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Divergent T follicular helper cell requirement for IgA and IgE production to peanut during allergic sensitization.

ABSTRACT: Immunoglobulin A (IgA) is the dominant antibody isotype in the gut and has been shown to regulate microbiota. Mucosal IgA is also widely believed to prevent food allergens from penetrating the gut lining. Even though recent work has elucidated how bacteria-reactive IgA is induced, little is known about how IgA to food antigens is regulated. Although IgA is presumed to be induced in a healthy gut at steady state via dietary exposure, our data do not support this premise. We found that daily food exposure only induced low-level, cross-reactive IgA in a minority of mice. In contrast, induction of significant levels of peanut-specific IgA strictly required a mucosal adjuvant. Although induction of peanut-specific IgA required T cells and CD40L, it was T follicular helper (T_FH) cell, germinal center, and T follicular regulatory (T_FR) cell-independent. In contrast, IgG1 and IgE production to peanut required T_FH cells. These data suggest an alternative paradigm in which the cellular mechanism of IgA production to food antigens is distinct from IgE and IgG1. We developed an equivalent assay to study this process in stool samples from healthy, nonallergic humans, which revealed substantial levels of peanut-specific IgA that were stable over time. Similar to mice, patients with loss of CD40L function had impaired titers of gut peanut-specific IgA. This work challenges two widely believed but untested paradigms about antibody production to dietary antigens: (i) the steady state/tolerogenic response to food antigens includes IgA production and (ii) T_FH cells drive food-specific gut IgA.

SUBMITTER: Zhang B

PROVIDER: S-EPMC8518330 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Group 2 Innate Lymphoid Cells Promote Development of T Follicular Helper Cells and Initiate Allergic Sensitization to Peanuts.

Project description:Peanut allergy is a growing public concern; however, little is known about the immunological mechanism(s) that initiate the disease process. Our knowledge is also limited regarding the role of group 2 innate lymphoid cells (ILC2s) in regulating humoral immunity. To fill these major gaps in our knowledge, we investigated the immunological mechanisms involved in peanut allergen sensitization by using mouse models. To mimic environmental exposure in humans, naive BALB/c mice were exposed to peanut flour by inhalation without any exogenous adjuvants. When exposed to peanut flour, naive mice developed T follicular helper (Tfh) cells in their lung draining lymph nodes and produced IgE Abs to peanuts. Mice deficient in IL-13 showed decreased numbers of Tfh cells and germinal center B cells and produced significantly fewer IgE Abs. IL-13 was necessary and sufficient for induction of CD11c+ MHC class IIhi dendritic cells that are implicated in Tfh cell development. Importantly, lung ILC2s served as a predominant early source of IL-13 when naive mice were exposed to peanut flour. Furthermore, mice that are deficient in lung ILC2s by bone marrow transfer from Rora sg/sg mice or by genetic manipulation produced significantly fewer IgE Abs to peanuts compared with control mice. These findings suggest lung ILC2s that serve as a rapid source of IL-13 upon allergen exposure play a major role in Tfh cell development, IgE Ab production, and initiation of peanut allergy.

| S-EPMC7309436 | biostudies-literature

IgE, but not IgG4, antibodies to Ara h 2 distinguish peanut allergy from asymptomatic peanut sensitization.

Project description:There are no available clinical tests that can accurately predict peanut allergy (PA) and/or anaphylaxis. This study is aimed at evaluating whether the component-resolved diagnostic (CRD) IgE and IgG4 tests can (i) distinguish PA from asymptomatic peanut sensitization (PS) and (ii) differentiate anaphylactic from nonanaphylactic PA.This study included 20 nonatopic controls, 58 asymptomatically peanut-sensitized children, 55 nonanaphylactic, and 53 anaphylactic PA cases from the Chicago Food Allergy Study. IgE and IgG4 to 103 allergens were measured using the ImmunoCAP ISAC technology and were compared among each group of children. The random forest test was applied to estimate each allergen's ability to predict PA and/or peanut anaphylaxis.Peanut allergy cases (with or without anaphylaxis) had significantly higher IgE reactivity to Ara h 1-3 (peanut allergens) and Gly m 5-6 (soy allergens) than asymptomatically sensitized children (P < 0.00001). Similar but more modest relationships were found for IgG4 to Ara h 2 (P < 0.01). IgE to Ara h 2 was the major contributor to accurate discrimination between PA and asymptomatic sensitization. With an optimal cutoff point of 0.65 ISU-E, it conferred 99.1% sensitivity, 98.3% specificity, and a 1.2% misclassification rate in the prediction of PA, which represented a higher discriminative accuracy than IgE to whole peanut extract (P = 0.008). However, none of the IgE and/or IgG4 tests could significantly differentiate peanut anaphylaxis from nonanaphylactic PA.IgE to Ara h 2 can efficiently differentiate clinical PA from asymptomatic PS, which may represent a major step forward in the diagnosis of PA.

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Prolonged Treatment of Peanut-Allergic Mice with Bortezomib Significantly Reduces Serum Anti-Peanut IgE but Does Not Affect Allergic Symptoms.

