Food allergy is a common disease that is rapidly increasing in prevalence for reasons that remain unknown. Current research efforts are focused on understanding the immune basis of food allergy, identifying environmental factors that may contribute to its rising prevalence, and developing immunotherapeutic approaches to establish immune tolerance to foods. Technological advances such as peptide microarray and MHC class II tetramers have begun to provide a comprehensive profile of the immune response to foods. The burgeoning field of mucosal immunology has provided intriguing clues to the role of the diet and the microbiota as risk factors in the development 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. 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.
Most food allergens share certain specific physicochemical characteristics that allow them to resist digestion, thus enhancing allergenicity. During allergic sensitization, these allergens are encountered by specialized dendritic cell populations in the gut, which leads to T-cell priming and the production of allergen-specific IgE production by B cells. Tissue-resident mast cells then bind IgE, and allergic reactions are elicited when mast cells are reexposed to allergen. Adjacent IgE molecules bound to the surface of the mast cell become cross-linked, causing mast cell degranulation and release of powerful vasoactive compounds that cause allergic symptoms.
There is a complex interplay of environmental influence and genetics that underlie the immunopathogenesis of food allergy and the manifestations of various food-induced allergic disorders. In this issue of the Journal, Oyoshi et al describe insights on etiology determined from murine models. Prior reviews address the role of antigen-presenting cells, T cells, humoral immune responses, homing receptors, signaling pathways, dietary factors, underlying inflammatory states, microbiota, effector cell function, and other aspects of the immune response to dietary antigens. Several observations from clinical studies that have recently revised our understanding of the cause of food allergy.
Food allergy is an immune provocation induced by certain food in susceptible individuals. Most of the food allergic manifestations are evident in the individual having impaired oral tolerance. In spite of worldwide prevalence, there is no permanent cure of food allergy. Food allergic reactions are complex immunological events that comprises of several immune molecules like IgE, IL-4, IL-13 and T-cells, therefore, researchers are trying to pick the correct molecule to find out pivotal therapeutic solutions. Being a key regulatory molecule in suppressing T-cells functional activities, cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) or cluster of differentiation-152 (CD-152) has contributed a novel and revolutionary dimension toward therapeutic research of several diseases. This different immunological and mechanistic perspectives of CTLA-4 in correlation with food allergy.
System for enhanced transepithelial transport of antigen in which both the amount of specific antigen and its rate of transport were dramatically increased in intestine of sensitized rats compared with controls. This study investigated the essential components mediating antigen uptake in mice genetically deficient for interleukin (IL)-4 or CD23. Actively sensitized IL-4+/+, but not IL-4−/− mice, displayed increased transepithelial antigen transport and CD23 expression on enterocytes.Passively sensitized IL-4+/+ and IL-4−/− mice displayed elevated antigen transport after transfer of immune serum but not if the serum was depleted of immunoglobulin (Ig) E or IL-4.IL-4 added to cultured IEC-4 cells up-regulated expression of CD23 messenger RNA.The augmented antigen uptake was inhibited by anti-CD23 and was absent in sensitized CD23−/− mice. Theses studies indicate that IL-4 regulates IgE/CD23-mediated enhanced transepithelial antigen transport in sensitized mouse intestine.
Immune tolerance is defined as nonresponsiveness of the adaptive immune system to antigens. Immune mechanisms preventing inappropriate immune reactivity to innocuous antigens include deletion of reactive lymphocytes and generation of regulatory T (Treg) cells. The normal response to food antigens is the generation of antigen-specific Treg cells. In patients with food allergy, the dominant immune response is a TH2-skewed T-cell response and the generation of food-specific IgE antibodies from B cells. It is not known whether a failure of the Treg cell response is behind this inappropriate immune response, but interventions that boost the Treg cell response, such as mucosal immunotherapy, might lead to a restoration of immune tolerance to foods. Tolerance has been notoriously difficult to restore in animal disease models, but limited data from human trials suggest that tolerance (sustained nonresponsiveness) can be re-established in a subset of patients. Furthermore, studies on the natural history of food allergy indicate that spontaneous development of tolerance to foods over time is not uncommon. The current challenge is to understand the mechanisms responsible for restoration of natural or induced tolerance so that interventions can be developed to more successfully induce tolerance in the majority of patients with food allergy.
