Dendritic Cells in Food Allergy, Treatment, and Tolerance.

Food allergy is a growing problem with limited treatment options. It is important to understand the mechanisms of food tolerance and allergy to promote the development of directed therapies. Dendritic cells are specialized antigen presenting cells that prime adaptive immune responses, such as those involved in the development of oral tolerance and food allergies. The dendritic cell subsets in the gut and skin are defined by their surface markers and function. The default response to an ingested innocuous antigen is oral tolerance, which requires either gut dendritic cells or a subset of newly identified RORγt+ antigen presenting cells to induce the development of gut peripheral T regulatory cells. However, dendritic cells in the skin, gut, and lung can also promote allergic sensitization when they are activated under certain inflammatory conditions, such as with alarmin release or gut dysbiosis. Dendritic cells also play a role in the responses to the various modalities of food immunotherapy. Langerhans cells in the skin appear to be necessary for the response to epicutaneous immunotherapy. It will be important to determine which real-world stimuli activate the dendritic cells that prime allergic sensitization and discover methods to selectively initiate a tolerogenic program in antigen presenting cells.

Oral anaphylaxis to peanut in a mouse model is associated with gut permeability but not with Tlr4 or Dock8 mutations.

BACKGROUND: The etiology of food allergy is poorly understood; mouse models are powerful systems to discover immunologic pathways driving allergic disease. C3H/HeJ mice are a widely used model for the study of peanut allergy because, unlike C57BL/6 or BALB/c mice, they are highly susceptible to oral anaphylaxis. However, the immunologic mechanism of this strain's susceptibility is not known. OBJECTIVE: We aimed to determine the mechanism underlying the unique susceptibility to anaphylaxis in C3H/HeJ mice. We tested the role of deleterious Toll-like receptor 4 (Tlr4) or dedicator of cytokinesis 8 (Dock8) mutations in this strain because both genes have been associated with food allergy. METHODS: We generated C3H/HeJ mice with corrected Dock8 or Tlr4 alleles and sensitized and challenged them with peanut. We then characterized the antibody response to sensitization, anaphylaxis response to both oral and systemic peanut challenge, gut microbiome, and biomarkers of gut permeability. RESULTS: In contrast to C3H/HeJ mice, C57BL/6 mice were resistant to anaphylaxis after oral peanut challenge; however, both strains undergo anaphylaxis with intraperitoneal challenge. Restoring Tlr4 or Dock8 function in C3H/HeJ mice did not protect from anaphylaxis. Instead, we discovered enhanced gut permeability resulting in ingested allergens in the bloodstream in C3H/HeJ mice compared to C57BL/6 mice, which correlated with an increased number of goblet cells in the small intestine. CONCLUSIONS: Our work highlights the potential importance of gut permeability in driving anaphylaxis to ingested food allergens; it also indicates that genetic loci outside of Tlr4 and Dock8 are responsible for the oral anaphylactic susceptibility of C3H/HeJ mice.

Food Matrix Composition Affects the Allergenicity of Baked Egg Products.

BACKGROUND: Egg allergy is common and caused by sensitization to ovomucoid and/or ovalbumin. Many egg-allergic patients are able to tolerate eggs baked into other foods, such as muffins. Although heating egg extensively reduces allergens, the effect of other food ingredients on allergenicity of eggs, or the "matrix effect," is less well studied. OBJECTIVE: We aimed to define how food matrices impact the matrix effect in egg allergenicity. METHODS: Enzyme-linked immunosorbent assay was used to quantify ovalbumin and ovomucoid in extracts from various baked egg products: plain baked egg without a matrix, and muffins baked using either wheat flour, rice flour, or a wheat flour/banana puree mix. Allergen-specific immunoglobulin E (IgE)-blocking enzyme-linked immunosorbent assays were performed using the egg product extracts on egg-allergic patient sera to determine whether the amount of extracted egg protein in each extract correlated with how well the extracts could bind patients' egg IgE. RESULTS: Baking eggs in any muffin matrix led to an increase in the amount of extractable ovalbumin and a decrease in the amount of extractable ovomucoid compared with plain baked egg. Compared with wheat muffins, rice muffins had more extractable ovalbumin and wheat/banana muffins had more extractable ovalbumin and ovomucoid. The egg allergens in the extracts were able to block egg-allergic patients' egg IgE. CONCLUSIONS: Food matrices affect egg allergen availability. Patients and families should be advised that substitutions in baked egg muffin recipes can affect the amount of egg allergens in foods and potentially affect the risk of food allergic reaction.