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| S-EPMC5102775 | biostudies-literature

Follicular helper T cells mediate IgE antibody response to airborne allergens.

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| S-EPMC5115999 | biostudies-literature

Identification of a T follicular helper cell subset that drives anaphylactic IgE.

Project description:Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (TFH) cells direct the affinity and isotype of antibodies produced by B cells. Although TFH cell-derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13-producing TFH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These "TFH13" cells have an unusual cytokine profile (IL-13hiIL-4hiIL-5hiIL-21lo) and coexpress the transcription factors BCL6 and GATA3. TFH13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking TFH13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.

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The role of the T follicular helper cells in allergic disease.

Project description:T follicular helper (Tfh) cells were discovered just over a decade ago as germinal centre T cells that help B cells make antibodies. Included in this role is affinity maturation and isotype switching. It is here that their functions become less clear. Tfh cells principally produce IL-21 which inhibits class switching to IgE. Recent studies have questioned whether the germinal centre is the main site of IgE class switching or IgE affinity maturation. In this review, I will examine the evidence that these cells are responsible for regulating IgE class switching and the relationship between Tfh cells and T helper 2 (Th2) effector cells.

| S-EPMC4002336 | biostudies-other

Dry roasting enhances peanut-induced allergic sensitization across mucosal and cutaneous routes in mice.

Project description: Not available

| S-EPMC4861634 | biostudies-literature

Prevalence of IgE-mediated sensitization in patients with suspected food allergic reactions in Jordan.

Project description:BACKGROUND:Despite the recognition of food allergies as a significant cause of morbidity and a growing public health burden worldwide, there are no epidemiological studies addressing food sensitization and allergy in Jordan. OBJECTIVE:To conduct an epidemiological study that retrospectively analyzes sensitization data from 3463 patients with suspected immunoglobulin E (IgE)-mediated food allergic reactions who performed specific IgE tests in our laboratories in Jordan. METHODS:Specific IgE (s-IgE) tests were analyzed for patients who performed enzyme allegro-sorbent testing based on either self-reported food allergy or upon physician's request. RESULTS:2.3% of the analyzed samples were cross-reactive to carbohydrate determinants. A quarter of the patients were sensitized to one or more food allergens, with males having higher odds of being s-IgE positive. Furthermore, a higher prevalence of sensitization was seen in infants and children compared with adults. s-IgE was most frequently found against cow milk (11.2%), pistachio (4.9%), soybean (4.6%), cherry (4.4%), and orange (4.4%). Interestingly, the s-IgE class distribution profile of pistachio differed from the rest of the top hits being skewed away from the weak class 1 leaning more towards higher IgE classes. Food allergen sensitization was age group-dependent: milk, tree nuts, and eggs were the main food groups causing sensitization in infants, while it was fruits followed by milk in children and adults. CONCLUSIONS:Our work represents the first epidemiological study addressing food sensitization in Jordan. This study lays a solid foundation for future studies that can help better guide food allergy diagnosis, patient dietary modifications, and food elimination plans, as well as assist decision-makers in the region to develop national strategies for an efficient and sustainable healthcare system.

| S-EPMC7416048 | biostudies-literature

Complex IgE sensitization patterns in ragweed allergic patients: Implications for diagnosis and specific immunotherapy.

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| S-EPMC9254219 | biostudies-literature

Intestinal allergic inflammation in birch pollen allergic patients in relation to pollen season, IgE sensitization profile and gastrointestinal symptoms.

Project description:BackgroundBirch pollen allergic patients frequently experience gastrointestinal upset accompanied by a local allergic inflammation in the small intestine especially during the pollen season. However, it is not known if the GI pathology is connected to the subjective symptoms of the patient. The objective of this study was to evaluate the immune pathology of the duodenal mucosa and the serum IgE antibody profiles in birch pollen allergic patients in relation to their gastrointestinal symptoms, during and outside the birch pollen season.MethodsThirty-two patients with birch pollen allergy and sixteen healthy controls were enrolled in the study. Twenty allergic patients had gastrointestinal symptoms and twelve did not. All participants underwent an allergy investigation and gastroscopy with duodenal biopsy. The duodenal biopsies were retrieved during the pollen season (May-June) and off-season (November-March). The biopsies were immunostained for mast cells (IgE and tryptase), eosinophils, T cells (CD3), and dendritic cells (CD11c). Pollen-specific IgE antibodies were determined by ImmunoCAP and component microarray (ISAC).ResultsPatients in both pollen allergic groups showed similar degree of intestinal allergic inflammation during the pollen season regardless of gastrointestinal symptoms. The eosinophils, mast cells and dendritic cells were increased in the mucosa. Patients with gastrointestinal symptoms had significantly elevated IgE antibodies to birch (rBet v 1), hazelnut (rCor a 1), and apple (rMal d1) during the pollen season.ConclusionsPatients allergic to birch pollen have clear signs of an ongoing allergic inflammation in their intestinal mucosa, which is aggravated during the pollen season. The magnitude of the allergic intestinal inflammation is not associated with subjective gastrointestinal symptoms of the individual patient.

| S-EPMC4048541 | biostudies-literature

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