Animal Models of Atopic Dermatitis

ROSANNA MARSELLA, DMV THIERRY OLIVRY, Dr Vet, PhD

topic dermatitis (AD) is a chronic inflammatory skin disease affecting over 10% of human (sic) children, and it is the most common cause of occupational disability in adults.1,2 Atopic dermatitis also is seen commonly in companion animals, especially in dogs, in which its prevalence has been estimated to be about 10% of the canine population.1,3,4 Numerous similarities exist between canine AD and its human counterpart, suggesting the possibility that canine AD could be used as a model for the human disease.5,6 Dogs have been used in the past as model for human allergic diseases. The most popular model has been the BasenjiGreyhound, which develops a recurrent, nonseasonal, pruritic dermatitis and asthma.7 Skin lesions include lichenified plaques and inflammatory papules and nodules. These dogs also display airway hyper-reactivity, with changes in pulmonary mechanics similar to those of symptomatic, human asthma, and they exhibit a variety of immunologic abnormalities analogous to the human disease. Cats also have been reported to develop AD, but our understanding of the condition in this species currently is limited. Certain similarities appear to exist between feline and human AD; however, the feline condition has some peculiar clinical features, and for this reason it will be described separately. Finally, AD recently has been described in laboratory animals, notably the NC/ Nga mouse, which is thought by some authors to be a promising animal model for AD.8 The purpose of this article is to review the latest information available on AD in companion animals and in mice and describe how these spontaneously arising diseases might serve as models to improve our understanding of human AD.

canine atopy is defined as a genetically determined predisposition for the development of IgE-mediated allergy to environmental allergens (syn. atopic state). AD is the most commonly diagnosed atopic disease in dogs. It is defined as a genetically determined, allergic, inflammatory, and pruritic skin disorder, with characteristic clinical features. Canine AD is most commonly associated with IgE antibodies to environmental allergens.10

Prevalence of AD and Risk Factors

In humans, the prevalence of AD in developed countries is approximately 15%, with a steady increase over the past few decades.11 The increased incidence of this disease has been hypothesized to be linked to increased indoor allergen load, decreased microbial load, and changing dietary habits.12 Atopic dermatitis develops as a result of a complex interrelationship between environmental exposure, genetic background, and immunologic factors. In humans, numerous candidate genes have been proposed as possibly involved in the pathogenesis.1316 Immunologic factors that appear to play a role include the pattern of local cytokine release, nature of the antigen, differentiation of helper T cells, immunoglobulin (Ig)E antibodies, infectious agents, and superantigens.1719 The first 6 months of life appear to represent a critical time window for the initiation of immunologic changes resulting in the development of atopic disease in humans.20,21 The selective development of a Th2 cytokine profile in high-risk children who develop atopy seems to be due to an increased production of Th2 cytokines. This increase is possibly caused by impaired allergen-induced interferon- production in the neonatal period.22 Furthermore, decreased allergen-induced IL-10 levels observed in atopic children at 12 months of age may result in lack of down-regulation of the inflammatory process.22 There are no reliable epidemiologic data on the true incidence and prevalence of AD in the general canine population, but it is suspected that canine AD could affect up to 10% of dogs.3,4 The typical age of onset of canine AD is between 6 months and 3 years ie, young adults. Various parameters have been evaluated as risk factors for canine AD. A strong breed predilection and familial occurrence suggest that genetic factors play an important role in canine AD.23 In one study, no clear association was demonstrated between atopy and dog
0738-081X/03/$see front matter doi:10.1016/S0738-081X(02)00369-3

Canine Atopic Dermatitis Definition

A task force of the American College of Veterinary Dermatology has recently revised the definition of atopy and AD in dogs.9 According to the latest criteria,
From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida; and the Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina Address correspondence to Rosanna Marsella, DVM, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, P.O. Box 100126, Gainesville, Florida 32610 0126. E-mail address: marsellar@mail.vetmed.ufl.edu 2003 by Elsevier Science Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010

