Focus in Patophysiology of Food Allergy

Food allergies, defined as an adverse immune response to food proteins, affect as many as 6% of young children and 3%-4% of adults in westernized countries, and their prevalence appears to be rising. In addition to well-recognized acute allergic reactions and anaphylaxis triggered by IgE antibody-mediated immune responses to food proteins, there is an increasing recognition of cell-mediated disorders such as eosinophilic gastroenteropathies and food protein-induced enterocolitis syndrome. We are gaining an increasing understanding of the pathophysiology of food allergic disorders and are beginning to comprehend how these result from a failure to establish or maintain normal oral tolerance. Many food allergens have been characterized at a molecular level, and this knowledge, combined with an increasing appreciation of the nature of humoral and cellular immune responses resulting in allergy or tolerance, is leading to novel therapeutic approaches.

Food allergies, defined as an adverse immune response to food proteins, affect as many as 6% of young children and 3%–4% of adults in westernized countries, and their prevalence appears to be rising. In addition to well-recognized acute allergic reactions and anaphylaxis triggered by IgE antibody–mediated immune responses to food proteins, there is an increasing recognition of cell-mediated disorders such as eosinophilic gastroenteropathies and food protein–induced enterocolitis syndrome. We are gaining an increasing understanding of the pathophysiology of food allergic disorders and are beginning to comprehend how these result from a failure to establish or maintain normal oral tolerance. Many food allergens have been characterized at a molecular level, and this knowledge, combined with an increasing appreciation of the nature of humoral and cellular immune responses resulting in allergy or tolerance, is leading to novel therapeutic approaches.

Generally, introduction of allergens through the digestive tract is thought to induce immune tolerance. In individuals who are predisposed to developing allergies (atopic syndrome), the immune system produces IgE antibodies against protein epitopes on non-pathogenic substances, including dietary components. The IgE molecules are coated onto mast cells, which inhabit the mucosal lining of the digestive tract. Upon ingesting an allergen, the IgE reacts with its protein epitopes and release (degranulate) a number of chemicals (including histamine), which lead to oedema of the intestinal wall, loss of fluid and altered motility. The product is diarrhea. The eight most common food allergies in North America and Europe are to eggs, milk, peanuts, soy, fish, shellfish, tree nuts, and wheat. Any food allergy has the potential to cause a fatal reaction.

Currently, management of food allergies consists of educating the patient to avoid ingesting the responsible allergen and initiating therapy if ingestion occurs. However, numerous strategies for definitive treatment are being studied, including sublingual/oral immunotherapy, injection of anti-IgE antibodies, cytokine/anticytokine therapies, Chinese herbal therapies, and novel immunotherapies utilizing engineered proteins and strategic immunomodulators.

