Pathogenesis Of Canine Atopic Dermatitis Research Articles

Update on the role of cytokines and chemokines in canine atopic dermatitis.

Cytokines and chemokines play central roles in the pathogenesis of canine atopic dermatitis (cAD). Numerous studies have been published and provide new insights into their roles in cAD. To summarise the research updates on the role of cytokines and chemokines in the pathogenesis of cAD since the last review by the International Committee on Allergic Diseases of Animals in 2015. Online citation databases, abstracts and proceedings from international meetings on cytokines and chemokines relevant to cAD that had been published between 2015 and 2022 were reviewed. Advances in technologies have allowed the simultaneous analysis of a broader range of cytokines and chemokines, which revealed an upregulation of a multipolar immunological axis (Th1, Th2, Th17 and Th22) in cAD. Most studies focused on specific cytokines, which were proposed as potential novel biomarkers and/or therapeutic targets for cAD, such as interleukin-31. Most other cytokines and chemokines had inconsistent results, perhaps as a consequence of their varied involvement in the pathogenesis of different endotypes of cAD. Inconsistent results for many cytokines and chemokines illustrate the difficulty of studying the complex cytokine and chemokine networks in cAD, and highlight the need for more comprehensive and structured studies in the future.

Pilot evaluation of a single oral fecal microbiota transplantation for canine atopic dermatitis

The gut microbiota has been suggested to be involved in the pathogenesis of canine atopic dermatitis (cAD). However, the gut microbiota has not been well characterized in dogs with atopic dermatitis (AD). In addition, the efficacy of fecal microbiota transplantation (FMT) in dogs with AD remains unclear. This research, therefore, aimed to characterize the gut microbiota of dogs with AD and conduct pilot evaluation of the efficacy of a single oral FMT on clinical signs and the gut microbiota of dogs with AD. For these purposes, we used 12 dogs with AD and 20 healthy dogs. The 16S rRNA analysis of the fecal microbiota revealed significant differences between 12 dogs with AD and 20 healthy dogs. Next, a single oral FMT was performed in 12 dogs with AD as a single-arm, open-label clinical trial for 56 days. A single oral FMT significantly decreased Canine Atopic Dermatitis Extent and Severity Index (CADESI)-04 scores from day 0 (median score, 16.5) to day 56 (8) and Pruritus Visual Analog Scale (PVAS) scores from days 0 (median score, 3) to day 56 (1). Furthermore, a single oral FMT changed the composition of the fecal microbiota of dogs with AD at the phylum and genus levels. The number of common amplicon sequence variants in the fecal microbiota between donor dogs and dogs with AD was positively correlated with CADESI-04 and PVAS reduction ratios 56 days after FMT. Our findings suggest that the gut microbiota plays a pivotal role in the pathogenesis of cAD, and that oral FMT could be a new therapeutic approach targeting the gut microbiota in cAD.

Bayesian model and selection signature analyses reveal risk factors for canine atopic dermatitis.

Canine atopic dermatitis is an inflammatory skin disease with clinical similarities to human atopic dermatitis. Several dog breeds are at increased risk for developing this disease but previous genetic associations are poorly defined. To identify additional genetic risk factors for canine atopic dermatitis, we here apply a Bayesian mixture model adapted for mapping complex traits and a cross-population extended haplotype test to search for disease-associated loci and selective sweeps in four dog breeds at risk for atopic dermatitis. We define 15 associated loci and eight candidate regions under selection by comparing cases with controls. One associated locus is syntenic to the major genetic risk locus (Filaggrin locus) in human atopic dermatitis. One selection signal in common type Labrador retriever cases positions across the TBC1D1 gene (body weight) and one signal of selection in working type German shepherd controls overlaps the LRP1B gene (brain), near the KYNU gene (psoriasis). In conclusion, we identify candidate genes, including genes belonging to the same biological pathways across multiple loci, with potential relevance to the pathogenesis of canine atopic dermatitis. The results show genetic similarities between dog and human atopic dermatitis, and future across-species genetic comparisons are hereby further motivated.

