Hypersensitivity type I- food allergies

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INTRODUCTION

Food allergy is a common disorder usually presented in early age and affects 4-8% of children and about 1-2% of the adult population. Once presented mostly in children, it is usual the child outgrow his/her food allergy, and sometimes the food can be reintroduced in an advanced age. Another fact is that the food allergies usually occur on people who have family history of atopic diseases, and infants that are exposed to common allergenic foods have increased risk of developing food allergy later. The heredity is the major factor involved on the development of a food allergy and when both parents are affected the risk of a child develops it doubles. (AL-MUHSEN et al., 2003)

Food intolerance can be caused by many factors, including toxic, immunologic, pharmacologic, metabolic, infectious and neuropsychological processes and about 30% of individuals can develop at least one episode of food intolerance in their lives. The food allergy involves an immunological mechanism and foods that are more likely to develop an allergic reaction are egg, cow`s milk, soy, wheat, tree nuts, peanuts fish and shellfish, and multiple food allergies are rarely seen. The peanuts represent one of the categories that are most commonly associated to severe reactions, as anaphylaxis, and food is the most common reason associated to anaphylaxis in the emergency departments. (CHANDRA et al., 2014) (AL-MUHSEN et al., 2003)

The basic mechanism that underlies the allergic reaction involves a hypersensitivity immune response and usually refers to an immunoglobulin E or type I-mediated hypersensitivity response and recognizing the IgE in patients can be the first step to diagnose it.

Because of the increased incidence and the low probability of self-resolution many studies are made to find an effective treatment based on immunotherapy, and a peanut-specific immunotherapy is currently being discussed as a treatment option.

IMMEDIATE HYPERSENSITIVITY

The basic mechanism behind the allergy reaction is aroused by the immunoglobulin E (IgE)-mediated stimulation when bonded to the mast cells. When in contact with antigens, IgE antibodies are produced to bind to the Fc receptors on mast cells. This complex activated induces the releasing of many mediators that are responsible for vasodilatation, increased vascular permeability, local inflammation and bronchial and visceral muscle contraction. This pathologic reaction is called immediate hypersensitivity. (ABBAS et al., 2003)

When an antigen, also called allergens in these cases, is detected Th2 cells specific for this antigen are activated and starts the production of IgE antibodies, which bind to the Fc receptors of the mast cells and after repeated exposure to the allergen induces the release of mediators (histamine, prostaglandins, leukotrienes, platelet activating factor). After this repeated exposure to the allergen the reactions starts in minutes. The binding of IgE to the mast cells are known as sensitization. (ABBAS et al., 2003)

The immediate hypersensitivity has a strong genetic component and many susceptibility genes were founded as the responsible for the development of the pathologic reaction. These reactions can be manifested in different ways, including mucosal and skin allergies, asthma, food allergy and the extreme systemic form, the anaphylaxis. Atopic individuals have demonstrated a higher production of IgE comparing to normal individuals when in contact to environmental allergens. This IgE synthesis depends on the activation od CD4+ T cells of the Th2 subset and their secretion of IL-4. (ABBAS et al., 2003)

The reactions that happen after the binding of IgE to the mast cells can be divided in two groups. The immediate reaction occurs in vascular and smooth muscle by contact with the mediators, including histamine and leukotrienes. The late-phase reaction happens 4 to 8 hours later and consists of the accumulation of inflammatory leukocytes, such as eosinophils, neutrophils, basophils Th2 and Th9 cells. The late phase is responsible for skin changes, such as swelling, erythema, warmth and pruritis and reduction in pulmonary function. The Th2 cells produce IL-4, IL-5, IL-9 and IL-13, causing the allergic inflammatory response. The Th9 cells produce IL-9, which results on the growth of mast cells and causes inflammatory reactions in the lungs and intestines. IL-9, when combined with TGF-beta, can induce the development of Th17 cells. Th17 cells produce IL-17 and IL-22, which are associated with autoimmune diseases such as psoriasis. The role of the Treg cells seems to be to down-regulate the T effector cell subsets by the production of anti-inflammatory cytokines, such as IL-10 and TGF-beta. These Treg cells suppress Th2 cells, mast cells, basophils, eosinophils and dendritic cells, and can prevent the development of autoimmune diseases. (RACHID et al., 2012)

The allergic components of the peanut identified are proteins of cotyledon and are named Ara h1 to Ara h8. More than 90% of peanut-allergenic patients have IgE antibodies to the proteins Ara h1 and Ara h2. (HUSAIN et al., 2012).

CLINICAL FEATURES

The clinical reactions of peanut allergy can appear from 2 seconds up to 2 hours after the exposure to the peanut protein. The first allergic reaction usually develops in children between 14 and 24 months of age. The symptoms can occur from cutaneous or airborne exposure to peanuts and they are rarely fatal. The reactions that are life-threatening usually occur in adolescents or adults with a history of atopy and asthma, and the presence of this last clinical condition or the delay in the administration of epinephrine are risk factors to the development of anaphylaxis. (AL-MUHSEN et al., 2003)

The most common kinds of exposures are through ingestion, skin contact and inhalation. The clinical symptoms can involve multiple systems such as cutaneous, cardiovascular, gastrointestinal, and respiratory systems. A study made in France detected that the most common reactions were atopic dermatitis (46%), urticarial/angioedema (32%), asthma (15%), generalized anaphylaxis (5%) and gastrointestinal symptoms (3%). Respiratory symptoms were observed in 52% of patients and included repetitive coughing, laryngeal edema, voice change, wheezing and upper and lower respiratory tract symptoms. The gastrointestinal manifestations appeared in 34% of cases. The most severe reaction, the anaphylaxis, includes cutaneous, gastrointestinal and respiratory symptoms, hypotension and dysrhythmia. (HUSAIN et al., 2012).

