Adverse skin reactions to food

Introduction

Atopic dermatitis (AD) is a chronic, inflammatory and pruritic dermatopathy that affects genetically predisposed dogs. Advances in understanding its etiopathogenesis suggest that it is a multifactorial clinical syndrome resulting from a complex combination of factors, such as skin barrier abnormalities, immune response dysfunctions and neurogenic hyperreactivity, which lead to recurrent infections and hypersensitivity to environmental allergens, food and/or microorganisms 1. Although allergies to environmental allergens are reported more commonly than adverse reactions to food antigens in dogs with AD, they can occur in up to 50% of AD cases 2, and should be considered whenever there is perennial itching, whether or not there are accompanying gastrointestinal signs. Such cases tend to occur in young dogs and are often difficult to treat/control 3, and can be associated with IgE-dependent reactions or cell-mediated inflammatory reactions to food allergens or dietary components 4. This article will discuss the main food allergens and review the immunological mechanisms and clinical aspects of dogs with chronic pruritus due to food-induced atopic dermatitis (FIAD).

Food allergens

Food allergens are molecules that, when ingested, can trigger hypersensitivity reactions. Proteins appear to be the main food allergens, but carbohydrates and lipids can also be responsible, especially when conjugated to proteins (lipoproteins or glycoproteins) 5. In general, the maximum size of an allergen is related to the absorption capacity of the enteric mucosa for the protein. In humans, food allergens are almost exclusively glycoproteins that are heat-stable, typically water-soluble, and resistant to digestive proteases, with a molecular weight (MW) of 10-70 kDa 6.

In dogs, 78% of reported cases of adverse food reactions (AFRs) are related to allergens found in beef, dairy and wheat, but reactions to chicken, pork and soya are also commonly observed 4. Studies have shown that dogs with AFRs primarily react to IgG, phosphoglucomutase and serum albumin from beef, although cross-reactions can occur due to the homology between ovine and bovine immunoglobulins 5,7. Bovine milk contains around 20 protein components, with β-lactoglobulin, casein, lactalbumin and serum albumin being apparently the most allergenic for dogs 8,9. The main allergens present in chicken meat are serum albumin, along with pyruvate kinase M1/M2, enolase 3, creatine kinase type M, aldolase, glyceraldehyde-3-phosphate dehydrogenase, lactate dehydrogenase, and triose phosphate isomerase 1 10,11. 

In eggs, the prominent proteins are ovomucoid and ovalbumin, along with ovotransferrin, ovomucin, lysozyme, albumin (from egg white), and lipovitellin (a low-density lipoprotein from egg yolk) 5.

Serum albumin may be associated with AFRs to pork, and also alpha-gal, an oligosaccharide expressed in glycoproteins in humans. However, as alpha-gal is produced in the canine body, classical hypersensitivity to this antigen is not triggered in this species 12. Among fish allergens triggering AFRs in dogs, enolase and aldolase are noteworthy 10, and cross-reactions have been observed in dogs between enolase and aldolase proteins from fish and chicken. Serological evaluations in dogs have also identified cross-reactions in various substances (pyruvate kinase, creatine kinase, alpha-actin, dehydrogenase, beta-enolase, aldolase, malate dehydrogenase, lactate dehydrogenase, triose phosphate isomerase, and glyceraldehyde-3-phosphate) present in chicken and fish meats 10. Additionally, a study in dogs using A-RISC (Allergens Relative Identity, Similarity, and Cross-reactivity) demonstrated a high theoretical risk of cross-reaction between food proteins from the same family of proteins in different species (such as l-lactate dehydrogenase from chicken, duck, turkey, ostrich, beef, sheep, horse, pork, rabbit, cod, salmon and alligator) 13.

