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Title:Intrinsic alterations of the skin barrier function promote the pathogenesis of atopic dermatitis in dogs
Author(s):Santoro, Domenico
Director of Research:Segre, Mariangela
Doctoral Committee Chair(s):Campbell, Karen L.
Doctoral Committee Member(s):Bunick, David; Graves, Thomas K.; Marsella, Rosanna; Tapping, Richard I.; Zuckermann, Federico; Segre, Mariangela
Department / Program:Vet Clinical Medicine
Discipline:VMS-Veterinary Clinical Medcne
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Canine Atopic Dermatitis
Skin barrier
filaggrin
antimicrobial peptides
Abstract:Canine atopic dermatitis (cAD) is a chronic inflammatory skin disease affecting up to 10% of the canine population, it is the second most common allergic disease in dogs. Canine AD has many similarities to human AD and for this reason the dog has been suggested to be a good animal model to study AD in people. Like people, dogs with AD have a high susceptibility to cutaneous secondary infections. In the past decades, it has been suggested that the reason for the high incidence of cutaneous infection in atopic people is due to defects in the skin barrier function such as deficiency of keratinocyte-secreted natural antimicrobial peptides (AMPs) and filaggrin. Antimicrobial peptides are small proteins secreted by many mammalian epithelial cells. Their main functions include: defense against external pathogens, orchestration of the innate and adaptive immunity, and regulation of the normal local homeostasis. Filaggrin is a structural protein present in keratinized epithelia. Its main functions are flattening of keratinocytes, forming a strong barrier against external agents, and producing natural moisturizing factors that lower cutaneous pH and increase skin hydration. Our studies have been focusing on the alterations of AMPs and filaggrin in the skin of atopic dogs to better understand the function that such proteins play in the pathogenesis of cAD. Our studies have shown that both AMPs and filaggrin mRNA expressions are increased in canine atopic skin when compared with healthy controls. However, this increase in mRNA transcription is not followed by an increase in protein expression suggesting that translational defects occur in atopic dogs. This alteration in expression could be due to intrinsic or extrinsic alterations that may lead an abnormal immunological response to common environmental stimuli such as house dust mites. Based on such hypotheses we isolated canine keratinocytes from healthy and atopic dogs and exposed them to several immunological stimuli (cytokines, bacterial antigens, house dust mite extract, and vitamin D3) to mimic the milieu present in inflamed skin. We were able to show that keratinocytes harvested from atopic dogs behave differently from keratinocytes harvested from healthy dogs. In particular, the former express a higher production of some AMPs (cBD3-like) at baseline, but they are not able to increase such production following stimulation with several immunostimulators. These results suggest that the lack of positive stimulation of some AMPs could have a rolein the high incidence of recurrent cutaneous infection in atopic dogs. Our studies also demonstrated that canine AMPs are able to effectively and rapidly kill the most common cutaneous canine pathogens at variable concentrations. The data showed that different AMPs have different affinity against microorganisms. Canine AMPs were more effective in killing bacteria more commonly involved in canine skin infections (Staphylococcus pseudintermedius and Malassezia pachydermatis) rather than pathogens involved in human skin diseases (Staphylococcus aureus and Candida albicans). In conclusion, we demonstrated that an altered expression of two markers of the skin barrier function analyzed, AMPs and filaggrin, is present in canine atopic skin. Our results suggest that such alterations may be the results of intrinsic abnormal cellular mechanisms that do not allow the “atopic” keratinocyte to respond promptly to external stimuli. This intrinsic defect of the skin barrier function may play a major role in the increased incidence of cutaneous infections present in atopic patients and contribute to the severity of allergic disease.
Issue Date:2014-01-16
URI:http://hdl.handle.net/2142/46917
Rights Information:Copyright 2013 Domenico Santoro
Date Available in IDEALS:2014-01-16
2016-01-16
Date Deposited:2013-12


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