Patophysiology

• Allergic reactions are hyperactive responses of the immune system to generally innocuous substances. When immune cells encounter the allergenic protein, IgE antibodies are produced; this is similar to the immune system’s reaction to foreign pathogens. The IgE antibodies identify the allergenic proteins as harmful and initiate the allergic reaction. The harmful proteins are those that do not break down due to the strong bonds of the protein. IgE antibodies bind to a receptor on the on the surface of the protein, creating a tag, just as a virus or parasite becomes tagged. It is not entirely clear why some proteins do not denature and subsequently trigger allergic reactions and hypersensitivity while others do not.
• Hypersensitivities are categorized according to the parts of the immune system that are attacked and the amount of time it takes for the response to occur. There are four types of Hypersensitivity reaction: Type 1, Immediate IgE-mediated, Type 2, Cytotoxic, Type 3, Immune complex-mediated, and Type 4, Delayed cell-mediated.  The pathophysiology of allergic responses can be divided into two phases. The first is an acute response that occurs immediately after exposure to an allergen. This phase can either subside or progress into a “late phase reaction” which can substantially prolong the symptoms of a response, and result in tissue damage.
• Many food allergies are caused by hypersensitivities to particular proteins in different foods. Proteins have unique properties that allow them to become allergens, such as stabilizing forces in the tertiary and quaternary structure which prevent degradation during digestion. Many theoretically allergenic proteins cannot survive the destructive environment of the digestive tract and thus don’t trigger hypersensitive reactions
• Food allergies are primarily the result of immune responses to food proteins. Normally, noninflammatory immune responses develop to ingested foods in a process called oral tolerance. For reasons that remain unclear, but likely include environmental and genetic factors, tolerance may be abrogated, leading to adverse immune responses. While sensitization (eg, development of an immunoglobulin E [IgE] immune response) to an allergen has been primarily assumed to occur from ingestion, this may not always be the case. For example, oral allergy syndrome (pollen-food related syndrome) describes an allergic response to specific raw fruits or vegetables that share homologous proteins with pollens; the initial route of sensitization is respiratory exposure to pollen proteins rather than oral exposure to food proteins. The skin may be another potential route of sensitization. 
• IgE antibody – mediated responses are the most widely recognized form of food allergy and account for acute reactions. Patients with atopy produce IgE antibodies to specific epitopes (areas of the protein) of one or more food allergens. These antibodies bind to high-affinity IgE receptors on circulating basophils and tissue mast cells present throughout the body, including the skin, gastrointestinal tract, and respiratory tract.
• Subsequent allergen exposure binds and cross links IgE antibodies on the cell surface, resulting in receptor activation and intracellular signaling that initiates the release of inflammatory mediators (eg, histamine) and synthesis of additional factors (eg, chemotactic factors, cytokines) that promote allergic inflammation. The effects of these mediators on surrounding tissues result in vasodilatation, smooth muscle contraction, and mucus secretion, which, in turn, are responsible for the spectrum of clinical symptoms observed during acute allergic reactions to food.
• Cell-mediated responses to food allergens may also mediate allergic responses, particularly in disorders with delayed or chronic symptoms. For example, food protein – induced enterocolitis syndrome (FPIES), a gastrointestinal food allergy, appears to be mediated by T-cell elaboration of the cytokine tumor necrosis factor (TNF)-alpha. Persons with atopic dermatitis that flares with ingestion of milk have been noted to have T cells that, in vitro, express the homing receptor cutaneous lymphocyte antigen, which is thought to home the cell to the skin and mediate the response.  Celiac disease is the result of an immune response to gluten proteins in grains; this disorder is reviewed in the eMedicine Pediatrics article Celiac Disease.
• Food allergens are typically water-soluble glycoproteins resistant to heating and proteolysis with molecular weights of 10-70 kd. These characteristics facilitate the absorption of these allergens across mucosal surfaces. Numerous food allergens are purified and well-characterized, such as peanut Ara h1, Ara h2, and Ara h3; chicken egg white Gal d1, Gal d2, and Gal d3; soybean-Gly m1; fish-Gad c1; and shrimp-Pen a1. Closely related foods frequently contain allergens that crossreact immunologically (ie, lead to the generation of specific IgE antibodies detectable by skin prick or in vitro testing) but less frequently crossreact clinically. Recently, delayed allergic reactions to meat proteins have been attributed to reactions to carbohydrate moieties

Mechanism of Food Allergy

• Normally, there is a delicate balance of the gastrointestinal mucosal immune system distinguishing between potentially harmful pathogens, beneficial commensal bacteria, and harmless food allergens which do not induce active immune responses. The mechanisms by which ingested proteins are able to interact with unique populations of antigen presenting cells leading to suppression of cellular and humoral immune responses has been termed oral tolerance. This has been demonstrated in a murine model in which subcutaneous antigen exposure resulted in cell-mediated and humoral responses to the antigen in vitro, but mice that were first orally exposed to the antigen then immunized subcutaneously had decreased immune responses in vitro.  Transfer of T cells from the orally fed mice to naïve mice resulted in decreased immune responses as well. Different mechanisms of tolerance can occur depending on the dose of allergen exposure. Studies suggest that “high dose” tolerance is due to deletion of effector T cells, whereas “low dose” tolerance involves activation of regulatory T cells.
• Loss of oral tolerance can occur or may be bypassed by antigen presentation via alternative routes, such as through cutaneous exposures or via the respiratory tract. Using a murine model, epicutaneous or epidermal exposure to peanut was demonstrated to induce Th2 immune responses and promoted allergic sensitization. In addition, higher rates of peanut allergy have been found in children with atopic dermatitis who used topical creams containing peanut oil (OR 6.8). Respiratory exposures are seen in pollen-food syndrome (PFS), an IgE-mediated allergy that is due to cross-reacting proteins in pollens (the initial sensitizing allergen) and foods, which results in oropharyngeal symptoms to raw fruits and vegetables.
• Breakdown of oral tolerance can also occur as a result of defective regulatory T cells. The disorder of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is due to a mutation in the FOXP3 gene, a transcription factor on CD4+CD25+ regulatory T cells that has been implicated in blocking Th1 and Th2 responses. Atopic dermatitis and food allergies are known manifestations of this disorder.  The importance of T regulatory cells in tolerance was also demonstrated in a study of non-IgE milk allergy. The development of tolerance to milk was associated with higher numbers of circulating CD4+CD25+ regulatory T cells.