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leukocyte antigen typing, although the combination of haplotypes DL-A3 and R15 seemed to be more prevalent in dogs with AD.24 No significant differences were found in IgE levels between normal and atopic dogs, and no relationship between serum IgE and DL-A was observed.24 Past attempts to establish colonies of dogs with AD have been unsuccessful.25 In one study, atopic dogs were bred to establish progeny predisposed to develop type I hypersensitivity.26 In a 2-year period, 72 pups were born and were then monitored for clinical evidence and immunologic markers of atopic disease. Thirteen dogs in the colony, belonging to the oldest age group, manifested clinical signs compatible with AD. Serial immunoglobulin levels including total IgE, endpoint titration of histamine, and fecal examinations for identification of parasites were investigated to evaluate possible correlation with development of atopic disease. A weak correlation between positive direct skintest results and the appearance of seasonal dermatitis were the only findings. Cutaneous clinical findings did not correlate with passive cutaneous anaphylaxis test results or radioallergosorbent procedures. Moreover, no correlation was found between seasonal dermatitis and measurements of specific IgE to airborne allergens, and lastly, no specific indicators were identified that predicted the development of the atopic state in these dogs. In a recent study, serum IgE levels and development of clinical signs of AD were monitored in 154 West Highland White Terriers up to 3 years of age.27 Clear evidence of heritability could not be demonstrated. No significant difference was noted in median serum IgE concentration between puppies that remained healthy and those that developed disease. This is in contrast to some studies in humans. Parasitic diseases have been reported to augment production of IgE against other environmental allergens and therefore might play a role in the development of disease in canine species.28 Viral infections or at least vaccination with modified live viral vaccine, also have been reported to result in increased production of IgE against environmental allergens, and might be important.29

The role of IgE in canine AD is less clear insofar as disease expression does not correlate closely with the presence of allergen-specific IgE or allergen exposure. Most dogs with canine AD have allergen-specific IgE demonstrable either by intradermal testing or by the use of serologic assays such as the enzyme-linked immunosorbent assay, although the agreement between these two tests is not highly correlated.3335 In atopic dogs, just as in humans, IgE is present on the surface of epidermal Langerhans cells and is suspected to aid in allergen capture and subsequent epidermal penetration.36 These associations, however, are not absolute, and some normal animals exhibit demonstrable circulating IgE, can be exposed to allergen and yet suffer no disease.10 Conversely, dogs can present with classic clinical signs of AD yet exhibit negative intradermal test and/or allergen-specific IgE serology, similarly to humans with intrinsic AD.37,38 Experimental sensitization of dogs has revealed that the capacity to produce high levels of IgE against a variety of allergens (high IgE responders), an essential characteristic of the atopic state, is a genetic trait inherited in a dominant manner.39 On the other hand, in high-IgE responder dogs, spontaneous production of IgE to inhaled allergens such as house dust mites represents an apparent phenotype very similar to that observed in human atopic families.40 The full potential of the high-IgE response gene appears to be fulfilled only under such conditions as early and repeated exposure to allergens. It also could be quite possible that the true human atopy phenotype is also inherited in a dominant fashion but not constantly expressed. It is important to note, however, that increased allergenspecific IgE does not necessarily cause disease and that additional factors that influence mediator release, such as IgE heterogeneity, could be involved.41,42 In canine AD, there are demonstrable abnormalities in T lymphocyte function, and it is possible that a number of other immunologic pathways besides IgE synthesis are involved in the pathogenesis of the disease.43

Role of Environmental Allergens

In human AD, a variety of environmental allergens have been implicated in the pathogenesis of disease.44,45 Moreover, IgE has been suggested to increase the efficiency of allergen capture and presentation.46 In a subgroup of patients with atopic eczema, exacerbations of itching and eczematous skin lesions have been described after contact with aeroallergens. Epicutaneous patch testing (atopy patch test) with aeroallergens has been reported to be a useful test that is positive in 30 70% of patients.47,48 Numerous environmental allergens have been incriminated in canine AD.49 52 They include dust and storage mite antigens; house dust; pollens from grasses,

Role of IgE
Most human patients with AD exhibit elevated total IgE, and many exhibit allergen-specific IgE to environmental and/or food antigens. Anti-IgE has been successfully used to reduce clinical signs in some affected individuals.30 A so-called intrinsic type of AD also has been described in which there are normal serum IgE levels and negative immediate-type skin reactions toward environmental allergens.31 The recently characterized human autoantigen Hom s 1 has been proposed to play a part in the pathogenesis of intrinsic AD.32

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trees, and weeds; mold spores; epidermal antigens; insect antigens; and miscellaneous antigens, such as kapok. An epidermal route of allergen exposure has been hypothesized based on a combination of clinical and histologic observations.36,53 Most dogs with AD benefit from frequent bathing, possibly because this can decrease allergen exposure and penetration.