DIAGNOSIS

The diagnosis of the food allergy starts with a detailed medical history and physical examination. It is important the collection of information such as the time of the beginning of symptoms, the type of symptoms, any allergy history or family history of atopy and the amount of peanut ingested. The confirmation is made by the detection of peanut-specific IgE, by skin prick test or fluoroenzyme immunoassay (ImmunoCAP-FEIA). A wheal 3 mm larger than the negative control can be considered a positive reaction. The results of ImmunoCAP-FEIA are measured semiquantitatively, and the values correlate with probability of clinical reaction but not with the severity of the reaction. Peanut-specific IgE higher than 15kUA/L has 95% predictive value for an allergic reaction on ingestion of peanut. The gold standard to confirm the allergy is a double-blinded placebo controlled peanut food challenge, but in clinical practice is mostly used an open or single-blind challenge. The patient ingests incremental portions of food or placebo and the symptoms of an allergic reaction are documented before each dose. If the allergic reaction occurs, the test is stopped and treatment is provided. (HUSAIN et al., 2012). Because of the increase in the public awareness about peanut allergy, there is an increasing number of false-positives and an appropriate follow-up is necessary to determine the greater of diagnosis and which patients might have outgrown their peanut allergy. (BURKS et al., 2008)

IMMUNOTHERAPY AND DESENSITIZATION

Immunotherapy is a kind of therapy that modulates the immune response to an antigen and desensitization is the ability to increase the amount of food protein required to induce a clinical reaction, while still on regular immunotherapy. The final goal of the immunotherapy is to achieve a state of tolerance, which is the ability of consume great amounts of the food protein after being off the treatment. The immunological changes that occurs in immunotherapy include decreased basophil responses and specific-immunoglobulin IgE, reduction of mast cells reactivity, increased IgG4 and induction of regulatory T cells. (MOUSALLEM et al.,2012).

A few years ago the most used therapy was the Subcutaneous Immunotherapy (SCIT), but it was associated with a very high rate of systemic reactions. Nowadays, the Oral Immunotherapy (OIT) and the Sublingual Immunotherapy (SLIT) have been used more frequently. (RACHID et al.,2012). The SCIT causes an initial increase in allergen-specific IgE followed by eventual decrease, increase in allergen-specific IgG4 and changes from a Th2 response to a Th1 response. OIT is usually made with the administration of small amounts of allergen by oral ingestion to first induce desensitization and then achieve the tolerance to the allergen, if the treatment works well. A study made with children following 4-22 months of maintenance dosing to assess desensitization. In this study, 93% of the children were able to tolerate 3-9g of peanut protein. Immunological changes included smaller titrated skin prick tests and basophils hyporesponsiveness. Peanut-specific IgE decreased and peanut-specific IgG4 increased. Serum factors inhibited IgE-peanut complex formation in an IgE-facilitated allergen binding assay. Secretion of IL-10, IL-5, interferon (IFN)-gama and tumor necrosis factor (TNF)-alfa from peripheral blood mononuclear cells increased over a period of 6–12 months. (MOUSALLEM et al.,2012).

In SLIT a food extract is placed under the tongue and then either swallowed or spit out. In a study with SLIT, this kind of therapy was associated with a decrease in skin prick test wheal size and basophil responsiveness. In the first 4 months there was an increase in the peanut-specific IgE levels and then decreased over the last 8 months, whereas the peanut-specific IgG4 increased during the 12 months. (MOUSALLEM et al.,2012).

Comparing the OIT and the SLIT, the oral route may be inherently associated with tolerance, maybe because the oral intake is associated to nutrient absorption. In SLIT, Langerhans cells within the oral mucosa take up the antigen, which is initially recognized by an allergen-specific IgE bound to the surface of FceR1. These cells also express high levels of MHC class I and II as well as co-stimulatory and co-inhibitory molecules. Another factor that contributes to the efficiency of the natural gastrointestinal mucosa to induce tolerance is the capacity of intestinal epithelial cells and monocytes to produce IL-10 and TGF-beta, which enhance Treg cell generation, the production of antigen-specific IgA and secretory IgA in the intestines, which can reduce the absorption of undigested antigens at the mucosal surfaces through a mechanism known as immune exclusion, preventing inflammatory responses. (RACHID et al.,2012). The mechanisms that results a successful desensitization are not very clear, but may involve similar mechanisms observed in allergen SCIT and SLIT, which includes mast cells and basophil suppression, up-regulation of natural or inducible Treg cells, food specific IgG4 antibodies formation or changes in food specific IgE/IgG4 ratios, a skewing from a Th2 to a Th1 profile and the development of anergy or deletion of allergen-specific cells. (RACHID et al.,2012).

A fact that needs to be mentioned is that most of studies do not include patients with a history of severe anaphylaxis, excluding patients with more severe diseases, who may require modified protocols and slower build-up and longer maintenance phase.

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