The state of knowledge about the healthy immune response to antigens in the diet and the basis of immune deviation that results in immunoglobulin E (IgE) sensitization and allergic reactivity to foods. The intestinal epithelium forms the interface between the external environment and the mucosal immune system, and emerging data suggest that the interaction between intestinal epithelial cells and mucosal dendritic cells is of particular importance in determining the outcome of immune responses to dietary antigens. Exposure to food allergens through non-oral routes, in particular through the skin, is increasingly recognized as a potentially important factor in the increasing rate of food allergy. There are many open questions on the role of environmental factors, such as dietary factors and microbiota, in the development of food allergy, but data suggest that both have an important modulatory effect on the mucosal immune system. Immune mechanisms of clinical manifestations of food allergy. New experimental tools, particularly in the field of genomics and the microbiome, are likely to shed light on factors responsible for the growing clinical problem of food allergy.
The role of dendritic cells in food allergy
The initiation of TH2-type immunity has increased significantly, yet the mechanism behind the induction of TH2 responses and allergic sensitization to food antigens largely remains an enigma. Dendritic cells (DCs) were first described almost 4 decades ago and have since been recognized as the most important antigen-presenting cells and crucial in the induction of T-cell differentiation. The role of DCs in food allergy. In both murine models and allergic patients, characteristics of DCs have been identified that might play a role in sensitization to food and enhance susceptibility to food allergy. In addition, it has now been shown that several allergens, including some from foods, can directly activate DCs to induce TH2 skewing. Other cell types with innate immune functions, such as epithelial cells and basophils, might also be involved in sensing of food allergens in human subjects, and interaction of DCs with these cells might facilitate sensitization. DCs appear to play an important role in allergen-specific immunotherapy and could be an attractive target for tolerance induction in patients with food allergy. Further characterization of differences in DC responses between human food-allergic and nonallergic subjects is necessary to gain a better insight into the role of DCs in sensitization and tolerance to food allergens.
Elucidating gene-environment interactions is crucial for understanding pathogenesis. For example, in a prospective study of 970 children, breast-feeding was associated with an increased risk of food sensitization, but the effect was dependent on functional genetic variants in the IL-12 receptor β1, Toll-like receptor 9, and thymic stromal lymphopoietin genes.
In another study taking a deeper look at the vitamin D hypothesis, Liu et al evaluated a Boston birth cohort (n = 649) and did not find an association of cord blood vitamin D levels with sensitization to food allergens in early childhood. Candidate gene single nucleotide polymorphisms, a significant interaction indicating a risk for sensitization was identified for an IL4 gene polymorphism and 3 other genes.
Gene–vitamin D interactions on food sensitization
It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. We aim to examine whether cord blood VDD is associated with FS and whether such association can be modified by genetic variants in a prospective birth cohort.
Among the 649 children, 44% had VDD and 37% had FS. When examined alone, VDD was not associated with FS. When examined jointly with SNPs, a significant interaction between IL4 gene polymorphism (rs2243250) and VDD was found: VDD increased the risk of FS among children carrying CC/CT genotypes. Similar but weaker interactions were observed for SNPs in MS4A2 (rs512555), FCER1G (rs2070901), and CYP24A1 (rs2762934). When all four SNPs were simultaneously considered, a strong gene–VDD interaction was evident (pinteraction = 9 × 10−6). These study demonstrate that VDD may increase the risk of FS among individuals with certain genotypes, providing evidence of gene–vitamin D interaction on FS.