Relationship with Food Allergy

Although the relationship between food allergy and human AD was debated in years past, recent information clearly establishes a link between the two, at least in children. Measurement of IgE in atopic patients with food allergy also has been reported to be useful.54 56 Between 33% and 38.7% of infants and young children with AD are reported to exhibit concurrent food allergies. In particular, very young age of AD onset, especially in patients with clinically severe disease, is correlated with the presence of food allergies. The role of cutaneous adverse food reactions in dogs has not been fully elucidated.57,58 Experimental models of induced food allergy and a few reports of spontaneous IgE-mediated food allergy suggest that at least some dogs with cutaneous adverse food reactions have IgE-mediated disease.59,60 In addition, cutaneous adverse food reactions and canine AD share a number of very similar historical and clinical features. It is speculated that AD and cutaneous adverse food reactions can coexist in some atopic canine patients.

and adherence of the bacteria to keratinocytes is greater in allergic dogs.64 This may explain, in part, why allergic dogs have recurrent staphylococcal infections. With remission of AD, the number of organisms and their adherence decreases. During infection, staphylococcal bacteria (both human and canine strains) release a variety of toxins (called exotoxins or enterotoxins) into the surrounding tissue.65 In humans, it is well established that some of these toxins serve as superantigens, ie, molecules that directly and nonspecifically activate large numbers of T lymphocytes in the absence of specific antigen.65 The toxins also facilitate homing (migration) of lymphocytes to the site of skin inflammation, and up-regulate the release of pro-allergic cytokines from these lymphocytes. Thus, the staphylococcal infection itself acts to amplify and maintain the allergic response in skin. Although we know that canine staphylococcal strains also secrete toxins, it has not been determined whether they have similar immunologic effects in dogs.

Cytokines
In human AD, skin-homing T cells that secrete interleukin (IL)-4, IL-5, and IL-13, play an important role in the development of high IgE levels and eosinophilia.66,67 Interestingly, this Th2-like response is found primarily in the acute inflammatory skin response. Moreover, IL-16 appears to be important in the initial infiltration of CD4 cells.68 In chronic skin lesions, there is conversion to a Th1-like response with evidence of increased interferon- , IL-12, and granulocyte-macrophage colony stimulating factor (GM-CSF). In patients with AD, tumor necrosis factor production is down-regulated. Since this cytokine increases interferon- production and decreases IL-5, IL-13, and IgE production, there is a potential role for tumor necrosis factor in the pathogenesis of AD.69 Cytokine production in dogs with AD has recently been investigated.70 One fourth of canine atopic samples exhibited clear type-2 cytokine profiles, whereas the remainder did not demonstrate polarized repertoires. Conversely, type-1 cytokine profiles were characterized in one fourth of normal control specimens.

Role of Infections
Dogs and humans with AD frequently have concurrent infection with Staphylococcus bacteria or Malassezia yeast.61 Clinicians commonly consider such infections secondary manifestations brought about by the underlying dermatitis. In humans, however, there is substantial evidence that the reverse also is true, ie, some infections have effects on the immune system that direct it toward allergy, thus augmenting and perpetuating the hypersensitivity state. Staphylococcus aureus is found in over 90% of human AD skin lesions and is thought to contribute to skin inflammation via the production of potent exotoxins. In contrast, less than 5% of normal subjects harbor S. aureus. This suggests that the atopic immune response itself could play a role in promoting preferential binding of S. aureus to the skin. In fact, a recent study in mice found that a T helper type 2 inflammatory environment promotes skin binding by S. aureus and this binding is mediated by fibronectin and fibrinogen.62 Canine AD also is commonly associated with superficial infections with Staphylococcus intermedius bacteria.63 This organism is harbored on the skin, haircoat, anal area, or nasal passages of many healthy dogs, at least transiently. Allergic dogs tend to have higher skin surface counts of S. intermedius than do healthy dogs,

Other Immunologic Abnormalities

Reduced skin reactivity to intradermal injections of substance P (SP) has been reported in dogs with AD.71 Wheal diameters for histamine and SP injections were significantly smaller in those dogs compared with clinically normal dogs. The results of this study are similar to human studies that also suggest a role for SP in AD pathogenesis. Desensitization of receptors to both SP and histamine is hypothesized.72 Leukocytes, including mast cells, of atopic dogs also have a greater tendency to release histamine than those of normal and artificially sensitized dogs. Because this