Adverse food reactions

Adverse food reactions include food hypersensitivity (FH) and food intolerance (FI) 9. FI is classified as a non-immunological response and can be caused by a pharmacologically active ingredient, a reaction to metabolites of certain ingredients, food idiosyncrasy, or pseudo-allergy 14. FH is classified as an immune response to food allergens or dietary components and can be mediated by IgE, leading to immediate hypersensitivity reactions type 1 (FA), a reaction involving the deposition of immune complexes (type 3 hypersensitivity) or chronic cell-mediated inflammation (type 4 hypersensitivity) 14,15. The most common food hypersensitivities in humans are immediate IgE-mediated reactions (type 1). Despite extensive exposure to various food antigens, only a small percentage of individuals develop food hypersensitivity, because a normal immune response to food proteins is associated with the proper induction of oral tolerance 9.

Factors that interfere with the mucosal barrier (e.g., viruses, bacteria, parasites, toxins) can contribute to the development of food allergies, as they can cause increased penetration and abnormal presentation of food antigens to the gut-associated lymphoid tissue (GALT), which encompasses Peyer’s patches, diffuse lymphoid tissue in the lamina propria, enterocytes, and intraepithelial lymphocytes 9. Food allergens may also have resistance to digestive enzymes and heat, bestowing them with an increased ability to penetrate the mucosa’s physiological barrier 9. Other factors that may be linked to the development of FH include an increase in gastric pH, a decrease in peristalsis, and alterations in the superficial enteric mucosa, the tight junctions of enterocytes, or intraluminal IgA 9.

AFR and atopic dermatitis

Atopic dermatitis is an inflammatory, chronic and itchy skin disease resulting from a complex interplay between a decrease in the physical barrier of the epidermis and immunological hyperreactivity, primarily stemming from the inflammatory response related to type 2 helper T lymphocytes (Th2) (Type 2 inflammatory response) 1.

Its clinical signs can be precipitated by environmental allergens, microbial toxins, and primary physical or chemical irritants that actively penetrate the skin. In around 25 to 50% of cases, signs of atopic dermatitis can be precipitated or exacerbated by food allergens, which can be absorbed through the digestive system; however, percutaneous penetration has been demonstrated only in humans. When the precipitating factor for the clinical signs of atopic dermatitis has an environmental origin, it is referred to as atopic dermatitis sensu stricto. When the precipitating factor has a food origin, it is termed food-induced atopic dermatitis (FIAD) 1,2,16 (Figure 1).

The mechanisms for the development of AFR in individual dogs with atopic dermatitis are not yet fully elucidated. In humans, preliminary results indicate that functional defects in the epidermal barrier, related to mutations in the filaggrin gene, are correlated with a higher risk of sensitization to environmental and food allergens with severe atopic dermatitis. Sensitization can occur not only through the intestinal route but also percutaneously 17.

In dogs, one study has concluded that exposure to raw animal-origin foods in puppies seems to have a protective effect on the onset of cutaneous signs of allergy/atopic dermatitis in adulthood. Conversely, exposure of puppies to heat-processed foods, mixed-oil supplements and fruit sugars seemed to favor the onset of cutaneous signs of allergy/atopic dermatitis in adulthood 18.

Skin reactions against food antigens that occur in dogs with atopic dermatitis, just like in humans, can be mixed, whereby food allergens are captured by pro-inflammatory dendritic cells, processed, and their peptides presented to Th0 cells. These in turn become Th2 cells and release cytokines such as IL-4, IL-5, IL-6, IL-13 and IL-31 (Type 2 inflammatory response). IL-4 and IL-13 trigger the proliferation of B lymphocytes, the formation of plasma cells, and the release of specific IgE, initiating the sensitization process 15,19. The secreted IgE will bind to specific receptors on mast cells, basophils, dendritic cells and keratinocytes, activating them whenever they encounter specific allergens, stimulating the integumentary inflammatory process 15,19. Additionally, IL-5 is chemotactic for eosinophils and IL-31 has a significant pruritic effect (Figure 2).