Microbe-host interactions in allergic diseases
The microbiome is emerging as an important “internal” environmental exposure, and treatment with prebiotics and probiotics is an avenue of therapy in response to this influence. The immune consequences are slowly being elucidated. The human body can be considered a metaorganism made up of its own eukaryotic cells and trillions of microbes that colonize superficial body sites, such as the skin, airways, and gastrointestinal tract. The coevolution of host and microbes brought about a variety of molecular mechanisms, which ensure a peaceful relationship. The mammalian barrier and immune functions warrant simultaneous protection of the host against deleterious infections, as well as tolerance toward harmless commensals. Because these pivotal host functions evolved under high microbial pressure, they obviously depend on a complex network of microbe-host interactions. The rapid spread of immune-mediated disorders, such as autoimmune diseases, inflammatory bowel diseases, and allergies, in westernized countries is thus thought to be due to environmentally mediated disturbances of this microbe-host interaction network. The importance of the intestinal microbiota in shaping host immune mechanisms, with particular emphasis on allergic diseases and possible intervention strategies.
Lactobacillus reuteri supplementation decreases allergen responsiveness
Forsberg et al reported on children undergoing probiotic supplementation in a controlled trial and found that this supplementation was associated with decreased allergen-induced production of IL-5 and IL-10 and higher levels of ovalbumin-induced CXCL10 at birth and CCL17 at 24 months, suggesting a greater capacity for immune regulation. Lactobacillus reuteri supplementation from pregnancy week 36 and to the infant through the first year of life decreased the prevalence of IgE-associated eczema at 2 years. The underlying immunological mechanisms are unknown, however.
The key immune factors responsible for allergy outcomes are under intense investigation. In the COFAR cohort described above, mononuclear cell allergen stimulation screening was performed with PCR analysis to 7 key markers of immune regulation and TH1/TH2 bias. Only allergen-induced IL4 expression was associated with clinical allergy to milk and sensitization to milk and peanut. This was noted in the absence of increased GATA3 mRNA expression, identifying a potential marker but also raising a question about the IL-4 not being of T-cell origin.
Probiotic treatment was associated with low cat-induced Th2-like responses at 6 months (IL-5, P = 0.01, and IL-13, P = 0.009), with a similar trend for IL-5 at 12 months. Cat-induced IFN-γ responses were also lower after probiotic than after placebo treatment at 24 months, with similar findings for the anti-inflammatory IL-10 at birth and at 12 months (P = 0.009). At 24 months, Th2-associated CCL22 levels were lower in the probiotic than in the placebo group after birch stimulation, with a similar trend after ovalbumin stimulation. Lower CCL22 levels were recorded at 12 and 24 months after PHA stimulation. Lactobacillus reuteri supplementation decreases allergen responsiveness and may enhance immunoregulatory capacity during infancy. L. reuteri supplementation from week 36 and during the first year of life significantly decreases IgE-associated eczema and lowers allergen and mitogen responsiveness.
The filaggrin gene are a significant risk factor
IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy.
Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients, and this association was replicated in the Canadian study. The association of filaggrin mutations with peanut allergy remains significant after controlling for coexistent atopic dermatitis. Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.
The importance of considering the route of sensitization on food allergy has been recently highlighted, such as sensitization through nonoral routes. It has long been appreciated that respiratory sensitization can result in food allergy, as demonstrated by pollen-food–related allergies, as well as some more esoteric examples, including cat-pork–related allergy (pork meat allergy attributed to initial environmental sensitization to cat serum albumin) and wheat allergy induced by using wheat protein–based soap.
Here again environment and genetics conspire. Skin exposure to environmental food allergens might be a sensitizing route, particularly when there is epithelial barrier dysfunction, such as in those with AD. This theory was supported by a study showing that filaggrin (FLG) loss-of-function mutations are associated with peanut allergy, and interestingly, the association remained significant after controlling for coexistent AD. FLG loss-of-function mutations were determined in a subset from a large cohort that was extensively tested for sensitization and clinical food allergy. After adjusting for eczema, FLG mutations were associated with food sensitization. However, after adjustment for risk of clinical food allergy among those sensitized, there was no further influence of FLG mutations, suggesting this mutation is not playing a role in progression of sensitization to clinical allergy.