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is independent of the concentration of total serum IgE or antigen-specific IgE, it suggests that there may be immunoregulatory abnormalities in atopic dogs intrinsic to the atopic state similar to those described in man.41,7375 Other features of canine AD analogous to the human disease include blunted cyclic adenosine monophosphate responsiveness to beta adrenergic agents, as well as in vivo release of histamine and slow-reacting substance of anaphylaxis in response to aerosol antigen challenge.76 78

Histopathology
AD in dogs has many histopathological features that are similar to the human disease.79 In human AD, cutaneous T lymphocytes comprise a heterogeneous population of Th1 and Th2 or Th0 cells80,81 In humans, both CD4 and CD8 memory/effector T cells with skinhoming properties play a specific and decisive role in the pathogenesis and exacerbation of AD.82 Langerhans cells expressing CD1a and HLA-DR and dermal dendritic cells expressing HLA-DR are potent antigen-presenting cells thought to play an important role in the pathogenesis of human AD.83 The immunophenotype of lesional skin in human AD involves increased numbers of CD1a /MHC class II dendritic cells in addition to activated T cells, mast cells, and macrophages. In canine AD, increased numbers of CD4 and CD8 T cells are found in lesional skin, with a predominance of CD4 T cells in the epidermis.84,85 In nonlesional atopic skin there is also infiltration with CD4 and CD8 T cells, but without the CD4 T cell predominance.84 Epidermal Langerhans cell counts are significantly higher in lesional than in nonlesional atopic skin. Numerous - T lymphocytes also are detected.85 This hyperplasia of epidermal T cells expressing the - T cell receptor appears specific to canine AD compared with its human counterpart. It could be explained by an interspecies difference in skin immune systems or, alternatively, by an active participation of these epitheliotropic - T cells in the cutaneous allergic immune response in dogs. Intact and degranulated eosinophils can also be seen below the stratum corneum of lesional canine AD skin. This is similar to the histologic appearance seen after epicutaneous allergen patch testing in humans affected with AD. IgE dendritic cells are seen in lesional atopic epidermis and dermis, and nonlesional atopic dermis, but not in normal control skin specimens.85,86 The percentages of IgE dendritic cells seem to correlate with total serum IgE levels. Increased epidermal Langerhans cell counts with bound IgE in lesional specimens suggest epidermal allergen contact in canine AD. IgE-mediated late-phase reactions have been characterized in dogs. In these reactions, early emigrating dermal cells were composed chiefly of neutrophils and activated eosinophils, while an influx of - T lympho-

cytes and dermal dendritic cells was observed in later stages of the late-phase reaction.87 Neutrophils and eosinophils were present in the dermis at 1 hour, maximal at 6 hours, and decreased at 24 hours, similarly to the human late-phase response.88 Mononuclear cells increased significantly at 6 hours and were the predominant cells present at 24 hours after antigen. Mast cells in the skin of atopic dogs are heterogeneous with respect to tissue fixation and staining properties.89 After antigen exposure, the number of typical mast cells detectable in tissue sections progressively decreased over a 24-hour period, whereas the number of atypical mast cells was lowest at 1 hour and had increased at 24 hours.90 The atypical mast cells participate in the early, acute response to antigen and the typical mast cells may be associated with the development of the late phase reaction.

Clinical Signs and Criteria for Diagnosis

Pruritus is the most constant feature of AD in dogs and humans.91 The most common clinical features of human AD include early age of onset; dermatitis in flexural areas, scalp, face, and neck; dry skin and erythema; excoriation and lichenification secondary to chronic scratching; and secondary infections.92 Some children with AD experience resolution of their eczema but subsequently develop asthma. Unfortunately, there are no absolutely pathognomic historical elements or clinical signs that allow definitive diagnosis of human or canine AD. Rather, diagnosis must be based on a constellation of clinical features and elimination of other important differential diagnoses.93 Since there is no laboratory test that specifically identifies human AD, a number of clinical criteria have been developed to aid in diagnosis. The most commonly used diagnostic criteria for AD entail major and minor clinical features that must be fulfilled to establish a diagnosis.94 It has recently been suggested that in addition to fulfillment of two of three principal criteria, ie, pruritus, typical morphology and distribution, and chronic or chronically relapsing dermatosis, that the presence of allergen-specific IgE should also be required to diagnose AD.95 In young children (less than 2 years of age), findings suggestive of AD include xerosis (100%), clinical course influenced by environmental factors (87%), facial erythema (54%), skin reactions provoked by ingested food (39%), itch associated with sweating (34%), positive skin prick test (29%), and hand eczema (28%). In canine AD, clinical lesions most commonly affect the ventral hairless areas (axillae, inguinal region, and interdigital areas) similarly to the lesions seen in allergic contact dermatitis. Lesions in the flexures (eg, anterior elbows) and zones of friction (eg, axillae) probably reflect areas in which chronic abrasion of the epidermal barrier facilitates rubbing of allergens into the epider-