House dust mite-derived serine protease upregulates gene expression of interleukin-33 in canine keratinocytes via protease-activated receptor-2.

The involvement of interleukin (IL)-33 produced by keratinocytes has been suggested in the pathogenesis of canine atopic dermatitis (cAD). House dust mite (HDM)-derived proteases induce the production of various cytokines and chemokines in keratinocytes via protease-activated receptor-2 (PAR-2); however, their effects on IL-33 mRNA expression in canine keratinocytes have not been determined. To clarify whether HDM-derived proteases induce IL-33 mRNA expression in canine keratinocytes via PAR-2. Expression of IL-33 mRNA was quantified by real-time PCR in a cell line of canine progenitor epidermal keratinocytes (CPEK) stimulated with Dermatophagoides farinae (Der f) whole body extract, Der f pre-treated with cysteine protease and serine protease inhibitors, and trypsin. Trypsin and Der f-mediated IL-33 mRNA expression also was measured in CPEK cells treated with a PAR-2 antagonist. Der f enhanced IL-33 mRNA expression in CPEK cells in incubation time- and dose-dependent manners. Der f pre-treated with a serine protease inhibitor, and not a cysteine protease inhibitor, abrogated an increase in IL-33 mRNA expression in CPEK cells. Trypsin also enhanced IL-33 mRNA expression in CPEK cells. Trypsin-mediated IL-33 mRNA expression was completely abolished by a PAR-2 antagonist, while Der f-mediated IL-33 mRNA expression was partially and significantly diminished by it. Der f-derived serine protease upregulated IL-33 mRNA expression in CPEK cells at least in part via PAR-2. These findings suggest that HDM may be involved in the development of C AD by increasing IL-33 mRNA expression in keratinocytes.

Serum canine thymus and activation-regulated chemokine (TARC/CCL17) concentrations correlate with disease severity and therapeutic responses in dogs with atopic dermatitis.

Thymus and activation-regulated chemokine (TARC/CCL17) has been implicated in the pathogenesis of canine atopic dermatitis (cAD). Serum TARC concentrations are a reliable biomarker for human atopic dermatitis; however, their potential as a biomarker for cAD has not been investigated. To investigate whether serum TARC concentrations correlate with disease severity and therapeutic responses for cAD. Thirty-nine dogs with cAD and 42 healthy dogs were recruited. Serum TARC concentrations in dogs with cAD and healthy dogs were measured by sandwich ELISA with anti-canine TARC antibodies. The clinical severity of cAD was scored using the validated Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04). Serum TARC concentrations were compared between dogs with cAD and healthy controls, and their relationship with CADESI-04 was examined. Serum TARC concentrations also were measured in 20 dogs with cAD treated with prednisolone or oclacitinib for four weeks. Serum TARC concentrations were significantly higher in dogs with cAD than in healthy dogs (P<0.001). In dogs with cAD, serum TARC concentrations correlated with CADESI-04 scores (ρ=0.457, P<0.01). Furthermore, serum TARC concentrations significantly decreased in treated dogs with the attenuation of clinical signs (P<0.001). Changes in serum TARC concentrations before and after treatment correlated with those in CADESI-04 scores (ρ=0.746, P<0.001). Serum TARC concentrations have potential as a clinical and research tool for the objective evaluation of disease severity and therapeutic responses for cAD.

IgE AND IgG antibody responses to Dermatophagoides pteronyssinus in dogs with demodicosis and atopic dermatitis

