses-containing eosinophils (arrowhead) are present below the stratum corneum in the lesional skin of a dog with AD (hematoxylin and eosin, bar 50 mm) (Olivry et al., 1997).
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the canine species. Recent unpublished observations suggest that genetically predisposed Beagle dogs can develop both allergen-speci®c IgE and macroscopic dermatitis following an epicutaneous sensitization with Dermatophagoides farinae house dust mites.1 Moreover, the epicutaneous application of Dermatophagoides or ¯ea saliva in sensitized dogs results in the development of macroscopic and microscopic reactions similar to those of spontaneously occurring canine AD.2 These recent studies give further credence to the natural occurrence of an epicutaneous (i.e. epidermal) route of allergen contact in canine AD. 5. Conclusions All the studies described herein contribute to the confusion regarding the route of allergen challenge in canine AD. Even though a de®nitive proof for a causative pathway has not been ®rmly established at this time, critical evaluation of the literature suggests that, for now, an epidermal allergen challenge is more plausible than that of a respiratory one. For this reason, it is logical to recommend that the terminology ``allergic inhalant dermatitis'' is to be discontinued. Conversely, the fact that inhaled or ingested allergens also could contribute to the exacerbation of canine AD skin lesions cannot be ruled-out, however. Future studies should be aimed at investigating, by means of aerosolization or cutaneous provocation, whether and how canine AD lesions can be provoked by environmental allergens. References Anderson, W., 1973. Canine allergic inhalant dermatitis. Published by author, Blue Island, IL. Bluestone, J.A., Khattri, R., Sciammas, R., Sperling, A.I., 1995. TCR gamma-delta cells: a specialized T-cell subset in the immune system. Ann. Rev. Cell. Dev. Biol. 11, 307±353. Bruynzeel-Koomen, C.A.F.M., van Wichen, D.F., Spry, C.J.F., Venge, P., Bruynzeel, P.L.B., 1988. Active participation of eosinophils in patch test reactions to inhalant allergens in patients with atopic dermatitis. Br. J. Dermatol. 118, 229±238. Butler, J.M., Peters, J.E., Hirshman, C.A., White, C.R., Margolin, L.B., Hanifin, J.M., 1983. Pruritic dermatitis in asthmatic Basenji±Greyhound dogs: a model for human atopic dermatitis. J. Am. Acad. Dermatol. 8, 33±38. Cannon, A.G., Olivry, T., Ihrke, P.J., Naydan, D.K., Moore, P.F., 1998. Gamma-delta T cells in normal and diseased canine skin. In: Kwochka, K.W., Willemse, T., vonTscharner, C. (Eds.), Advances in Veterinary Dermatology, Vol. 3. Butterworths/Heinemann, Oxford, UK, pp. 137±143. Day, M.J., 1996. Expression of major histocompatibility complex class II molecules by dermal inflammatory cells, epidermal Langerhans cells and keratinocytes in canine dermatological disease. J. Comp. Pathol. 115, 317±326. 1
McCall, C., Geoly, F., Clarke, K.B., 2001. Transdermal allergen exposure of genetically high IgE Beagle puppies elicits allergen-specific IgE and dermatitis at the site of exposure. In: Proc. Ann. Meeting of Amer. Acad. Vet. Dermatol. Amer. Coll. Vet. Dermatol., Norfolk, VA, p. 37. 2 Olivry, T., Geoly, F., Dunston, S.M., Clarke, K.B., McCall, C.A., 2001. Histological and immunohistochemical characterization of ``atopy patch tests'' in IgE hyperresponsive Beagle dogs: a pilot study. In: Proc. Ann. Meeting of Amer. Acad. Vet. Dermatol. Amer. Coll. Vet. Dermatol., Norfolk, VA, p. 38.
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