Background

An adverse food reaction, specifically food allergy, is a phenomenon that has been studied in depth in humans. Unfortunately, very little scientific data have been collected for this disease in dogs and cats. Studies that have been performed in animals have not proven an immunologic mechanism. In addition, these studies were not consistent in their choice of an elimination diet (home prepared versus commercially prepared), the length of the trial, and whether rechallenging with the original diet was performed at the end, making interpretation of results and comparisons difficult.¹ Since it is possible that canine and feline food allergy is analogous to the human disease, it is important to review what is known about the pathophysiology in humans.

Immunopathogenesis in Humans

In humans, adverse food reactions may be either nonimmunologic or immune-mediated.^2,3 Nonimmunologically mediated reactions consist of toxic reactions and food intolerance. Toxic reactions typically are dose related and may affect many individuals without previous exposure or sensitization. An example of a toxic reaction is food poisoning. Food intolerance is mediated by a variety of nonimmunologic mechanisms, including metabolic, pharmacologic, and idiosyncratic mechanisms.³ This reaction, like toxic reactions, does not require previous exposure and is typically dose related. In contrast to toxic reactions, food intolerance affects only a small population of individuals in a group. Examples of food intolerance include humans with lactase deficiency (metabolic mechanism), histidine conversion to histamine in poorly preserved fish, or reactions to foods that contain caffeine (pharmacologic mechanisms).³

There are four types of immunologically mediated adverse food reactions described in humans.^3,4 They are Type I hypersensitivity (including both immediate and late-phase reactions), Type III hypersensitivity (immune complex), Type IV hypersensitivity (delayed or cell-mediated immunity), and lastly a combination of both Type I and Type IV hypersensitivities (mixed reaction).^3–5

Before hypersensitivity reactions are described, there are a few concepts that need to be understood. Lymphocytes are small round cells found in blood, lymph, lymphoid organs, and tissues. They are responsible for recognizing foreign antigens and mounting immune responses, both antibody mediated and cell mediated.⁶ Lymphocytes are a heterogeneous group of cells that may be defined by their cell surface proteins. These proteins include cell surface receptors (e.g., CD4, CD8) and adhesion molecules (integrins, selectins or immunoglobulin superfamily). CDs (clusters of differentiation) are cell-surface molecules that have been detected with monoclonal antibodies. Adhesion molecules are cell-surface structures that mediate cell-to-cell or cell-to-matrix binding and interaction. These molecules help regulate cell-to-cell signaling and are also responsible for the movement of lymphocytes in tissues. Lymphocytes may also be differentiated by the types of cytokines they produce when activated (e.g., IL-2, IL-4). Cytokines are proteins or glycoproteins secreted from cells that function in cell-to-cell communication. They regulate the immune response by cells by controlling cellular interactions, cell growth, secretion, and function. Lymphocytes may also be segregated based on their organ of origin. Those that originate in the thymus are called T-cells, whereas those that originate in the bone marrow (bursa of Fabricius in birds) are known as B-cells.⁶

Major histocompatibility complex (MHC) molecules are specialized cell-surface glycoprotein receptors that are involved in antigen presentation to T-cells. MHC I receptors are present on most nucleated cells, while MHC II receptors are constitutively present only on professional antigen-presenting cells (macrophages, B-cells, dendritic cells). The presentation of antigen to T-cells must be in the context of antigen-MHC II in order to activate the T-cell.⁶

Type I hypersensitivity is biphasic, with an immediate reaction that is followed by a late-phase reaction. The immediate hypersensitivity Type I reaction is immunoglobulin E (IgE) mediated and requires prior exposure (sensitization phase). When a susceptible individual is exposed a second time to a complete antigen (elicitation phase), this antigen cross-links two IgE molecules that are bound to mast cells. This causes release of preformed molecules (histamine, serotonin, tryptase, chymases, carboxypeptidases, kallikreins, proteoglycans [chondroitin sulfate], eosinophilic chemotactic factor of anaphylaxis [ECF-A], neutrophilic chemotactic factor of anaphylaxis [NCF-A], and heparin) within seconds from the mast cell granules.⁴ These preformed mediators, having vasoactive properties, are responsible for the wheal and flare associated with degranulation of mast cells. There are lipid metabolites (LTB4, LTC4, PAF, PGD₂), which are synthesized and secreted in minutes. Lastly, there are cytokines (IL2, IL6, IL13, TNFα), which are synthesized and secreted, but this occurs hours after the initial mast cell degranulation. These cytokines are responsible for the late-phase reactions. Symptoms associated with these inflammatory mediators include pruritus, urticaria, and anaphylaxis.^4,6,7

