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Prenatal and early postnatal life represent key periods of immune system development. In addition to genetics and host biology, environment has a large and irreversible role in the immune maturation and health of an infant. One key player in this process is the gut microbiota, a diverse community of microorganisms that colonizes the human intestine. The diet, environment and medical interventions experienced by an infant determine the establishment and progression of the intestinal microbiota, which interacts with and trains the developing immune system. Several chronic immune-mediated diseases have been linked to an altered gut microbiota during early infancy. The recent rise in allergic disease incidence has been explained by the ‘hygiene hypothesis’, which states that societal changes in developed countries have led to reduced early-life microbial exposures, negatively impacting immunity. Although human cohort studies across the globe have established a correlation between early-life microbiota composition and atopy, mechanistic links and specific host–microorganism interactions are still being uncovered. Here, we detail the progression of immune system and microbiota maturation in early life, highlight the mechanistic links between microbes and the immune system, and summarize the role of early-life host–microorganism interactions in allergic disease development.In this Review, the authors consider how early-life environmental exposures shape the immune system. They highlight how diet, medicines and other environmental factors influence the establishment of the gut microbiota and can impact susceptibility to allergic disease development.

Allergies, including asthma, food allergy and atopic dermatitis, are increasing in prevalence, particularly in westernized countries. Although a detailed mechanistic explanation for this increase is lacking, recent evidence indicates that, in addition to genetic predisposition, lifestyle changes owing to modernization have an important role. Such changes include increased rates of birth by caesarean delivery, increased early use of antibiotics, a westernized diet and the associated development of obesity, and changes in indoor and outdoor lifestyle and activity patterns. Most of these factors directly and indirectly impact the formation of a diverse microbiota, which includes bacterial, viral and fungal components; the microbiota has a leading role in shaping (early) immune responses. This default programme is markedly disturbed under the influence of environmental and lifestyle risk factors. Here, we review the most important allergy risk factors associated with changes in our exposure to the microbial world and the application of this knowledge to allergy prevention strategies.Here, the authors explore how the modern way of life increases the risk of allergy and asthma, in particular by affecting the formation and diversity of the microbiota in early life. Understanding these changes highlights strategies for allergy prevention.

Key Points There are many forms of food allergy, the most common of which are IgE mediated. Common IgE-mediated food allergies include those to peanuts, tree nuts, cow's milk, egg, soy, wheat, shellfish and fish. The immune system normally develops tolerance to food proteins, at least in part due to the actions of CD4 + regulatory T cells. Food allergy develops when the immune system mounts a T helper 2 (T H 2) cell-mediated response against food epitopes. T H 2 cell sensitization may occur initially at the skin, rather than in the gastrointestinal tract. The early introduction of potentially allergenic foods may prevent the development of food allergies. Patients with established food allergy may become desensitized to food allergens by oral immunotherapy, which is thought to involve a shift from allergen-specific T H 2 cells to CD4 + regulatory T cells, anergic cells and apoptotic cells. Typically, patients must continue regular consumption of food allergen to maintain desensitization. Some desensitized individuals proceed to develop sustained unresponsiveness and no longer require regular ingestion of food allergen to maintain immune system nonresponsiveness. The mechanism and predictors of the transition from desensitization to apparent tolerance are unknown. Research into the immune mechanisms associated with healthy tolerance to common foods, the inflammatory response underlying food allergies, and immunotherapy-induced desensitization promises new approaches to the diagnosis, prevention and treatment of food allergy. Food allergy is a pathological, potentially deadly, immune reaction triggered by normally innocuous food protein antigens. The prevalence of food allergies is rising and the standard of care is not optimal, consisting of food-allergen avoidance and treatment of allergen-induced systemic reactions with adrenaline. Thus, accurate diagnosis, prevention and treatment are pressing needs, research into which has been catalysed by technological advances that are enabling a mechanistic understanding of food allergy at the cellular and molecular levels. We discuss the diagnosis and treatment of IgE-mediated food allergy in the context of the immune mechanisms associated with healthy tolerance to common foods, the inflammatory response underlying most food allergies, and immunotherapy-induced desensitization. We highlight promising research advances, therapeutic innovations and the challenges that remain.

The incidence of autoimmune diseases has been steadily rising. Concomitantly, the incidence of most infectious diseases has declined. This observation gave rise to the hygiene hypothesis, which postulates that a reduction in the frequency of infections contributes directly to the increase in the frequency of autoimmune and allergic diseases. This hypothesis is supported by robust epidemiological data, but the underlying mechanisms are unclear. Pathogens are known to be important, as autoimmune disease is prevented in various experimental models by infection with different bacteria, viruses and parasites. Gut commensal bacteria also play an important role: dysbiosis of the gut flora is observed in patients with autoimmune diseases, although the causal relationship with the occurrence of autoimmune diseases has not been established. Both pathogens and commensals act by stimulating immunoregulatory pathways. Here, I discuss the importance of innate immune receptors, in particular Toll-like receptors, in mediating the protective effect of pathogens and commensals on autoimmunity.

