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

BACKGROUND: 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. OBJECTIVES: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSIONS AND CLINICAL RELEVANCE: 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.

Update on the role of genetic factors, environmental factors and allergens in canine atopic dermatitis.

BACKGROUND: Canine atopic dermatitis (cAD) is a common, complex and multifactorial disease involving, among others, genetic predisposition, environmental factors and allergic sensitisation. OBJECTIVE: This review summarises the current evidence on the role of genetic and environmental factors and allergic sensitisation in the pathogenesis of cAD since the last review by ICADA in 2015. MATERIALS AND METHODS: Online citation databases and proceedings from international meetings on genetic factors, environmental factors and allergens relevant to cAD that had been published between 2015 and 2022 were reviewed. RESULTS: Despite intensive research efforts, the detailed genetic background predisposing to cAD and the effect of a wide range of environmental factors still need more clarification. Genome-wide association studies and investigations on genetic biomarkers, such as microRNAs, have provided some new information. Environmental factors appear to play a major role. Lifestyle, especially during puppyhood, appears to have an important impact on the developing immune system. Factors such as growing up in a rural environment, large size of family, contact with other animals, and a nonprocessed meat-based diet may reduce the risk for subsequent development of cAD. It appears that Toxocara canis infection may have a protective effect against Dermatophagoides farinae-induced cAD. House dust mites (D. farinae and D. pteronyssinus) remain the most common allergen group to which atopic dogs react. Currently, the major allergens related to D. farinae in dogs include Der f 2, Der f 15, Der f 18 and Zen 1. CONCLUSIONS AND CLINICAL RELEVANCE: Canine atopic dermatitis remains a complex, genetically heterogeneous disease that is influenced by multiple environmental factors. Further, well-designed studies are necessary to shed more light on the role of genetics, environmental factors and major allergens in the pathogenesis of cAD.

Update on the skin barrier, cutaneous microbiome and host defence peptides in canine atopic dermatitis.

BACKGROUND: Canine atopic dermatitis (AD) is a complex inflammatory skin disease associated with cutaneous microbiome, immunological and skin barrier alterations. This review summarises the current evidence on skin barrier defects and on cutaneous microbiome dysfunction in canine AD. OBJECTIVE: To this aim, online citation databases, abstracts and proceedings from international meetings on skin barrier and cutaneous microbiome published between 2015 and 2023 were reviewed. RESULTS: Since the last update on the pathogenesis of canine AD, published by the International Committee on Allergic Diseases of Animals in 2015, 49 articles have been published on skin barrier function, cutaneous/aural innate immunity and the cutaneous/aural microbiome in atopic dogs. Skin barrier dysfunction and cutaneous microbial dysbiosis are essential players in the pathogenesis of canine AD. It is still unclear if such alterations are primary or secondary to cutaneous inflammation, although some evidence supports their primary involvement in the pathogenesis of canine AD. CONCLUSION AND CLINICAL RELEVANCE: Although many studies have been published since 2015, the understanding of the cutaneous host-microbe interaction is still unclear, as is the role that cutaneous dysbiosis plays in the development and/or worsening of canine AD. More studies are needed aiming to design new therapeutic approaches to restore the skin barrier, to increase and optimise the cutaneous natural defences, and to rebalance the cutaneous microbiome.

Canine Pruritus Visual Analog Scale: how does it capture owners' perception of their pet's itching level?

BACKGROUND: Accurate measurement of pruritus severity is difficult in veterinary medicine. OBJECTIVES: To determine how the changes in Pruritus Visual Analog Scale (PVAS) scores at follow-up visits agree with the owners' perceptions of improvement of their pet's pruritus. ANIMALS: One hundred and ninety two pruritic dogs were included in the prospective study and 196 in the retrospective study. METHODS AND MATERIALS: Owners were randomly assigned into five groups and PVAS scores were recorded during two consecutive visits. Group A: previous scores were shown before completing the PVAS; Group B: PVAS was completed then owners were shown previous scores and asked to repeat the PVAS; Group C: PVAS was completed as reported previously; Group D: PVAS and a 0-10 verbal scale (VS) were completed. Retrospectively, PVAS scores were analysed during at least three consecutive visits. The average percentage and kappa agreements were calculated for all groups. In addition, PVAS and VS scores were compared in Group D. RESULTS: The average percentage and kappa agreements were higher in groups A (96%; 0.81), B [before (80%; 0.54), after (82%; 0.59) previous score] and D (85%; 0.47). Group C (79%; 0.37) had the lowest agreement. PVAS and VS scores were not significantly different (P = 0.56) in Group D. The average percentage and kappa agreements for the retrospective study were 50.8% and 0.25. The highest values (63%; 0.355) were noted at 30-60 day visit intervals. CONCLUSIONS AND CLINICAL IMPORTANCE: Showing owners previous scores could improve how PVAS captures the owner's perception of their dog's itching level.

