Immunopathology of Atopic Dermatitis
World Small Animal Veterinary Association World Congress Proceedings, 2007
Ralf S. Mueller, DACVD, FACVSc, DECVD, FAAAAI
Professor, Medizinische Kleintierklinik, Ludwig-Maximilian-University
Munich, Germany

Allergic diseases result from an exaggerated and often deleterious response of the immune system to specific antigens.1 An increase in transepidermal water loss2 and enzymes degrading components of the stratum corneum3 and a decrease in ceramides was documented in human atopic dermatitis.4 More recently, loss of function variants of the gene encoding filaggrin have been identified as a major predisposing factor for atopic dermatitis.5 In dogs, abnormalities in essential fatty acids contributing to the skin barrier6 and in the intercellular lipid lamellae7 have been identified. These changes may lead to an increased penetration of antigens into the skin and subsequent binding to IgE on the surface of antigen presenting cells (APC) such as Langerhans cells.8,9

Activated dendritic cells then contribute to the generation of allergen-specific CD4+ T helper (TH) cells. Once generated, effector TH2 cells produce IL-4, IL-5, IL-9 and IL-13, cytokines with several regulatory and effector functions. Among other functions these cytokines induce the production of allergen-specific IgE by B cells and development and recruitment of eosinophils.10 The degranulation of basophils and mast cells by IgE-mediated cross-linking of receptors is the key event in type I hypersensitivity. Although in humans TH2 cells are initially involved in the development of allergic diseases, TH1 cells may play an important role in the chronic and effector phase of allergic disease or decrease allergic inflammation depending on disease type and stage of inflammation. Distinct TH1 and TH2 subpopulations of T cells counter-regulate each other and play an important role in distinct diseases. In the dog, a TH2 response with overproduction of IL-4 mRNA in lesional infiltrated lymphocytes11 and low expression of IFN-γ mRNA in peripheral blood monocytes (PBMC)12 has been reported.

However, commonly patients with atopic dermatitis deteriorate due to other factors contributing to the clinical signs. These factors frequently are not strictly speaking part of the atopic dermatitis but do occur in many atopic patients due to the pathologic changes associated with the disease. The three major groups of flare factors are other hypersensitivities (such as flea bite hypersensitivity or adverse food reaction), infections (with bacteria and yeast) and psychogenic factors. Those flare factors are also associated with pruritus and inflammation and thus increase the clinical signs of present atopic dermatitis or may mimic the signs of atopic dermatitis currently controlled with therapy or in remission. Without their diagnosis and appropriate treatment, significant improvement or remission is unlikely to occur in our atopic patients. Psychogenic factors are known to aggravate atopic dermatitis in human patients. Neurogenic peptides may cause clinical pruritus and affect lymphocytes and antigen presenting cells in lesional atopic dermatitis. In our canine and feline patients, atopic flares have also been observed during period of increased stress, but objective evaluation of psychogenic factors in canine or feline atopic dermatitis is difficult and little has been published in this regard. When considering flare factors for atopic dermatitis (AD), the threshold phenomenon is important in explaining increased pruritus in those patients. Each patient has a threshold up to which stimuli can be tolerated without obvious clinical signs. If that threshold is surpassed, clinical pruritus results. With each additional pruritic disease, clinical signs become more pronounced. Thus, patients with atopic dermatitis will show often dramatically increased pruritus when other pruritic skin diseases occur concurrently. In addition, the predisposition for atopic dermatitis predisposes for other hypersensitivities as well and the microenvironment of inflamed skin is conducive to proliferation of bacteria and yeast organisms that further contribute to inflammation and pruritus by release of enzymes and other pro-inflammatory substances. Hypersensitivities to these organisms are also likely in a number of atopic patients as allergen-specific IgE and positive skin test reactions against bacterial and Malassezia antigens have been reported in the dog.

Adverse food reaction (AFR) is a nonseasonal pruritic skin disorder associated with the ingestion of a substance found in the dog's diet. It can be immunologically mediated (food allergy or anaphylaxis) but toxic, metabolic, pharmacologic and idiosyncratic food reactions are known in human medicine and may play a role in veterinary medicine as well. In humans, the disease "atopic dermatitis" may be caused by environmental as well as dietary antigens. Thus, human medicine has considered the fact that cutaneous lesions of dermatitis caused by an allergic reaction to food antigens are impossible to differentiate clinically from lesions derived from a hypersensitivity to environmental allergens, that food antigen-specific IgE has been demonstrated and in vitro immunologic reactions to food antigens resemble those seen with environmental allergens. In small animals, skin lesions caused by food adverse reactions are also not clinically distinguishable from atopic dermatitis, although concurrent gastrointestinal signs are evidence of food adverse reaction and not seen commonly with hypersensitivities to environmental allergens. Intradermal testing and serum testing for food allergen-specific IgE is offered but highly controversial.13-15 The gold standard for the diagnosis of AFR is an elimination diet and at this point AFR is considered a separate entity from AD.

Secondary bacterial infection is common in dogs and humans with atopic dermatitis. The by far most common organism involved is Staphylococcus intermedius. It has been shown that S. intermedius adherence to corneocytes of atopic patients is increased.16 Inflammation associated with atopic dermatitis creates a suitable environment for bacterial overgrowth. In addition, bacterial superantigens nonspecifically activate a large number of T cells, contributing further to inflammatory changes.17 Production of allergen-specific IgE against bacterial antigens has been shown in humans and dogs.18,19 Bacterial pyoderma may be diagnosed by clinical examination in conjunction with microscopic examination of cytologic specimens, trial therapy with antibiotics, bacterial culture and sensitivity and/or biopsy. As normal skin may also be inhabited by bacteria and S. intermedius has been demonstrated in normal dogs, a positive bacterial culture obtained by swabbing a skin surface is not necessarily a proof of bacterial pyoderma. Thus, a bacterial culture of the skin surface is not routinely done and cytology or response to antimicrobial therapy is more meaningful.