Canine demodicosis is a common inflammatory parasitic skin disease caused by Demodex mites. House dust mites, such as Dermatophagoides spp., play an important role in the pathogenesis of canine atopic dermatitis (AD). The goal of this experimental work was to investigate whether demodectic dogs could be previously exposed/sensitized to house dust mites’ antigens. First the prevalence of demodicosis in a southeastern region of Brazil was investigated by analyzing clinical files of dogs that were admitted to a Veterinary Hospital. Subsequently, the IgG responses to Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) and IgE to D. pteronyssinus (Dp) were evaluated in two groups, AD or demodicosis dogs. Additionally, the major IgE-binding Dp proteins that are recognized by sera from dogs with demodicosis and AD were evaluated. A total of 2,599 clinical files were analyzed to identify the major parasitic skin diseases in dogs from this region, considering the age, sex and breed of the animals. The epidemiological study identified 111 animals with skin diseases; from these 20.7% presented demodicosis. Afterwards, serum samples were obtained from another groups of demodicosis, AD, and healthy dogs, and analyzed for Dp and Df-specific IgG, and IgE antibody levels, Dp IgG avidity by ELISA and IgE-binding Dp-specific proteins by immunoblot. IgG and IgE antibodies to Dp were detected in sera from additional groups of dogs with AD, demodicosis or healthy, with higher IgE levels to Dp in AD than demodectic or healthy dogs. IgG to Df was detected, despite with smaller levels compared to Dp in sera from demodectic dogs, and also in healthy dogs. Immunoblot showed IgE-binding to Dp proteins in sera of dogs with demodicosis and AD; with strong reactivity for the 72 and 116 kDa antigens detected by sera from demodicosis dogs. However, sera from healthy dogs &gt;12 months old also presented reactivity to these bands. In conclusion, the detection of Dp-IgG and IgE antibodies in sera from demodectic dogs indicates previous exposure and sensitization to the house dust mite, respectively, more than cross-reactivity between demodex mites and Dp antigens detected by canine antibodies. Additionally, higher Dp-specific IgE levels were found in dogs with AD compared with those with demodicosis or healthy, suggesting that Dp-specific IgE could better discriminate dogs with AD from healthy ones or even those with demodicosis.

Alterations in circulating concentrations of IL‐17, IL‐31 and total IgE in dogs with atopic dermatitis

The pathogenesis of canine atopic dermatitis (AD) is complex. Dysregulation of the cutaneous immune system is considered an important regulator of the allergic response. Exploration of association of interleukin-17 (IL-17), IL-31, IgE and leukogram attributes with canine AD could provide novel insights into its immunopathology. To investigate possible associations of IL-17, IL-3, IgE and leukogram attributes of canine AD. 17 dogs diagnosed with AD and six healthy dogs. Circulating concentrations of IL-17, IL-31 and total IgE from sera samples were determined using commercial canine-specific quantitative immunoassay kits. Complete blood cell counts were analysed by an automated haematology analyser. Statistical differences between the two groups were determined using an unpaired t-test. The degree of relationship between the IL-17, IL-31, IgE, total leukocyte count (TLC) values and clinical signs scores (Canine Atopic Dermatitis Lesion Index and pruritus Visual Analog Scale pVAS) was determined by Pearson's r correlation statistic. Dogs with AD had significantly (P<0.0001) higher circulating concentrations of IL-17, IL-31 and total IgE compared with healthy dogs. Dogs with AD also had significantly higher TLC (P<0.0002), absolute neutrophils (P<0.0001) and absolute eosinophils (P<0.0001) counts, and percentage of neutrophils (P<0.03) and eosinophils (P<0.0001) compared with healthy controls. A significant positive correlation (r2 =0.396; P<0.007) between the pVAS and IL-31 was observed in dogs with AD. Marked elevation in circulating IL-17, IL-31 and total IgE along with the abnormalities in leukogram may be associated with canine AD and could be possible targets in the therapeutic management of canine AD.

Circulating CD4(+)CD25(+)Foxp3(+) T regulatory cell levels in an experimental model of canine atopic dermatitis.

The pathogenesis of canine atopic dermatitis (cAD) is characterized immunologically by an imbalanced T-cell response. Mechanisms of immune regulation in cAD have not yet been completely elucidated. To investigate peripheral blood T regulatory (Treg) cells and their associated cytokines (TGF-β and IL-10) in an experimental model of cAD. Eight beagle dogs that were initially naïve and subsequently sensitized to house dust mites (HDM). T regulatory cell phenotyping was performed by flow-cytometric analysis on peripheral blood; serum cytokine levels were measured by ELISA, before sensitization and after challenge with HDM allergens. Additionally, clinical scores and allergen-specific IgE were determined. After challenge of sensitized dogs to HDM allergen, a significant increase of Treg cells and simultaneous decrease in the serum TGF-β were observed. However, in most dogs, serum IL-10 values were below the detection limit. Treg cell proportions before sensitization were significantly negatively correlated with the HDM-specific IgE levels and clinical scores after induction of AD signs. The results confirm that Treg responses are involved in the pathogenesis of an experimental model cAD. Further investigations are required to clarify the precise immune modulating function of canine Treg cells and their interplay with other immune cell types.