Late-phase reaction is the second part of the biphasic Type I hypersensitivity reaction, and it is also dependent on mast cell degranulation. However, in contrast to the immediate reaction that occurs within minutes and resolves within an hour, this reaction occurs 2 to 8 hours after mast cell degranulation. The cytokines that are released from mast cells activate and attract neutrophils and eosinophils to the skin about 6 hours after exposure. Eight to 24 hours after cytokine release, the influx of inflammatory cells changes to primarily mononuclear cells. These are primarily CD4⁺ T-cells, specifically Th₂ αβ cells and CD1+ dermal dendritic cells.^4,6,7

Type III hypersensitivity (immune complex deposition, serum sickness) involves deposition of circulating antigen-antibody complexes. Soluble antigen needs to be in circulation for prolonged periods (typically more than 6 days) so that when the antibody is produced there is circulating antigen to bind. The immune complex typically involves immunoglobulin G (IgG) or immunoglobulin M (IgM), which are able to fix complement. The immune complexes are then deposited in tissues (blood vessels, kidneys, joints), and there is activation of complement, which attracts neutrophils. Neutrophils cause tissue damage by releasing proteases and reactive oxygen metabolites. Clinical signs may include arthralgias, fever, edema, and maculopapular or urticarial lesions.^4,6,7

Type IV (delayed) hypersensitivity reaction is the only one of the hypersensitivities that does not involve antibody formation. Instead, it involves primarily macrophages and T-cells. An antigen (frequently an incomplete antigen known as a hapten) combines with a host molecule (frequently a protein) and forms a complete antigen. This antigen is phagocytized by antigen-presenting cells. The antigen-presenting cells process the antigen and then present the antigen on their surfaces via MHC II molecules. These antigen-bearing, antigen-presenting cells are poor stimulators of unprimed T-cells. These cells leave the gastrointestinal (GI) tract and migrate to the regional lymph node. During this journey they undergo profound phenotypic changes, thereby acquiring the ability to evoke a strong antigen-specific response in resting T-cells in the lymph node. Upon subsequent exposure (elicitation phase), the antigen-presenting cell will again phagocytize the antigen, process it, and present it on its cell surface complexed with a MHC II molecule. The antigen-presenting cell then presents this antigen–MHC II molecule to an antigen-specific, primed T-cell. This complex is very effective in activating primed T-cells. T-cells that have cutaneous lymphocyte antigen (CLA—a glycoprotein receptor on T-cells that is responsible for the migration of the T-cell through the skin) on their surfaces are then attracted to and migrate through the skin. These activated T-cells (CD4⁺ Th1-cells) release cytokines that damage the tissues (IFNγ and TNFα) and also help activate cytotoxic T-cells (CD8⁺) by up-regulating MHC I molecule expression on cells (IFNγ). Whether the first phase of a Type IV hypersensitization reaction (sensitization phase) occurs in the intestinal mucosa or to an absorbed antigen is unknown. Cutaneous signs include erythema, exudation, erosion, and ulceration.^4,6,7

As in the skin, the GI tract has many defense mechanisms to prevent absorption of potential antigens.^3,4,7 These include the following:

Many antigens that penetrate the GI tract elicit oral tolerance.^3,4 Tolerance is the immunologic unresponsiveness of an individual to an antigen.⁶ Oral tolerance may involve active cellular suppression via T suppressor cells or suppressor cytokines (IL10, TGFβ). Tolerance may also occur via clonal anergy. Clonal anergy is the prolonged, antigen-specific suppression of a clone of T-cells. In order for an antigen-presenting cell to activate a T-cell, the T-cell must receive multiple signals. One signal is the binding of the antigen-presenting cell via its MHC II–antigen complex. Second signals are provided by the binding of CD80 or CD86 on the antigen-presenting cell to CD28 on the T-cell. If an antigen-presenting cell only binds its MHC II–antigen complex to the T-cell receptor without supplying a second signal, or if an antigen alone binds to the T-cell receptor without its MHC II molecule, anergy occurs. When low doses of antigen are present, active cellular suppression occurs. High doses of antigen exposure will provoke clonal anergy.^4,6