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Figure 1. Erythema on the limbs and ventral aspect of the body in a Bassett Hound with AD. There is also periocular lichenification because of concurrent allergic conjunctivitis (North Carolina State University, case material).

mis.91 Typical clinical symptoms in dogs include pruritus of the face, ears, paws, extremities, and/or ventrum (Fig 1). Generalized pruritus is reported in 40% or more of dogs with AD. Secondary skin lesions are common and reflect ongoing pruritus, chronic inflammation, and trauma to the skin.91 Secondary lesions include redbrown salivary staining, excoriations, self-induced alopecia (Fig 2), dry lusterless hair, hyperpigmentation, scaling, and lichenification. These lesions (Fig 3) are observed principally at sites of itching, such as the face (muzzle, periocular skin), (Fig 4) concave ears, dorsal and ventral aspect of the paws (Fig 5), flexural aspects of joints on the extremities (Fig 6), axillae, abdomen, groin and medial thighs.91 Otis externa or aural pruritus commonly occurs, at least historically, in as many as 86% of dogs, and conjunctivitis is present in up to 50%. Respiratory signs are reportedly uncommon in canine AD.

A similar list of criteria for diagnosis was created for canine AD in the 1980s, and many veterinary dermatologists consider these criteria in evaluation of potentially allergic dogs.96 A patient must have at least three major features of AD (from a list including pruritus, typical morphology and distribution, presence of chronic dermatitis, and individual or family history of atopy and/or breed predisposition) plus at least three minor features (including onset of signs before 3 years of age, facial erythema and cheilitis, bacterial conjunctivitis, superficial staphylococcal pyoderma, hyperhidrosis, positive intradermal test reactions, and positive allergen-specific IgE serology). More recently, five major criteria for canine AD were proposed by European veterinary dermatologists.97 These five criteria included corticosteroid-sensitive pruritus, erythema of the pine, bilateral erythematous pododermatitis of the forefeet, cheilitis, and appearance of the first signs between the ages of 6 months and 3 years. The presence of three out of five of these criteria in a canine patient reportedly results in diagnostic sensitivities and specificitys each of approximately 80%. Because of patient variability, such lists of clinical criteria are not infallible. In practical terms, if a patient meets these clinical criteria, clinicians ought to include AD as a primary differential diagnosis; but failure to meet these criteria should not preclude consideration of AD.98

Management of Canine Atopic Dermatitis

The successful management of AD in human beings requires a multifaceted approach that includes increasing skin hydration as well as identifying and avoiding flare factors such as irritants, allergens, microbes and stress.100,101 When skin lesions interfere with quality of life, antiinflammatory pharmacotherapeutic agents are recommended. A recent meta-analysis of randomized, controlled, clinical trials studying human AD treatment measures found that only topical glucocorticoids, oral cyclosporin, and ultraviolet light therapy showed clear efficacy.101 Remarkably, glucocorticoids, cyclosporine, and ultraviolet light have in common the ability to down-regulate the activation of the various immune cell types involved in AD pathogenesis. The treatment of canine AD also requires a systematic multi-pronged approach, which can involve one or more of the following steps: 1) allergen avoidance and prevention of allergen contact; 2) antiinflammatory pharmacotherapy; 3) allergen-specific immunotherapy; and 4) antimicrobial therapy.102 Veterinary clinicians can elect to combine the therapeutic steps in varying order, depending on the relevant triggering flare-factors in each individual canine patient. Many drugs have been used to relieve the clinical signs of canine AD. At the time of this writing, there is good evidence that oral prednisone and prednisolone

Figure 2. Periocular and perinasal self-induced alopecia are often seen as markers for pruritus associated with allergic conjunctivitis and rhinitis (courtesy of Dr. B.A. Atlee).