Expression of ZO-1 and claudin-1 in a 3D epidermal equivalent using canine progenitor epidermal keratinocytes.

Previous studies indicate that tight junctions are involved in the pathogenesis of canine atopic dermatitis (cAD). An in vitro skin model is needed to elucidate the specific role of tight junctions in cAD. A 3D epidermal equivalent model using canine progenitor epidermal keratinocytes (CPEK) has been established; the expression of tight junctions within this model is uncharacterized. To investigate the expression of tight junctions in the 3D epidermal equivalent. Two normal laboratory beagle dogs served as donors of full-thickness skin biopsy samples for comparison to the in vitro model. Immunohistochemical techniques were employed to investigate the expression of tight junctions including zonula occludens (ZO)-1 and claudin-1 in normal canine skin, and in the CPEK 3D epidermal equivalent. Results demonstrated the expression of ZO-1 and claudin-1 in the CPEK 3D epidermal equivalent, with staining patterns that were similar to those in normal canine skin. The CPEK 3D epidermal equivalent has the potential to be a suitable in vitro research tool for clarifying the specific role of tight junctions in cAD.

Expression of IL-33 in chronic lesional skin of canine atopic dermatitis.

In humans, interleukin (IL)-33 plays a critical role in the enhancement of allergic skin inflammation. However, it currently remains unclear whether IL-33 is involved in the pathogenesis of canine atopic dermatitis (cAD). To examine the expression of IL-33 in chronic lesional skin of cAD. Eight dogs with spontaneous cAD and five healthy dogs were used. The transcription of il-33 in chronic lesional skin of cAD was quantified by quantitative reverse transcription PCR. The expression of IL-33 was evaluated immunohistochemically using an anti-human IL-33 monoclonal antibody with cross-reactivity to canine IL-33. The transcription levels of il-33 in chronic lesional skin of cAD were significantly higher than those in normal skin of healthy dogs. Keratinocytes were a major cellular source of IL-33 production in chronic lesional skin of cAD. The results indicate that IL-33 is involved in chronic lesional skin of cAD.

Transcriptional analysis of the IL-33 receptor suppression of tumourigenicity 2 and its effects on canine Type 2 T helper cells: a preliminary study.

Interleukin (IL)-33 has been implicated in the pathogenesis of canine atopic dermatitis, a Type 2 T helper cell (Th2)-associated disease. In humans, IL-33 mediates its biological effects through the receptor suppression of tumourigenicity 2 (ST2), which is preferentially expressed on Th2 cells. The effects of IL-33 on canine Th2 cells are unclear. ST2 may be preferentially expressed on canine Th2 cells; IL-33 may induce the transcription of Th2 cytokines from these cells. Three healthy dogs were used. The transcription level of st2 was quantified in helper T cells, cytotoxic T cells and Th2 cells isolated from healthy dogs. The transcription levels of Th2 cytokines including il-4, il-5, il-13 and il-31 were quantified in Th2 cells stimulated with recombinant canine (rc) IL-33 and/or recombinant human (rh) IL-2. Transcription of st2 was the strongest in Th2 cells. Th2 cells also transcribed the genes for il-5 and il-13 after being stimulated with rcIL-33 and rhIL-2. These results indicate that canine Th2 cells activated by IL-33 enhance Th2-mediated inflammation through the production of IL-5 and IL-13.