The initiation of type 2 immune responses by the epithelial cell–derived cytokines IL-25, IL-33 and TSLP has been an area of extensive research in the past decade. Such studies have led to the identification of a new innate lymphoid subset that produces the canonical type 2 cytokines IL-5, IL-9 and IL-13 in response to IL-25 and IL-33. These group 2 or type 2 innate lymphoid cells (ILC2 cells) represent a critical source of type 2 cytokines in vivo and serve an important role in orchestrating the type 2 response to helminths and allergens. Further characterization of ILC2 cell biology will enhance the understanding of type 2 responses and may identify new treatments for asthma, allergies and parasitic infections. Interactions between ILC2 cells and the adaptive immune system, as well as examination of potential roles for ILC2 cells in the maintenance of homeostasis, promise to be particularly fruitful areas of future research.

IL-9-producing CD4+ T cells have been considered to represent a distinct T helper cell (TH cell) subset owing to their unique developmental programme in vitro, their expression of distinct transcription factors (including PU.1) and their copious production of IL-9. It remains debatable whether these cells represent a truly unique TH cell subset in vivo, but they are closely related to the T helper 2 (TH2) cells that are detected in allergic diseases. In recent years, increasing evidence has also indicated that IL-9-producing T cells may have potent abilities in eradicating advanced tumours, particularly melanomas. Here, we review the latest literature on the development of IL-9-producing T cells and their functions in disease settings, with a particular focus on allergy and cancer. We also discuss recent ideas concerning the therapeutic targeting of these cells in patients with chronic allergic diseases and their potential use in cancer immunotherapy.This Review covers our current understanding of the roles of IL-9-producing T cells in allergy and cancer. Should these cells be classified as a distinct IL-9-producing T helper cell subset? And can we therapeutically target them for the treatment of chronic allergic diseases and cancer?

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1 , the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1 + Tac1 + nociceptor–MRGPRB2 + mast cell sensory clusters represents a key early event in the development of allergic skin reactions. Gaudenzio and colleagues show that house dust mite extracts directly activate TRPV1 + sensory neurons, which promote allergic skin inflammation by inducing the degranulation of mast cells through the release of the neuropeptide substance P and activation of MRGPRB2.

Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

Targeting of immunoglobulin E (IgE) represents an interesting approach for the treatment of allergic disorders. A high-affinity monoclonal anti-IgE antibody, ligelizumab, has recently been developed to overcome some of the limitations associated with the clinical use of the therapeutic anti-IgE antibody, omalizumab. Here, we determine the molecular binding profile and functional modes-of-action of ligelizumab. We solve the crystal structure of ligelizumab bound to IgE, and report epitope differences between ligelizumab and omalizumab that contribute to their qualitatively distinct IgE-receptor inhibition profiles. While ligelizumab shows superior inhibition of IgE binding to FcεRI, basophil activation, IgE production by B cells and passive systemic anaphylaxis in an in vivo mouse model, ligelizumab is less potent in inhibiting IgE:CD23 interactions than omalizumab. Our data thus provide a structural and mechanistic foundation for understanding the efficient suppression of FcεRI-dependent allergic reactions by ligelizumab in vitro as well as in vivo. Immunoglobulin E (IgE) plays a central role in allergic responses, yet therapeutic targeting of IgE with antibodies such as omalizumab is met with various limitations. Here the authors characterize the molecular properties and crystal structure of a new anti-IgE antibody, ligelizumab, for mechanistic insights related to its enhanced suppression activity.

Key Points GATA-binding protein 3 (GATA3) expression and signal transducer and activator of transcription 5 (STAT5) activation are two key events for T H 2 cell differentiation in vitro and possibly in vivo . Epithelial cells, dendritic cells and basophils are responsible for sensing allergens and helminth products and thus initiate T H 2-type immune responses in vivo . Epithelial cells produce the T H 2-promoting cytokines thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25) and IL-33, and basophils produce IL-4, TSLP and IL-25 during the initiation stage of T H 2 cell development. These cytokines may have important roles in inducing T H 2-type responses, but the relative importance of each cytokine differs among individual models of T H 2 cell-associated diseases. Both dendritic cells and basophils can serve as T H 2-inducing antigen-presenting cells. Although basophils are crucial for some T H 2-type responses, they are dispensable in other models where dendritic cells or other potential antigen-presenting cells are involved. IL-25 and IL-33 responsive non-B non-T cells produce T H 2-associted cytokines, including IL-5 and IL-13, following IL-25 or IL-33 stimulation. These cells can be thought to be innate effector cells during T H 2-type responses. IL-4, TSLP, IL-25 and IL-33 are also involved in the amplification of the T H 2-type responses by affecting several cell types. T helper 2 (T H 2) cells have a central role in protection against helminth infections but are also responsible for the development of asthma and other allergic inflammatory diseases. This Review provides a comprehensive overview of the cellular and molecular mechanisms involved in the initiation and amplification of T H 2-type immune responses in vivo . CD4 + T helper (T H ) cells have crucial roles in orchestrating adaptive immune responses. T H 2 cells control immunity to extracellular parasites and all forms of allergic inflammatory responses. Although we understand the initiation of the T H 2-type response in tissue culture in great detail, much less is known about T H 2 cell induction in vivo . Here we discuss the involvement of allergen- and parasite product-mediated activation of epithelial cells, basophils and dendritic cells and the functions of the cytokines interleukin-4 (IL-4), IL-25, IL-33 and thymic stromal lymphopoietin in the initiation and amplification of T H 2-type immune responses in vivo .