Host factors

• Several host factors can influence the development of food allergies. Different mouse strains are not equally susceptible to food allergies, suggesting that genetic predisposition is important. Furthermore, the age of exposure to food allergens can determine whether tolerance or allergy develops. In a murine model, sensitization occurred when mice were orally fed ovalbumin in the first week of life, however, tolerance was induced when the mice were orally exposed to ovalbumin at 2-3 weeks of age. In humans, epidemiologic studies show a higher rate of food allergies in young children as compared to adults,  suggesting that gut maturity may be a factor in the development of food allergies. On the other hand, population studies suggest that early introduction may be beneficial in some cases. In Israel, where infants are fed peanut proteins starting at an early age, there is a lower incidence of peanut allergy as compared to the UK where peanut is not introduced to children until a much later age.  The Learning Early About Peanut Allergies (LEAP) study is currently exploring the role of timing of peanut allergen exposure in the development of peanut allergy.
• Several studies suggest that disruption of normal gut barrier functions, such as gastric pH and commensal bacteria, can increase the risk of food allergies. Gastric digestion normally serves to breakdown food proteins, and in many cases destroys immunogenic epitopes in the process. The role of gastric acidity was investigated by Untersmayr et al. using a murine model. Mice fed caviar extract in combination with antacids had elevated specific IgE and demonstrated immediate skin reactivity to the protein after immunization. However, mice which were not fed antacids did not demonstrate these immunologic responses, suggesting that use of antacid medications increased the risk of food allergen sensitization. In a human study of 152 patients on antacid treatment for dyspepsia, increased food allergen sensitization was seen in 25% after 3 months.  Gastric enzymes can affect allergenicity of food proteins. Specifically, the allergenicity of ovomucoid has been demonstrated to be reduced after gastric digestion.  Additionally, commensal bacterial serve an important role. Mice raised in a germ-free environment do not develop normal tolerance,  and mice treated with antibiotics or those lacking in toll like receptor 4 (TLR4) are more easily sensitized to peanut than wild-type control mice.
• Additional host factors can modulate the clinical response of food allergy. For example, asthma has been shown to be a risk factor for more severe anaphylaxis. In a study of fatal food allergic reactions, the majority of victims had underlying asthma.  Host factors such as exercise, use of medication (alcohol, aspirin, beta-blockers, angiotensin converting enzyme inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants), and concurrent infection may increase the severity of anaphylactic reactions or diminish the efficacy of epinephrine. Recently, low serum platelet-activating factor acetylhydrolase (PAF-AH) activity has been found to be a risk factor for more severe food-induced anaphylaxis.

Food allergen factors

• Food allergies can produce an array of clinical symptoms. The presence of specific IgE to sequential or conformational epitopes can distinguish between different phenotypes of milk and egg allergy. Several studies show that binding of conformational epitopes is associated with transient allergy to milk and egg whereas binding of sequential epitopes in these proteins is a marker for persistent allergy. Recent studies demonstrate that the majority of milk and egg allergic individuals can tolerate extensively heated or baked forms of these foods,  indicating that these individuals identify conformational epitopes that are disrupted by heating. Furthermore, studies show that different patterns of epitope recognition or epitope diversity may correlate with clinical manifestations of allergic reactions to peanut and milk.
• Although heating appears to render many proteins less allergenic, heating does not have the same effect on all food proteins. Roasting peanuts involves very high temperatures, and this causes a Maillard reaction leading to increased stability and allergenicity of peanut allergens. This finding may explain the differences in prevalence of peanut allergy in the U.S. where peanuts are primarily consumed in the roasted form and China where boiled or fried peanuts predominate.
• Additional properties of peanut make it a highly allergenic protein. Glycosylated Ara h 1, a major peanut allergen, has been shown to act as a Th2 adjuvant by activating dendritic cells to drive Th2 cell maturation.
• In contrast, deglycoslyated Ara h 1 did not activate dendritic cells. Recently, peanut proteins were shown to have the ability to induce production of complement (C3a) leading to increased platelet-activating factor and histamine production by macrophages, basophils, and mast cells