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Figure 3. Macules of erythema in a dog (a) with AD (University of Florida, case material) and in a human patient (b) with AD (Courtesy of Dr. R. Skidmore, University of Florida).

are effective.103 Additionally, there is fair evidence to support the use of oral cyclosporine, misoprostol, and pentoxifylline.105 In contrast, there is insufficient evidence to recommend for or against treatment with oral antihistamines, topical tacrolimus, oral leukotriene in-

hibitors, oral serotonin-reuptake antagonists and capsaicin, and oral essential fatty acids.104 106 Such recommendation schemes hopefully will be modified in the future by the performance of additional blinded randomized controlled trials with larger number of dogs.

Figure 4. Erythema and alopecia on pinnae in a Weimaraner with AD (a) (University of Florida, case material) and scaling and erythema of pinna of a human patient with AD (b) (Courtesy of Dr. R. Skidmore, University of Florida).

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Figure 5. Dorsal aspect of front paws in a mixed breed dog with AD (a). Note the erythema and alopecia (University of Florida, case material). Erythema, excoriations and scaling on the dorsal aspect of the foot in a patient with AD (b) (Courtesy of Dr. R. Skidmore, University of Florida).

Feline Atopic Dermatitis

For decades, cats have been diagnosed with pruritic skin diseases associated with the presence of skin-fixed or circulating IgE antibodies specific for environmental allergens. The various clinical syndromes have been grouped under the generic terms feline atopy or feline AD. Whether or not these syndromes truly correspond to ADas recognized in humans and dogs awaits further study. Nevertheless, in this paper, the term feline AD will be employed in the following sections. As in its human and canine counterpart, feline AD appears to have a genetic component and familial proclivity.107 The exact frequency of feline AD is unknown, but some investigators consider it the second most common allergy after flea allergy.108 Feline AD seems to be caused by an exaggerated IgE and IgG response to environmental allergens.109,110 The feline IgE heavy chain has recently been cloned, and numerous similarities with its canine homologue have been identified.111,112 Just as in dogs, measurement of allergenspecific IgE does not discriminate between normal and

atopic cats.95,113 Synthesis of allergen-specific IgE can be induced, but serum levels do not appear to correlate with the development of positive skin tests or clinical signs, suggesting that IgE antibodies are functionally heterogeneous in cats.113 Dendritic cells may play a role in the mechanism of lesion formation in feline AD. In one study, epidermal and dermal CD1a cells and MHC class II cells were evaluated in lesional feline AD skin and in healthy control animals.114 Immunohistochemistry revealed that MHC class II epidermal dendritic cells were CD1a in normal feline skin. Significantly increased numbers of CD1a cells and MHC class II cells were present in the epidermis and dermis of lesional skin. These data provided the first correlative documentation of CD1a expression by feline dendritic cells containing Birbeck granules. The role of T cells in feline AD also has been investigated recently. A significantly greater number of T cells was found in lesional skin of domestic shorthaired cats with allergic dermatitis compared to healthy controls.115 A predominant increase of CD4 T cells and

Figure 6. Erythema, alopecia and papular dermatitis on the fore legs of a dog (a) (University of Florida, case material) and erythema and papular dermatitis on the arms of a human patient (b) (Courtesy of Dr. R. Skidmore, University of Florida).