IgE specific for galactose alpha-1,3-galactose (alpha-gal)
Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody (Ab) response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), that has been associated with two distinct forms of anaphylaxis: (1) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and (2) delayed onset anaphylaxis 3-6 h after ingestion of mammalian food products (e.g., beef and pork). The results of our studies strongly suggest that tick bites are a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the southern, eastern and central United States. Patients with IgE Ab to alpha-gal continue to emerge and, increasingly, these cases involve children. This IgE Ab response cross-reacts with cat and dog but does not appear to pose a risk for asthma; however, it may impair diagnostic testing in some situations.
Patients with IgE antibodies against the carbohydrate epitope galactose-α-1,3-galactose (α-Gal) have reported severe allergic reactions after consumption of red meat. Investigations have revealed associations between IgE to α-Gal and tick bites. We provide the first direct evidence that α-Gal is present within ticks thus potentially explaining the relationship between tick exposure and sensitization to α-Gal, with development of red meat allergy as a secondary phenomena. Serum from Swedish patients with delayed severe reactions to red meat was included in the study. A dose-dependent inhibition of IgE responses to α-Gal by the tick Ixodes ricinus is demonstrated. Furthermore, using cryostat-cut sections of I. ricinus, that both a monoclonal and a polyclonal antibody against α-Gal stains the gastrointestinal tract of the tick. The same pattern is seen when staining with patient sera IgE positive to α-Gal. These results confirm that the α-Gal epitope is present in I. ricinus and imply host exposure to α-Gal during a tick bite. This provides further evidence that tick bites are associated with IgE responses to α-Gal and red meat allergy.
Despite a thorough history and comprehensive testing, many children who present with recurrent symptoms consistent with allergic reactions elude diagnosis. Recent research has identified a novel cause for “idiopathic” allergic reactions; immunoglobulin E (IgE) antibody specific for the carbohydrate galactose-α-1,3-galactose (α-Gal) has been associated with delayed urticaria and anaphylaxis that occurs 3 to 6 hours after eating beef, pork, or lamb. IgE antibody to α-Gal was present in sera of pediatric patients who reported idiopathic anaphylaxis or urticaria. A novel form of anaphylaxis and urticaria that occurs 3 to 6 hours after eating mammalian meat is not uncommon among children in our area. Identification of these cases may not be straightforward and diagnosis is best confirmed by specific testing, which should certainly be considered for children living in the area where the Lone Star tick is common.
A very interesting and novel form of food allergy that is manifested clinically by delayed allergic responses and anaphylaxis hours after ingestion of mammalian meat has been linked to sensitization to carbohydrate galactose-α-1,3-galactose (α-Gal). The route of sensitization appears to be from tick bites based on clinical circumstances and detection of α-Gal in the gut of the tick Ixodes ricinus. The α-Gal epitope is a major blood group substance of nonprimate mammals, and there is likely a predilection for sensitization among those with B-negative blood groups.82 The reason for the delayed reactions remains to be elucidated. Thus α-Gal allergy is unique for the allergen being a carbohydrate, the exposure being through the intracutaneous route, and the time course of the reaction being delayed. Elucidating these factors further will likely provide more insights on the pathophysiology of other food allergies as well.
The manner of food preparation and processing and the nonprotein components of foods also likely play a role in pathogenesis. This might go beyond the notion that heating destroys some relevant food allergens, such as birch homologous proteins in fruits or tertiary protein structures in milk or egg, or creates more potent allergens, such as through the Maillard reaction of nonenzymatic browning in which heating results in a chemical reaction between reducing sugars and proteins to form advanced glycation end-products in roasted peanut. For example, invariant natural killer T cells can be activated by sphingolipids presented through CD1d molecules to produce TH2 cytokines, raising the possibility that these components in foods might direct an allergic response to foods. In a series of experiments comparing PBMC responses from children with CMA, egg allergy with tolerance of milk, and healthy control subjects, Jyonouchi et al showed that milk sphingomyelin can induce invariant natural killer T-cell activation and TH2 cytokine production and that the response is more exuberant in children with CMA.