Malassezia pachydermatis is a lipophilic yeast, but the only member of the Malassezia group that is not lipid-dependent. It is a normal commensal, but under certain circumstances can proliferate extensively and cause clinical signs. Factors involved may be genetic predispositions (West Highland White Terrier, American Cocker Spaniel, Basset hound), underlying hypersensitivity, changes in sebum composition and production due to keratinization defects or hormonal diseases and increased humidity and temperature (due to climatic or anatomical conditions). In dogs with atopic dermatitis and Malassezia infection, allergic reactions to Malassezia antigens may be present. Positive skin test reactions to Malassezia antigen in atopic dogs with yeast infections and positive Prausnitz-Kuestner Tests provided evidence for Malassezia-specific IgE in those dogs, although cell-mediated immunity against Malassezia antigens in atopic dogs with Malassezia infections was not different from those dogs with no history or clinical evidence of such infection.20-22

References

1.  Olivry T. The ACVD Taskforce on canine atopic dermatitis: forewords and lexicon. Vet Immunol Immunopathol 2001 81 143-146.

2.  Werner Y, Lindberg M. Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis. Acta Derm Venereol 1985 65 102-105.

3.  Hara J, Higuchi K, Okamoto R, Kawashima M, Imokawa G. High-expression of sphingomyelin deacylase is an important determinant of ceramide deficiency leading to barrier disruption in atopic dermatitis. J Invest Dermatol 2000 115 406-413.

4.  Macheleidt O, Kaiser HW, Sandhoff K. Deficiency of epidermal protein-bound omega-hydroxyceramides in atopic dermatitis. J Invest Dermatol 2002 119 166-173.

5.  Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006 38 441-446.

6.  Taugbol O, Baddaky-Taugbol B, Saarem K. The fatty acid profile of subcutaneous fat and blood plasma in pruritic dogs and dogs without skin problems. Can J Vet Res 1998 62 275-278.

7.  Inman AO, Olivry T, Dunston SM, Monteiro-Riviere NA, Gatto H. Electron microscopic observations of stratum corneum intercellular lipids in normal and atopic dogs. Vet Pathol 2001 38 720-723.

8.  Mudde GC, Van Reijsen FC, Boland GJ, de Gast GC, Bruijnzeel PL, Bruijnzeel-Koomen CA. Allergen presentation by epidermal Langerhans' cells from patients with atopic dermatitis is mediated by IgE. Immunology 1990 69 335-341.

9.  Olivry T, Moore PF, Affolter VK, Naydan DK. Langerhans cell hyperplasia and IgE expression in canine atopic dermatitis. Arch Dermatol Res 1996 288 579-585.

10. Romagnani S. Regulation of the development of type 2 T-helper cells in allergy. Curr Opin Immunol 1994 6 838-846.

11. Nuttall TJ, Knight PA, McAleese SM, Lamb JR, Hill PB. Expression of Th1, Th2 and immunosuppressive cytokine gene transcripts in canine atopic dermatitis. Clin Exp Allergy 2002 32 789-795.

12. Hayashiya S, Tani K, Morimoto M, et al. Expression of T helper 1 and T helper 2 cytokine mRNAs in freshly isolated peripheral blood mononuclear cells from dogs with atopic dermatitis. J Vet Med A Physiol Pathol Clin Med 2002 49 27-31.

13. Jeffers JG, Shanley KJ, Meyer EK. Diagnostic testing of dogs for food hypersensitivity. J Am Vet Med Assoc 1991 198 245-250.

14. Kunkle G, Horner S. Validity of skin testing for diagnosis of food allergy in dogs. J Am Vet Med Assoc 1992 200 677-680.

15. Mueller RS, Tsohalis J. Evaluation of serum allergen-specific IgE for the diagnosis of food adverse reactions in the dog. Veterinary Dermatology 1998 9 167-171.

16. McEwan NA. Adherence by Staphylococcus intermedius to canine keratinocytes in atopic dermatitis. Res Vet Sci 2000 68 279-283.

17. Hendricks A, Schuberth HJ, Schueler K, Lloyd DH. Frequency of superantigen-producing Staphylococcus intermedius isolates from canine pyoderma and proliferation-inducing potential of superantigens in dogs. Res Vet Sci 2002 73 273-277.

18. Ide F, Matsubara T, Kaneko M, Ichiyama T, Mukouyama T, Furukawa S. Staphylococcal enterotoxin-specific IgE antibodies in atopic dermatitis. Pediatr Int 2004 46 337-341.

19. Morales CA, Schultz KT, DeBoer DJ. Antistaphylococcal antibodies in dogs with recurrent staphylococcal pyoderma. Vet Immunol Immunopathol 1994 42 137-147.

20. Morris DO, Clayton DJ, Drobatz KJ, Felsburg PJ. Response to Malassezia pachydermatis by peripheral blood mononuclear cells from clinically normal and atopic dogs. Am J Vet Res 2002 63 358-362.

21. Morris DO, DeBoer DJ. Evaluation of serum obtained from atopic dogs with dermatitis attributable to Malassezia pachydermatis for passive transfer of immediate hypersensitivity to that organism. Am J Vet Res 2003 64 262-266.

22. Morris DO, Olivier NB, Rosser EJ. Type-1 hypersensitivity reactions to Malassezia pachydermatis extracts in atopic dogs. Am J Vet Res 1998 59 836-841.

Speaker Information
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Ralf S. Mueller, DACVD, FACVSc, DECVD, FAAAAI
Ludwig Maximilian University Munich
Germany


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