Altered lipid properties of the stratum corneum in Canine Atopic Dermatitis

Skin barrier disruption plays a role in the pathogenesis of atopic dermatitis (AD) in humans. However, little is known about skin barrier (dys-) function in Canine Atopic Dermatitis. The properties of lipids located in the outermost layer of the skin, the stratum corneum (SC) are considered to be important for the barrier. In the present study the lipid composition and lipid organization of the SC of AD dogs and control dogs were examined. The lipid composition of lesional AD skin as compared to control skin, showed a reduced free fatty acid level and a decreased ratio of ceramide[NS] C44/C34, in which C44 and C34 are the total numbers of carbon atoms of the sphingosine (S) and non-hydroxy (N) acyl chains. As a consequence of the observed changes in lipid composition in AD lesional skin the lamellar organization of lipids altered and a shift from orthorhombic to hexagonal lipid packing was monitored. Simultaneously an increased conformational disordering occurred. These changes are expected to compromise the integrity of the skin barrier. The C44/C34 chain length ratio of ceramide[NS] also showed a decreasing nonlinear relationship with the AD severity score (CADESI). Taken together, canine atopic skin showed alterations in SC lipid properties, similar to the changes observed in atopic dermatitis in humans, that correlated with a disruption of the skin barrier. Hence lipids play an important role in the pathogenesis of Canine Atopic Dermatitis.

Transcription of thymic stromal lymphopoietin via Toll-like receptor 2 in canine keratinocytes: a possible association of Staphylococcus spp. in the deterioration of allergic inflammation in canine atopic dermatitis.

Colonization, overgrowth and subsequent infection by Staphylococcus spp. is frequently observed in canine atopic dermatitis (CAD), where it contributes to the intensity of cutaneous inflammation. The mechanisms by which staphylococci contribute to the pathogenesis of CAD are unclear. Studies suggest that thymic stromal lymphopoietin (TSLP), a cytokine induced by a cell wall component of Staphylococcus spp., may play a critical role in Th2 responses including the pathogenesis of CAD. To determine if synthetic triacylated lipopeptide (TLR1/2 ligand), a cell wall component of Staphylococcus spp., induces the transcription of TSLP via TLR2 in canine keratinocytes. Transcription of TSLP was quantified in a canine keratinocyte cell line after stimulation with synthetic triacylated lipopeptide, and again after inhibition of TLR2 by a targeted small interfering RNA. The transcription of TSLP was enhanced 6 h after stimulation with the synthetic triacylated lipopeptide; it was completely suppressed by knockdown of TLR2. The results demonstrated that a synthetic cell wall component of Staphylococcus spp. induced transcription of TSLP via TLR2 in canine keratinocytes. Additional studies will be required to investigate whether Staphylococcus spp. contributes to Th2 responses in CAD through TLR2-mediated TSLP production.

Increased numbers of FoxP3-expressing CD4+ CD25+ regulatory T cells in peripheral blood from dogs with atopic dermatitis and its correlation with disease severity.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease of humans and dogs. Regulatory T cells (Tregs) are essential controllers of immune homeostasis and have been shown to play a key role in human AD, even though frequencies of Tregs in atopic human patients vary greatly. Only two studies have reported Treg numbers in the peripheral blood of dogs with canine AD (CAD). This study aimed to assess the numbers of circulating Tregs in healthy and atopic dogs, and to determine whether Treg numbers correlate with age, sex, disease severity or pre-treatment. Client-owned dogs including 14 healthy dogs and 35 dogs with CAD. Expression of Tregs in peripheral blood mononuclear cells was evaluated by flow cytometry. Tregs were phenotypically identified as T cells triple positive for CD4, CD25 and FoxP3. The percentage of circulating CD4(+) CD25(+) FoxP3(+) Tregs in atopic dogs was increased significantly compared to healthy dogs (mean 2.1% versus 1%, P=0.002) and correlated with disease severity (Pruritus Scale: r=0.48, P=0.003; CADESI-04: r=0.34, P=0.044). No significant differences in age or sex were found in either group and pre-treatment had no influence on results for atopic dogs. Data suggest that, as in humans, CD4(+) CD25(+) FoxP3(+) Tregs may contribute to the pathogenesis of CAD as indicated by an association between Treg frequency and disease severity. Further investigation is required to improve the understanding of the role of Tregs in atopic dogs.