A key immunologic feature of food allergy (FA) is the presence of a T(h)2-type cytokine bias. Ligation of the invariant natural killer T cell (iNKT) T-cell receptor (TCR) by sphingolipids presented via the CD1d molecule leads to copious secretion of T(h)2-type cytokines. Major food allergens (eg, milk, egg) are the richest dietary source of sphingolipids (food-derived sphingolipids [food-SLs]). Nonetheless, the role of iNKTs in FA is unknown. Milk-sphingomyelin, but not egg-ceramide, can engage the iNKT-TCR and induce iNKT proliferation and T(h)2-type cytokine secretion. Children with FA, especially those with MA, had significantly fewer peripheral blood iNKTs and their iNKTs exhibited a greater T(h)2 response to αGal and milk-sphingomyelin than iNKTs of healthy controls. iNKTs from children with FA, especially those with MA, are reduced in number and exhibit a T(h)2 bias in response to αGal and milk-sphingomyelin. These data suggest a potential role for iNKTs in FA.
Ilchmann et al observed that heating ovalbumin with glucose enhanced activation of ovalbumin-specific CD4+ T cells and increased IL-4 levels. Myeloid dendritic cell uptake of the processed ovalbumin was enhanced, and specific dendritic cell receptors were identified that mediated the process.
The Maillard reaction occurs between reducing sugars and proteins during thermal processing of foods. It produces chemically glycated proteins termed advanced glycation end products (AGEs). The glycation structures of AGEs are suggested to function as pathogenesis-related immune epitopes in food allergy. Compared with the controls (native OVA and OVA thermally processed without glucose), AGE-OVA enhanced the activation of OVA-specific CD4(+) T cells on coculture with mDCs, indicating that the glycation of OVA enhanced the T-cell immunogenicity of the allergen. The mDC uptake of AGE-OVA was significantly higher than that of the controls. We identified scavenger receptor class A type I and II (SR-AI/II) as a mediator of the AGE-OVA uptake, whereas the receptor for AGEs and galectin-3 were not responsible. Importantly, the activation of OVA-specific CD4(+) T cells by AGE-OVA was attenuated on coculture with SR-AI/II-deficient mDCs. SR-AI/II targets AGE-OVA to the MHC class II loading pathway in mDCs, leading to an enhanced CD4(+) T-cell activation. The Maillard reaction might thus play an important role in the T-cell immunogenicity of food allergens.
Regulate dendritic cell function and suppress allergic sensitization
Masilamani et al showed that dietary isoflavones suppressed allergic sensitization to peanut; these are abundant in soy and not peanut, perhaps explaining why one legume is more allergenic than another. These observations and others set the stage for additional work to identify characteristics of foods that promote allergic responses and might elucidate immune intervention strategies.
Although peanut and soybean proteins share extensive amino acid sequence homology, the incidence and severity of allergic reactions to soy are much less than those to peanut. Soybeans are rich in anti-inflammatory isoflavones and are the most common source of isoflavones in the human food supply. Dietary isoflavones significantly reduced the anaphylactic symptoms and mast cell degranulation in vivo after peanut challenge. Serum peanut-specific antibodies were markedly reduced in mice fed the isoflavone diet. Isoflavones inhibited cholera toxin-induced DC maturation in the mesenteric lymph nodes and human MDDCs and subsequent DC-mediated CD4(+) T-cell function in vitro. These data suggest that dietary isoflavones suppress allergic sensitization and protect against peanut allergy in vivo. Dietary supplementation of soybean isoflavones could be a novel strategy to prevent the development of allergic reactions to food.
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