Rodrigo Jiménez-Saiz

Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo

Eosinophil degranulation of peroxidase promotes DC activation and mobilization from the intestine to LNs to induce Th2 immunity and food allergy.

Comprehensive metabolomics identifies the alarmin uric acid as a critical signal for the induction of peanut allergy.

Food allergy, in particular peanut allergy, is a growing concern in Western countries. The prevalence of allergy to peanut, which currently stands at 1.4%, nearly tripled between 1997 and 2008. Allergic sensitization is a particularly difficult process to study as it is clinically silent.

Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway

Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway.

Lifelong memory responses perpetuate humoral TH2 immunity and anaphylaxis in patients with food allergy

Background: A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease‐transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long‐lived IgE+ plasma cells (PCs), this has not been directly and comprehensively tested. Objective: We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens. Methods: We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18–20 months). Results: Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long‐lived IgE+ PCs. Instead, lifelong reactivity is conferred by allergen‐specific long‐lived memory B cells that replenish the IgE+ PC compartment. B‐cell reactivation requires allergen re‐exposure and IL‐4 production by CD4 T cells. We define the half‐lives of antigen‐specific germinal centers (23.3 days), IgE+ and IgG1+ PCs (60 and 234.4 days, respectively), and clinically relevant cell‐bound IgE (67.3 days). Conclusions: These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease‐transforming potential.

Lifelong memory responses perpetuate humoral TH2 immunity and anaphylaxis in food allergy

Background: A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease‐transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long‐lived IgE+ plasma cells (PCs), this has not been directly and comprehensively tested. Objective: We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens. Methods: We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18–20 months). Results: Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long‐lived IgE+ PCs. Instead, lifelong reactivity is conferred by allergen‐specific long‐lived memory B cells that replenish the IgE+ PC compartment. B‐cell reactivation requires allergen re‐exposure and IL‐4 production by CD4 T cells. We define the half‐lives of antigen‐specific germinal centers (23.3 days), IgE+ and IgG1+ PCs (60 and 234.4 days, respectively), and clinically relevant cell‐bound IgE (67.3 days). Conclusions: These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease‐transforming potential.

IgG1+ B-cell immunity predates IgE responses in epicutaneous sensitization to foods

The generation of IgE‐mediated food allergy in humans is silent and only diagnosed upon manifestation of clinical symptoms. While experimental models have been used to investigate some mechanisms of allergic sensitization, the generation of humoral immunity and memory remains to be elucidated. Here, we defined the evolution of allergen‐specific B‐cell responses during epicutaneous sensitization to foods.

Initiation, Persistence and Exacerbation of Food Allergy

Th2 humoral immunity (IgE) is protective against venoms and parasites but detrimental when mounted against innocuous proteins such as food allergens. The generation of IgE immunity toward harmless allergens is initiated at the body barriers (i.e. mucosae and skin) where the allergen and the immune system first meet. Epithelial cytokines (such as TSLP, IL-25, and IL-33), damage-associated molecular patterns (DAMPs), alarmins, or barrier disruption at the time of allergen encounter can deviate dendritic cells (DCs) away from the natural tolerogenic response to a food allergen. Then, instructed DCs migrate to draining lymph nodes and facilitate Th2 CD4 T cell polarization by limiting IL-12p40 production and upregulating costimulatory molecules such as OX40L. In this setting, IL-4 production by CD4 Th2 cells is crucial for the emergence of IgE+ B cells and plasma cells. The lifespan of allergen-specific IgE+ plasma cells is short, thereby limiting their ability to sustain IgE titres over time. In contrast, long-lasting immunological memory that includes CD4 T and B cells is imprinted at the time of sensitization. These cells are activated on allergen exposure and replenish the transient IgE+ plasma cell compartment in an IL-4 dependent manner. While immunological memory provides sustainable immunity against pathogens, it underlies persistence and exacerbation of food allergy. Therefore, reaching a better understanding of Th2 immune memory and the cellular and molecular mechanisms driving IgE-generating secondary responses is a major undertaking in the search for novel therapeutic targets in food allergy.

The Initiation of Th2 Immunity Towards Food Allergens

In contrast with Th1 immune responses against pathogenic viruses and bacteria, the incipient events that generate Th2 responses remain less understood. One difficulty in the identification of universal operating principles stems from the diversity of entities against which cellular and molecular Th2 responses are produced. Such responses are launched against harmful macroscopic parasites and noxious substances, such as venoms, but also against largely innocuous allergens. This suggests that the established understanding about sense and recognition applied to Th1 responses may not be translatable to Th2 responses. This review will discuss processes and signals known to occur in Th2 responses, particularly in the context of food allergy. We propose that perturbations of homeostasis at barrier sites induced by external or internal subverters, which can activate or lower the threshold activation of the immune system, are the major requirement for allergic sensitization. Innate signals produced in the tissue under these conditions equip dendritic cells with a program that forms an adaptive Th2 response.

Lifelong memory responses perpetuate humoral T H 2 immunity and anaphylaxis in food allergy

Background: A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease‐transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long‐lived IgE+ plasma cells (PCs), this has not been directly and comprehensively tested. Objective: We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens. Methods: We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18–20 months). Results: Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long‐lived IgE+ PCs. Instead, lifelong reactivity is conferred by allergen‐specific long‐lived memory B cells that replenish the IgE+ PC compartment. B‐cell reactivation requires allergen re‐exposure and IL‐4 production by CD4 T cells. We define the half‐lives of antigen‐specific germinal centers (23.3 days), IgE+ and IgG1+ PCs (60 and 234.4 days, respectively), and clinically relevant cell‐bound IgE (67.3 days). Conclusions: These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease‐transforming potential.