In addition to this type 2 inflammatory response, dendritic cells when binding to the food antigens can initiate a cell-mediated inflammatory response and stimulate the formation of Th1 lymphocytes 12 hours or more after exposure to food 19,20. Th1 cells release inflammatory cytokines such as IL-2, IL-6, interferon-gamma (IFN-γ), and TNF-α, stimulating the migration of cytotoxic T lymphocytes, neutrophils, macrophages and eosinophils 14. These T cells can trigger direct toxic effects, inducing cell apoptosis, or can act to releasing more cytokines that stimulate the cell-mediated immune response 19,20 (Figure 3). This latter event triggers cutaneous inflammation and chronic, perennial pruritus associated with dyskeratosis and cutaneous lichenification in affected animals 20. Continuous and chronic exposure to food allergens may be associated with moderate to severe atopic dermatitis, often affecting large areas of the body surface and with a profound effect on the patient’s quality of life.

Continuous stimulation of the type 2 inflammatory response, via IL-6, can lead to Th0 cells being converted to Th22, and chronic lesions are often associated with upregulation of Th22 cytokines, with a positive correlation between IL-22 mRNA levels and the severity of clinical signs. The upregulation of Th22 is reportedly associated with keratinocyte proliferation, epidermal hyperplasia, hyperkeratosis, and other barrier abnormalities 20.

The inflammatory response can aggravate primary skin barrier disorders, decrease the production of ceramides and antimicrobial peptides, and may perpetuate the penetration of environmental allergens, with further sensitization and prolonged recurrent infections 15.

Clinical aspects

In humans, the prevalence of food allergy is generally higher in infants, and a genetic predisposition for its development is particularly relevant in children with atopic dermatitis 21. It has also been observed that the type of food triggering atopic dermatitis may vary with the patient’s age. In the western world, allergens inducing atopic dermatitis in infants are often found in cow milk, eggs and peanuts, and trophallergens from wheat, nuts, and fish more frequently appear as eczema triggers in older patients 21.

One study in dogs diagnosed with FIAD reported that the initial clinical signs occurred before 1 year of age in 48% of cases and before 3 years of age in 83% of cases, with no seasonal disposition noted 3. West Highland White Terriers, Boxers, Rhodesian Ridgebacks, Pugs and German Shepherd Dogs were predisposed 3, although in another study the Pug, French Bulldog, Lhasa Apso, Shih Tzu, Yorkshire Terrier, Labrador Retriever and Maltese Terrier were the most prevalent breeds 4.

Clinical signs of AFR in dogs with and without atopic dermatitis are variable and may manifest as erythema and chronic, early-onset, recalcitrant, and non-seasonal pruritus in the distal limbs, axillae, inguinal and flexural regions, and otitis, usually associated with self-induced alopecia and excoriations 3. Additionally, perioral and perianal pruritus has been observed 4. In chronic cases, hyperkeratosis, acanthosis and lichenification are frequently seen and are related to the progression of the inflammatory process (Figure 4). Dogs with atopic dermatitis related to food have up to three times more otitis compared to unaffected animals 20, occurring in 26-80% of cases 22,23. Generally, ear infections linked to adverse reactions to food in dogs with atopic dermatitis are bilateral and recurrent, with a tendency to become chronic, and are associated with lichenification, epidermal hyperplasia, stenosis of the ear canals, aural dysbiosis, and middle ear infections 3,4. Recurrent pyoderma and yeast infections are reported to be frequent in FIAD dogs 1,3.

Simultaneous gastrointestinal and dermatological signs are observed in 20-83% of dogs with adverse skin reactions to food, including vomiting (82.2%), diarrhea, flatulence (86.7%), borborygmus (64.4%), tenesmus, abdominal distension, visceral colic, and increased peristaltic movements (8.8%) 24,25.

Finally, although hypersensitivity reactions of type 1 or 4 are related to adverse food reactions in dogs, other hypersensitivity reactions and chronic inflammatory responses have been documented in this species and are responsible for atypical clinical presentations, such as vasculitis and onychitis 26.

Conclusion

Adverse skin reactions to food allergens may be associated with flare and stimulation of the inflammatory course of atopic dermatitis in dogs, causing chronic, intense and non-seasonal pruritus, lichenification, otitis and recurrent infections, which can make the disease recalcitrant and difficult to control. Minimizing exposure to food allergens in dogs with food-induced atopic dermatitis is therefore essential for multimodal control of the disease.