Review: Lymphocytes, cytokines, chemokines and the T-helper 1-T-helper 2 balance in canine atopic dermatitis.

BACKGROUND: 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-helper 2-polarized' lymphocyte response, recent evidence suggests that clinical disease is associated with the development of multiple lymphocyte phenotypes. OBJECTIVES: 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. METHODS: 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. RESULTS: 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-helper 2 but also T-helper 1, T-helper 17 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 amyloid A and a number of protease inhibitors, as well as genes involved in epidermal barrier formation, innate immunity receptors, cell cycle proteins and apoptosis. CONCLUSIONS: 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: Innate immunity, lipid metabolism and nutrition in canine atopic dermatitis.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS AND CLINICAL IMPORTANCE: 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: The role of antibodies, autoantigens and food allergens in canine atopic dermatitis.

BACKGROUND: Canine atopic dermatitis (AD) is considered to be an immunoglobulin E (IgE)-mediated hypersensitivity response to environmental allergens. The role of other antibody isotypes and nonenvironmental allergens in disease pathogenesis remains unclear. OBJECTIVES: 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. METHODS: Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed. Where necessary, older articles were included for background information. RESULTS: 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 immunoglobulin G 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. CONCLUSIONS AND CLINICAL IMPORTANCE: 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 or skin test reactivity from those without. There is no convincing evidence demonstrating a pathogenic role for either allergen-specific immunoglobulin G or autoallergens in canine AD, but food items may be triggers for disease flares in certain individuals.

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

BACKGROUND: Multiple levels of evidence support the role of genetics and the environment in the pathogenesis of canine atopic dermatitis (AD). OBJECTIVES: This review summarizes the current evidence in genetics and the effect of environmental factors on the development and perpetuation of canine AD. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Review: Pathogenesis of canine atopic dermatitis: skin barrier and host-micro-organism interaction.

BACKGROUND: Canine atopic dermatitis (AD) is a common, genetically predisposed, inflammatory and pruritic skin disease. The pathogenesis of canine AD is incompletely understood. OBJECTIVES: The aim of this review is to provide an in-depth update on the involvement of skin barrier and host-microbiome interaction in the pathogenesis of canine AD. METHODS: Online citation databases and abstracts from international meetings were searched for publications related to skin barrier and host-microbiome interaction (e.g. bacteria, yeast, antimicrobial peptides). RESULTS: A total of 126 publications were identified. This review article focuses on epidermal barrier dysfunction and the interaction between cutaneous microbes (bacteria and yeasts) and the host (antimicrobial peptides). Epidemiological updates on the presence of pathogenic organisms and canine AD are also provided. CONCLUSIONS AND CLINICAL IMPORTANCE: Major advances have been made in the investigation of skin barrier dysfunction in canine AD, although many questions still remain. Skin barrier dysfunction and host-microbiome interactions are emerging as primary alterations in canine AD. Based on this review, it is clear that future studies focused on the development of drugs able to restore the skin barrier and increase the natural defences against pathogenic organisms are needed.

Review: Clinical and histological manifestations of canine atopic dermatitis.

BACKGROUND: Many studies focusing on clinical and histological signs of canine atopic dermatitis (AD) have been published since its early descriptions decades ago. Findings of these studies contributed to our current knowledge about the disease pathogenesis and allowed establishment of diagnostic criteria used by clinicians and researchers. OBJECTIVES: This review serves as an update on the clinical and histological features of canine AD published by the American College of Veterinary Dermatology Task Force on Canine Atopic Dermatitis in 2001 and summarizes the recent discoveries in these fields. RESULTS: The overall findings of studies focusing on clinical features mirrored those published by the Task Force in 2001. The novelty was the larger number of animals included in these studies, which allowed establishment of a new set of diagnostic criteria that exceeded the sensitivity and specificity of the previous criteria. The same study uncovered some clinical differences between dogs with food-induced and nonfood-induced AD; however, the authors concluded that these two entities cannot be distinguished based on clinical signs only. Another study demonstrated some major breed-specific phenotypes. Several publications addressed the histological features of canine AD skin lesions in experimental models of AD, but none of those addressed naturally occurring lesions. Nevertheless, the histopathological description of the skin reactions was generally similar to that published by the Task Force in 2001. CONCLUSIONS: Considerable work has been done in recent years to provide a better definition of the clinical appearance and histopathology of canine AD. New sets of diagnostic criteria have been developed, and additional breed-associated differences in phenotypes have been demonstrated.