Lymphocyte subpopulations and Treg cells in dogs with atopic dermatitis receiving ciclosporin therapy: a prospective study.

Canine atopic dermatitis (CAD) is a chronic dermatological disease partly due to dysregulation of the immune system. Inappropriate activation of CD4(+) lymphocytes could favour and promote the allergic response. An inadequate activation system of regulatory T cells (Tregs) is suspected to be a key immunological feature of the allergic response in atopic dogs. To evaluate the difference in the CD4/CD8 lymphocyte ratio and the percentage of Tregs in healthy dogs, in a breed predisposed to CAD, and in dogs affected by CAD before and during therapy with ciclosporin (CsA). Additionally to assess the improvement in pruritus and skin lesions during therapy with CsA, and to compare this with CD4/CD8/Treg values. Ten atopic dogs of different breed, sex and age, ten healthy dogs and ten English bulldogs were included. Peripheral blood from all dogs was tested using flow cytometry to assess the CD4/CD8 ratio and percentage of Tregs. For atopic dogs, sampling was repeated after 30 and 90 days of therapy with CsA. The CD4/CD8 ratio was not significantly different between the three groups. The Treg percentage was higher, but not statistically significant, in atopic dogs compared with controls. Therapy with CsA led to clinical improvement; it was not associated with statistically significant differences in haematological variables. This study suggests that Tregs may be involved in the pathogenesis of CAD and that ciclosporin therapy does not affect the circulating lymphocyte subpopulations.

Gene transcription of pro-inflammatory cytokines and chemokines induced by IL-17A in canine keratinocytes.

Pro-inflammatory cytokines and chemokines produced by activated keratinocytes play an important role in the pathogenesis of canine atopic dermatitis (AD) as well as human AD. Recent studies suggest that keratinocytes activated by IL-17A are involved in the pathogenesis of human AD. However, the role of IL-17A in canine keratinocytes is poorly understood. Interleukin-17A would induce the transcription of pro-inflammatory cytokines and chemokines in canine keratinocytes. The transcription levels of pro-inflammatory cytokines and chemokines were quantified in a canine keratinocyte cell line stimulated with recombinant canine (rc) IL-17A. The transcription of GM-CSF, S100A8, IL-8 and IL-19 in cultured keratinocytes was significantly enhanced at 24 h after stimulation with rcIL-17A. Keratinocytes activated by IL-17A have the ability to produce various pro-inflammatory cytokines and chemokines, suggesting that IL-17A may play a central role of the development of Th2-associated inflammation in canine AD.

Review: Lymphocytes, cytokines, chemokines and the T-helper1-T-helper2 balance in canine atopic dermatitis.

The development of atopic dermatitis (AD) and other cutaneous hypersensitivities involves the activation and differentiation of allergen-specific lymphocytes. Although hypersensitivity is often considered to be a 'T-helper2-polarized' lymphocyte response, recent evidence suggests that clinical disease is associated with the development of multiple lymphocyte phenotypes. The purpose of this paper is to review recent advances in the understanding of the roles of lymphocytes, cytokines and noncytokine factors in the pathogenesis of canine AD. Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed in this update. Where necessary, older articles were included for background information. The development of canine AD is associated with changes in both cutaneous and circulating lymphocyte populations. These lymphocyte responses are characterized by the production of a complex variety of cytokines, including not only T-helper2 but also T-helper1, T-helper17 and regulatory T-cell responses. In addition, microarray gene expression analysis has enabled the identification of a number of noncytokine factors that appear to be associated with atopic inflammation. These include the calcium-binding protein S100A8, serum amyloidA and a number of protease inhibitors, as well as genes involved in epidermal barrier formation, innate immunity receptors, cell cycle proteins and apoptosis. The development of AD in dogs is characterized by the development of a delicate balance between a variety of T-cell phenotypes and inflammatory mediators, including cytokines, chemokines and noncytokine factors.

