Pathogenesis of canine atopic dermatitis: 2004 hypothesis

Abstract

The exact pathogenesis of canine atopic dermatitis (AD) remains elusive at this time. However, information on selected aspects of the immunological mechanisms of canine AD can be derived from the results of static (fixed‐point) and dynamic studies. Static studies yield data from samples collected at single time points and are thus fraught with imprecision dependent on the immunological stage of the lesions. In contrast, dynamic investigations provide information from sequential samples collected after immune cell activation with or without allergens. Examples of dynamic studies include stimulation of normal and atopic canine skin with intradermal injections of anti‐IgE antibodies, epicutaneous application (e.g. patch tests) with house dust mite allergens on sensitized dogs, and environmental challenges of sensitized dogs with house dust mites. This lecture will review results from selected static studies investigating epidermal lipids, epidermotropic and dermal immune cells, and cytokines detected in the skin of dogs with AD. Cellular inflammatory infiltrates and cytokines released during dynamic experiments will be reviewed subsequently. The information collated from various studies enables the generation of a working hypothesis for the pathogenesis of canine AD. In the acute phase of AD, a putative epidermal barrier defect could facilitate the contact of environmental allergens and microbes with epidermal immune cells at skin sites of friction and trauma. Epidermal Langerhans cells capture allergens with antigen‐specific IgE and migrate to the dermis and regional lymph nodes. Keratinocytes release chemokines that include thymus and activation‐regulated chemokine (TARC/CCL17). Allergen‐specific IgE‐coated dermal mast cells release histamine, proteases including chymase and tryptase, chemokines, and cytokines including TNFα and stem cell factor. There is an early influx of granulocytes (neutrophils and eosinophils), allergen‐specific Th2 lymphocytes and dermal dendritic cells. Eosinophils degranulate upon allergen challenge and release proteins that induce dermal and epidermal damage and inflammation. Th2 lymphocytes release cytokines promoting IgE synthesis (IL‐4 and IL‐13) and eosinophil survival (IL‐5). In chronic canine AD, microbes, self‐trauma and neuromediators are suspected to contribute to chronic inflammation. Chemokines are released in a continuous allergen‐dependent and ‐independent cycle, with subsequent influx and activation of leucocytes and further release of chemokines and other mediators. There is infiltration of T lymphocytes expressing type‐2 and type‐1 cytokines (IL‐12 and IFNγ). The failure to down‐regulate proinflammatory mechanisms leads to self‐perpetuating cutaneous inflammation.