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the CD4 /CD8 ratio was quantitated in lesional skin of 10 cats with allergic dermatitis. A cutaneous CD4 / CD8 cell ratio of healthy control animals could not be determined because CD8 cells were not present in the skin. The peripheral blood CD4 /CD8 cell ratio of 10 cats with allergic dermatitis did not differ significantly from that in 10 healthy control animals. The cutaneous CD4 /CD8 cell ratio and predominance of CD4 T cells in the lesional skin of cats with allergic dermatitis was comparable to the situation in human AD. In addition, increased CD4 T cells in nonlesional skin of cats with allergic dermatitis compared to the skin of healthy cats, was similar to what is seen in humans. At this time, there are no studies evaluating cytokine profiles in cats with AD. Environmental allergens are believed to play a role in exacerbating feline AD. In one study, 50% of cats with AD exhibited detectable IgE against nonseasonal allergens, and 48% were positive against nonseasonal and seasonal allergens.116 House dust mite is a common allergen for cats; usually more than 80% of atopic cats have detectable IgE against Dermatophagoides farinae.117,119 The role of food allergens in feline AD has not been investigated, but concurrent allergies to environmental and food allergens have been reported.119 One study found that 25% of cats with AD had concurrent food allergy, flea allergy, or both.120 Clinically, feline AD and food allergy appear to be indistinguishable. As with the human disease, young cats appear to be predisposed to AD, the majority ( 75% of cases) developing clinical signs between 6 and 24 months of age (3,121) . The most common and consistent clinical symptom is pruritus, often localized to the face and neck.122 The distribution of pruritus is thought to be linked to the distribution of mast cells in the skin. For example, one study showed that the highest number of mast cells occurred on the caudal aspect of the pinna and on the chin.123 Beside pruritus and consequent alopecia, cats with AD may develop peculiar skin lesions known as the eosinophilic granuloma complex (indolent ulcer, eosinophilic granuloma, and eosinophilic plaque).124,125 These syndromes are distinctive from their human and canine counterparts. Clinically, macules, papules, plaques, and excoriations are visible on the ventral abdomen, groin, lateral thorax, and back legs. Recurrent otitis may also be seen. In addition, cats with AD may develop a crusted dermatitis called military dermatitis. This distinctive feature of feline allergies has not been reported in dogs or humans. As with eosinophilic granuloma complex, military dermatitis is not specific for AD but a generic manifestation of allergy in cats. Cats with flea allergy and food allergy can also develop similar clinical lesions. In contrast to human and canine disease, cats with AD rarely develop secondary skin infection, and the role of infections in feline AD has not been investigated.

As with dogs and humans, there is no perfect diagnostic test for feline AD. Diagnosis is based on suggestive history, clinical signs, and exclusion of other causes of pruritus. Serology for the detection of allergenspecific IgE does not distinguish between normal and atopic cats, and intradermal testing is often suboptimal due to the nervous nature of most cats. Such tests are used either to identify allergens to implement avoidance measures or before the initiation of allergen-specific immunotherapy, which appears to give satisfactory results in this species.106 Symptomatic treatment of pruritus with oral or injectable glucocorticoids, antihistamines, serotonin-antagonists and/or essential fatty acids is often instituted in conjunction with immunotherapy.126

A Murine Models of AD
NC/Nga (NC) is a recently developed line of mice that has been proposed as a model for human AD.127 These mice develop skin lesions that are clinically and histologically very similar to human AD, and dermatitis is accompanied by an overproduction of IgE. It is interesting to note that skin lesions develop only when those mice are raised under conventional conditions. When, on the other hand, they are raised in specific pathogenfree conditions, skin lesions do not occur, suggesting that certain environmental factors trigger the AD-like signs and symptoms.128 Studies done to identify the loci responsible for the onset of dermatitis in these animals have identified several candidates. These include Thy1, CD3d, CD3e, CD3g, IL10ra, IL18, and Csk.129 Csk is considered the strongest for NC dermatitis, since its map position is most tightly linked to the derm1 locus.129 These mice also have been used to evaluate IgE overproduction and its effects. In one study, it was found that IgE hyperproduction in both NC/Nga mice and patients with AD leads to constitutive and enhanced Janus kinase 3 phosphorylation in B cells highly sensitive to CD40 ligand and IL-4.130 These mice also have a deficient Th1 response to bacterial stimulation, and it is hypothesized that this deficiency may lead to a Th2-dominant state.131 This could induce an abnormal cellular immune response in the skin accompanied with an overproduction of IgE. Another murine model of AD also has been described.132 In this model, the cutaneous lesions are food induced. Female C3H/HeJ mice were sensitized by mouth to cows milk or peanut and then subjected to low-grade allergen exposure. An eczematous eruption developed in approximately one third of mice after low-grade exposure to milk or peanut proteins. This was accompanied by peripheral blood eosinophilia and elevated serum IgE levels. Histologic examination of the lesional skin revealed spongiosis and a cellular

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infiltrate consisting of CD4 lymphocytes, eosinophils, and mast cells resembling characteristics of human AD. In addition, IL-5 and IL-13 mRNA expression was elevated only in the skin of mice with the eczematous eruption, leading to the conclusion that this model also could be useful for studying immunopathogenic mechanisms of food hypersensitivity in AD.

Conclusions
Atopic dermatitis has been reported in both companion and laboratory animals. Numerous similarities exist between the human disease and the animal counterparts to the extent that animals could be used as models to improve our understanding of the pathogenesis of human AD.

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