Development of a food allergy occurs when there is a defect in the barrier function or digestive ability of the GI tract and subsequent absorption of foreign antigens. Complete digestion of food protein results in the production of free amino acids and small peptides, which are probably poor antigens. Thus an incompletely digested food protein has a greater potential to incite an allergic response. In the susceptible individual, one with a defective immune system, sensitization to these antigens then occurs. Most of these antigens that cause food allergy are water-soluble glycoproteins that are heat, acid, and protease stable. Multiple factors determine whether a substance is able to elicit an immune response. These include the following:

Food allergy in humans most commonly occurs in infancy and early childhood.³ Factors in humans in this age group that may contribute to food allergy include the following:

In humans, food allergy occurs in 33% to 38.7% of infants and young children with atopic dermatitis.^1,3 Food allergy, especially in children, is associated with a Type I (IgE-mediated) hypersensitivity reaction.^1,3,7,9 Not surprisingly, this reaction is characterized by an acute onset of symptoms (urticaria, angioedema, and anaphylaxis). There is also a subset of patients with a Type IV (cell-mediated) reaction that is characterized by subacute or chronic symptoms (eczema).³

Since the occurrence of food allergy—that is, an immunologically based reaction to food—has not been well documented in dogs and cats, cutaneous adverse food reaction is a more accurate term.¹ Even though there have been a few reports of naturally occurring IgE-mediated food allergy in dogs,^10,11 the immunologic pathogenesis of food allergy in dogs and cats has not been well established. Whether dogs and cats have the same immunologic basis for cutaneous adverse food reaction as occurs with food allergy in humans awaits determination.

Signalment and History

Whether the disease is called cutaneous adverse food reaction or a food allergy in dogs and cats, many things are known about this disease. The following discussion addresses the facts that are known concerning cutaneous adverse food reactions.

In dogs, there is no age, sex, or breed predilection.⁴ The age of onset in dogs varies from as young as 4 months to as old as 12.5 years.⁹ However, neonatal puppies exhibiting otitis externa due to a cutaneous adverse food reaction may be “cured” before seeing a specialist for their skin disease. The index of suspicion for cutaneous adverse food reactions exceeds environmental allergen–induced atopic dermatitis (atopy) when the onset of clinical signs occurs in geriatric dogs.

In cats, the Siamese may be predisposed, but any breed can be affected.^4,5 The age of onset ranges from 3 months to 11 years (mean 4 to 5 years).

Historical information that would be consistent with cutaneous adverse food reaction would include nonseasonal pruritus, recurrent or unresolved otitis externa, bacterial pyoderma, and Malassezia dermatitis. Responsiveness of pruritus to antiinflammatory doses (¼ mg/pound q 12 hours orally) of prednisone or prednisolone varies from complete to poor. Therefore if a pruritic dog is poorly responsive to glucocorticoids, diseases such as uncomplicated environmental allergen–induced atopic dermatitis (atopy) are very unlikely, while cutaneous adverse food reaction would still be likely. If a pruritic dog responds well to glucocorticoids, both environmental allergen–induced atopic dermatitis (atopy) and cutaneous adverse food reaction would be ruled out. The only consistent sign of cutaneous adverse food reaction is pruritus. The distribution of the pruritus is not much different than that of dogs with environmental allergen–induced atopic dermatitis (atopy) (face, feet, flexor surfaces of the limbs and folds) or with flea allergy dermatitis (rump and tail head). However some dogs have a propensity for otic and perineal pruritus. As with environmental allergen–induced atopic dermatitis (atopy), dogs with cutaneous adverse food reaction may only have otic disease. In one study, 20% of dogs with cutaneous adverse food reaction had only otitis externa as the presenting clinical sign.¹² Of these dogs, there were a number who had only unilateral disease.¹³ Otitis externa as the only presenting sign is more common in dogs with cutaneous adverse food reaction than in environmental allergen–induced atopic dermatitis (atopy).¹⁴ Dogs and cats with otitis externa may show very little, if any, clinical signs, in which case the diagnosis is established only by otoscopic examination. This occurs most commonly, in the author’s experience, in dogs or cats having previous episodes of otitis externa. It appears that some animals become somewhat tolerant of otitis externa if they have experienced it previously. More commonly, dogs and cats show (any or all of) the following clinical signs:

Stay updated, free articles. Join our Telegram channel

Join