Food-specific immunoglobulin A does not correlate with natural tolerance to peanut or egg allergens.

ImmunoglobulinA (IgA) is the predominant antibody isotype in the gut, where it regulates commensal flora and neutralizes toxins and pathogens. The function of food-specific IgA in the gut is unknown but is presumed to protect from food allergy. Specifically, it has been hypothesized that food-specific IgA binds ingested allergens and promotes tolerance by immune exclusion; however, the evidence to support this hypothesis is indirect and mixed. Although it is known that healthy adults have peanut-specific IgA in the gut, it is unclear whether children also have gut peanut-specific IgA. We found in a cohort of non-food-allergic infants (n = 112) that there is detectable stool peanut-specific IgA that is similar to adult quantities of gut peanut-specific IgA. To investigate whether this peanut-specific IgA is associated with peanut tolerance, we examined a separate cohort of atopic children (n = 441) and found that gut peanut-specific IgA does not predict protection from development of future peanut allergy in infants nor does it correlate with concurrent oral tolerance of peanut in older children. We observed higher plasma peanut-specific IgA in those with peanut allergy. Similarly, egg white-specific IgA was detectable in infant stools and did not predict egg tolerance or outgrowth of egg allergy. Bead-based epitope assay analysis of gut peanut-specific IgA revealed similar epitope specificity between children with peanut allergy and those without; however, gut peanut-specific IgA and plasma peanut-specific IgE had different epitope specificities. These findings call into question the presumed protective role of food-specific IgA in food allergy.

Wheat oral immunotherapy.

PURPOSE OF REVIEW: The prevalence of food allergy is increasing on a global scale, and therefore increased attention is being paid to specific food allergy epidemiology and management. There has been a large amount of progress made in the last decade on human trials of wheat oral immunotherapy (WOIT). RECENT FINDINGS: To date, there has been one multicenter, double-blind, randomized controlled trial of WOIT, one randomized, noncontrolled trial of WOIT, and several smaller, nonrandomized clinical trials of WOIT. WOIT trials are generally limited by smaller sample sizes, affecting the demographic skew of evaluated patients. In addition, there is minimal standardization of efficacy and safety outcomes between trial protocols, making head-to-head comparison challenging. However, some common themes emerge. The majority of WOIT regimens result in successful desensitization, and success is more likely with higher maintenance dosing for longer periods of time. Limited studies have looked at sustained unresponsiveness in WOIT. WOIT can induce allergic reactions, including anaphylaxis, but more severe reactions often have an associated augmenting factor, such as exercise. Lower maintenance doses likely are associated with less severe reactions, and food modification and/or adjunct therapeutics may also decrease the risk of reactions. SUMMARY: WOIT trials are ongoing and will optimize updosing protocols and maintenance doses to improve efficacy and safety.

Antigen-Presenting Cells in Food Tolerance and Allergy.

Food allergy now affects 6%-8% of children in the Western world; despite this, we understand little about why certain people become sensitized to food allergens. The dominant form of food allergy is mediated by food-specific immunoglobulin E (IgE) antibodies, which can cause a variety of symptoms, including life-threatening anaphylaxis. A central step in this immune response to food antigens that differentiates tolerance from allergy is the initial priming of T cells by antigen-presenting cells (APCs), primarily different types of dendritic cells (DCs). DCs, along with monocyte and macrophage populations, dictate oral tolerance versus allergy by shaping the T cell and subsequent B cell antibody response. A growing body of literature has shed light on the conditions under which antigen presentation occurs and how different types of T cell responses are induced by different APCs. We will review APC subsets in the gut and discuss mechanisms of APC-induced oral tolerance versus allergy to food identified using mouse models and patient samples.