Isolation of bacterial skin flora of healthy sheep, with comparison between frequent and minimal human handling.

BACKGROUND: Few data are available regarding skin bacterial flora of healthy sheep and meticillin-resistant Staphylococcus carriage. HYPOTHESIS/OBJECTIVES: To compare skin, ear and mucosal bacterial populations between minimally and frequently handled sheep; to determine whether the frequency of meticillin-resistant Staphylococcus aureus varied between groups. ANIMALS: One hundred and three healthy feedlot and show sheep from eight farms. METHODS: Swabs were collected from the dorsum, right ear and right nostril of each sheep. Two groups from each farm were evaluated, except from one farm, which had only one group. Bacterial isolates were identified to the genus or species level using phenotypic analysis or matrix-associated laser desorption/ionization time-of-flight mass spectrometry. Antimicrobial susceptibility testing and spa typing were performed on isolates of S. aureus. RESULTS: Sixteen bacterial genera were identified and 11 staphylococcal species, including S. aureus. The skin and mucosal bacterial flora were compared between the groups. The only statistically significant difference in bacteria was Streptococcus spp. on the dorsum (P = 0.0088), with carriage being more common in frequently handled sheep. Antimicrobial susceptibility testing did not find meticillin-resistant S. aureus. There was no significant difference in S. aureus carriage in the ear (P = 0.33), nostril (P = 0.43) or dorsum (P = 0.053) between frequently and minimally handled sheep. The S. aureus isolates belonged to six different spa types. Three were of the ST398 lineage. CONCLUSIONS AND CLINICAL IMPORTANCE: Sheep are a potential source of livestock-associated meticillin-sensitive Staphylococcus aureus ST398.

Adverse events in 50 cats with allergic dermatitis receiving ciclosporin.

Ciclosporin is an immunosuppressive drug that has been used to treat allergies and other immune-mediated diseases in cats, dogs and humans. Information about the adverse effects of ciclosporin in cats has been limited to smaller studies and case reports. Adverse effects in dogs are mainly gastrointestinal in nature, but humans can also experience hypertension and altered renal function. The aim of this retrospective case series study was to document the occurrence and clinical appearance of adverse events in cats receiving ciclosporin to treat allergic skin disease. The medical records of 50 cats with allergic dermatitis treated with oral ciclosporin (1.9-7.3 mg/kg/day) were reviewed. Adverse events occurred in 66% (33 cats). Adverse events likely to be associated with ciclosporin included the following: vomiting or diarrhoea within 1-8 weeks of receiving ciclosporin (24%), weight loss (16%), anorexia and subsequent hepatic lipidosis (2%) and gingival hyperplasia (2%). Other adverse events less likely to be associated with ciclosporin therapy included the following: weight gain (14%), dental tartar and gingivitis (10%), otitis (4%), chronic diarrhoea (4%), inflammatory bowel disease with indolent gastrointestinal lymphoma (2%), urinary tract infection (2%), cataract (2%), elevated liver enzymes (2%), hyperthyroidism and renal failure (2%) and transient inappropriate urination (2%). Some cats experienced multiple adverse events. Case-control studies are needed to prove cause and effect of ciclosporin with regard to these adverse events.

The expression of histamine H4 receptor mRNA in the skin and other tissues of normal dogs.

The histamine 4 (H(4)) receptor was first cloned and characterized in 2000 using the human H(3) receptor DNA sequence. The H(4) receptor has been shown to participate in various aspects of inflammation, such as chemotaxis, upregulation of adhesion molecule expression and modulation of cytokine secretion. The primary goal of this study was to determine whether H(4) receptor mRNA is expressed in normal canine skin by performing an RT-PCR. An additional goal was to determine the expression of this receptor in the colon, liver, spleen and kidney. Tissues were collected from five healthy, young-adult pit bull dogs. Samples were immediately placed in RNAlater(®) solution and stored at -20°C until processed. The amplified products in all skin samples in addition to the colon, liver, spleen and kidney (variable expression) had the expected size of 400-500 bp. The sequenced amplicons matched the National Center for Biotechnology Information published sequence for the canine H(4) receptor. The study results showed that canine normal skin expresses the H(4) receptor mRNA. Further studies using immunohistochemistry should be conducted to demonstrate the expression of the H(4) receptor at the protein level and to localize the expression of this receptor in the skin.