 Acute response and Late-phase response

• Acute response.  In the early stages of allergy, a type I hypersensitivity reaction against an allergen, encountered for the first time, causes a response in a type of immune cell called a T_H2 lymphocyte, which belongs to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These T_H2 cells interact with other lymphocytes called B cells, whose role is the production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage are sensitized to the allergen.
• If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule, and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, the allergen, and the mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system and eczema is localized to the dermis.
• Late-phase response After the chemical mediators of the acute response subside, late phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils, and macrophages to the initial site. The reaction is usually seen 2–24 hours after the original reaction. Cytokines from mast cells may also play a role in the persistence of long-term effects. Late phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils, and are still dependent on activity of T_H2 cells

Degranulation process in allergy.

1 – antigen;

2 – IgE antibody;

• 3 – FcεRI receptor;
• 4 – preformed mediators (histamine, proteases, chemokines, heparine);
• 5 – granules;
• 6 – mast cell;
• 7 – newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)

 

Protein structure, function  and organization

• Proteins are composed of amino acid monomers linked by peptide bonds.  The higher order structure of a protein depends on the sequence of amino acids which form its primary sequence, as various non-covalent interactions between these amino acids ensure proper protein folding. Proteins have specific amino acid sequences, which all identical proteins share.
• A protein’s secondary structure is created by hydrogen-bond interactions between the amide and carboxyl groups of the amino acid backbone. Secondary structure includes the formation of alpha helices and beta sheets.
•  The tertiary structure is the overall shape of the protein, and is usually driven by the protein’s tendency to orient hydrophobic amino acid side chains internally, although hydrogen bonding, ionic interactions and disulfide bonds also help to stabilize proteins in the tertiary state  Quaternary structure is the overall combination of polypeptide subunits to form the functional unit.
• Protein function. Protein folding is essential to the overall function of the individual protein; some protein structures allow them to resist degradation in the acidic environment of the digestive tract.Polypeptide chains are often very long and flexible, which leads to a wide variety of ways for a protein to fold. Non-covalent interactions control the shape and structure of the nascent protein. A protein’s proper amino acid sequence is absolutely required to induce proper folding into the quaternary structure. Two common folding patterns seen in proteins are the alpha helix and beta sheets.

 

• The gastrointestinal tract plays an important role in the mucosal immune response. While acting as a conduit allowing the transfer of nutrients from the intestinal lumen to the systemic circulation, it also protects against invasion by microbes and other antigens by the induction of an immune response. A downregulation of these immune responses to nonharmful antigenic substances is termed oral tolerance. A breakdown or underdevelopment of oral tolerance may therefore lead to the development of food allergy. Adverse immunologic reactions to food may be a consequence of both IgE- and non-IgE-mediated mechanisms. Although genetic factors play a major role in the development of allergic disease, other factors involved in an immature mucosal immune response have been implicated. Non-IgE-mediated allergic responses tend to involve a T cell-mediated delayed hypersensitivity reaction, and released cytokines act as determinants of the immune response. The “hygiene hypothesis” proposes that a reduction in infections in early infancy predisposes to allergic responses. Early childhood infections promote the induction of a T-helper type 1 response that protects against the development of allergy, which is predominantly a T-helper type 2 response. The role of B cells and T cells in the development of food allergy is incompletely under- stood, but advances in the evaluation and characterization of food allergens has opened exciting new avenues in this study.

Reference :

• Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol. Feb 2010;125(2 Suppl 2):S116-25.
• Scott H. Sicherer and Hugh A. Sampson. Food Allergy: Recent Advances in Pathophysiology and Treatment. Annual Review of Medicine Vol. 60: 261-277 (Volume publication date February 2009)
• Sampson H (2004). “Update on food allergy”. J Allergy Clin Immunol 113 (5): 805–819. http://www.jacionline.org/article/PIIS0091674904011455/fulltext.
• Julie Wang and Hugh A Sampson. Food allergy: recent advances in pathophysiology and treatment. Allergy Asthma Immunol Res. 2009 October; 1(1): 19–29.

 

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