Review: The role of antibodies, autoantigens and food allergens in canine atopic dermatitis.

Canine atopic dermatitis (AD) is considered to be an immunoglobulinE (IgE)-mediated hypersensitivity response to environmental allergens. The role of other antibody isotypes and nonenvironmental allergens in disease pathogenesis remains unclear. The objective of this review is to provide an update on advances in the understanding of the relevance of specific antibody isotypes, autoallergens and nonenvironmental allergens in the pathogenesis of canine AD. Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed. Where necessary, older articles were included for background information. Neither total nor allergen-specific IgE necessarily correlates with clinical disease in canine AD. Some dogs exhibit clinical signs that are indistinguishable from AD but have no demonstrable allergen-specific IgE (atopic-like dermatitis). Allergen-specific immunoglobulinG may be demonstrated in canine AD, but there is no evidence that this isotype plays a role in disease development. Although humans with AD may develop serum IgE against autoallergens, this finding has not been substantiated in the dog. In contrast, adverse food reactions are frequently co-associated with AD in the dog. Ingestion of food and environmental allergens may trigger exacerbations of AD. Determination of the role of IgE in the pathogenesis of canine AD still requires clarification. Clinical trials and research studies must distinguish atopic dogs with allergen-specific IgE orskin test reactivity from those without. There is no convincing evidence demonstrating a pathogenic role for either allergen-specific immunoglobulinG or autoallergens in canine AD, but food items may be triggers for disease flares in certain individuals.

Review: Innate immunity, lipid metabolism and nutrition in canine atopic dermatitis.

The pathogenesis of canine atopic dermatitis (AD) involves dysfunction of the adaptive immune system. Recent evidence suggests that nonantigen-specific inflammatory elements may play a role in the development and perpetuation of canine AD. The objective of this review is to provide an update on recent advances in the understanding of the role of innate immune cells, keratinocytes, lipid metabolism and nutrition in the pathogenesis of AD in dogs. Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 are reviewed in this update. Where necessary, older articles are included for background information. Members of the innate immune system (including dendritic cells, Langerhans cells and mast cells) and keratinocytes interact with each other and with environmental antigens during both induction and effector phases of atopic inflammation. The responses of these cells and associated noncellular factors (such as complement and protease-activated receptors) to environmental stimuli influence the entire future course of the immune response to a given agent. Abnormalities in lipid metabolism may also influence the pathogenesis of canine AD via the production of inflammatory mediators and by alteration of epidermal barrier function and antigen presentation. However, a lack of fully controlled studies precludes definitive interpretation of these data. Evidence indicates that the cells and noncellular components of the innate immune system and the epidermis may play critical roles during both the sensitization and the effector phases of canine AD. Derangements in lipid metabolism may be involved in the pathogenesis of AD in dogs, but additional controlled studies are required in this area.

Review: Role of genetics and the environment in the pathogenesis of canine atopic dermatitis.

Multiple levels of evidence support the role of genetics and the environment in the pathogenesis of canine atopic dermatitis (AD). This review summarizes the current evidence in genetics and the effect of environmental factors on the development and perpetuation of canine AD. Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed in this update. Where necessary, older articles were included for background information. Canine AD is a heritable disease, in which interaction with environmental factors influences disease risk and phenotype. A study of British guide dogs indicated that nearly 50% of the risk of developing AD was determined by an individual's genotype. Genomic studies performed so far in canine AD have uncovered numerous gene candidates likely to be involved in pathogenesis through their role in immunity, skin barrier formation, apoptosis and inflammation. In addition to genetics, there is evidence to suggest that exposure to certain environmental factors influences the prevalence and course of canine AD. For example, living in rural areas or feeding noncommercial diets was negatively associated with the development of AD in dogs, while exposure to high levels of smoke was associated with increased prevalence of allergic skin disease. It is becoming clear that canine AD is genotypically complex and influenced by a variety of environmental factors. Well-designed studies with sufficient statistical power will be critical to identify the complex genetic and environmental factors involved in disease development and progression. Recognition of such factors may help to identify new targets for therapy and enable better disease prevention and management.