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Purpose of ReviewTo provide an overview of the prevalence and clinical manifestation of non-specific lipid transfer proteins (LTP)-mediated allergies outside the Mediterranean area and to address potential reasons for the different geographical significance of LTP-driven allergies.Recent FindingsLTPs are major allergens in the Mediterranean area, which frequently can elicit severe reactions. Pru p 3 the LTP from peach is reported as genuine allergen and is considered a prototypic marker for LTP-mediated allergies. However, both food and pollen LTP allergies exist outside the Mediterranean area, but with lower clinical significance, different immunogenicity, and less clarified role.SummaryEvidence has been reported that in areas with high exposure to pollen, in particular to mugwort, pollen-derived LTPs can act as a primary sensitizer to trigger secondary food allergies. Co-sensitization to unrelated allergens might be causative for less severe reactions in response to LTPs. However, the reason for the geographical different sensitization patterns to LTPs remains unclear.

Nanomedicine provides a promising platform for manipulating dendritic cells (DCs) and the ensuing adaptive immune response. For the induction of regulatory responses, DCs can be targeted with nanoparticles incorporating tolerogenic adjuvants and auto-antigens or allergens. Here, we investigated the tolerogenic effect of different liposome formulations loaded with vitamin D3 (VD3). We extensively phenotyped monocyte-derived DCs (moDCs) and skin DCs and assessed DC-induced regulatory CD4+ T cells in coculture. Liposomal VD3 primed-moDCs induced the development of regulatory CD4+ T cells (Tregs) that inhibited bystander memory T cell proliferation. Induced Tregs were of the FoxP3+ CD127low phenotype, also expressing TIGIT. Additionally, liposome-VD3 primed moDCs inhibited the development of T helper 1 (Th1) and T helper 17 (Th17) cells. Skin injection of VD3 liposomes selectively stimulated the migration of CD14+ skin DCs. These results suggest that nanoparticulate VD3 is a tolerogenic tool for DC-mediated induction of regulatory T cell responses.

Background. Several studies have shown an inverse association between helminth infections and atopy, but none have clearly established that the pathogens themselves, rather than other associated factors, cause the suppression of atopy. To show a direct link, prospective intervention studies are required. Methods. A randomized, controlled trial was performed to study whether repeated anthelminthic treatment results in increased allergic sensitivity to house dust mites (HDMs) in chronically infected children. The trial population consisted of 317 Gabonese schoolchildren with a high prevalence of intestinal helminths. Intervention consisted of treatment every 3 months with praziquantel and mebendazole and with placebo in the control group. Follow-up lasted 30 months: at 6-month intervals, skin-test sensitivity to mites, helminth infection status, and levels of total IgE were determined. Results. Treatment resulted in a significant increase in the rate of developing skin sensitivity to HDMs (hazard ratio, 2.51; 95% confidence interval, 1.85–3.41), which was mediated, in part, by reductions in Ascaris and/or Trichuris infections. Levels of total IgE were reduced, but this did not mediate the effect of treatment on skin-test reactivity. Conclusions. Anthelminthic treatment of chronically infected children results in increased atopic reactivity, which indicates that helminths directly suppress allergic reactions.

Peanut allergy is a potentially life-threatening disease with substantial impact on the quality of life of patients and carers.1 Many initiatives are underway to develop treatment alternatives for strict peanut avoidance. In real-life settings, risk factors such as exercise, viral infections, or poor treatment adherence might be less consciously monitored and thereby increase the risk of severe adverse events. Overall, the study by Chinthrajah and colleagues4 has confirmed earlier reports that OIT is very effective, but the protection is rapidly lost on cessation of treatment. Because of the high number of severe adverse events, current OIT is not a viable option for treatment where most needed—ie, in individuals with severe anaphylaxis.

Profilins are ubiquitous proteins, present in all eukaryotic cells and identified as allergens in pollen, latex and plant foods. The highly conserved structure justifies the cross-reactive nature of IgE antibodies against plant profilins and their designation as pan-allergens. Primary sensitization to profilin seems to arise from pollen sensitization with later development of cross-reactive IgE antibodies against plant food (and possibly latex) profilins. The role of profilin in inducing allergic symptoms needs to be evaluated and raises important issues in allergy diagnosis due to cross-reactivity. IgE cross-reactivity among profilins is associated with multiple pollen sensitization and with various pollen-food syndromes. In respiratory allergy, sensitization to pollen to which the patient has virtually no environmental exposure has been identified as a manifestation of profilin sensitization. As a food allergen, profilin usually elicits mild reactions, such as oral allergy syndrome, is not modified by processing and is especially important in allergy to some fruits, such as melon, watermelon, banana, tomato, citrus fruit and persimmon. Purified natural and recombinant profilins for in vitro and in vivo allergy tests are helpful in the diagnostic work-up. Herein we review the current state of knowledge about the allergen profilin and its implications in the diagnosis and treatment of allergic diseases. We conclude that, although its role in triggering allergic symptoms is still controversial, profilin is undoubtedly a relevant allergen. As a pan-allergen, profilin is associated with multiple pollen sensitization and pollen-food-latex syndromes that the allergist has to be aware of in order to accomplish an accurate diagnosis and successful treatment of allergic diseases.

Dendritic cells (DCs) are well-established as major players in the regulation of immune responses. They either induce inflammatory or tolerogenic responses, depending on the DC-subtype and stimuli they receive from the local environment. This dual capacity of DCs has raised therapeutic interest for their use to modify immune-activation via the generation of tolerogenic DCs (tolDCs). Several compounds such as vitamin D3, retinoic acid, dexamethasone, or IL-10 and TGF-β have shown potency in the induction of tolDCs. However, an increasing interest exists in defining tolerance inducing receptors on DCs for new targeting strategies aimed to develop tolerance inducing immunotherapies, on which we focus particular in this review. Ligation of specific cell surface molecules on DCs can result in antigen presentation to T cells in the presence of inhibitory costimulatory molecules and tolerogenic cytokines, giving rise to regulatory T cells. The combination of factors such as antigen structure and conformation, delivery method, and receptor specificity is of paramount importance. During the last decades, research provided many tools that can specifically target various receptors on DCs to induce a tolerogenic phenotype. Based on advances in the knowledge of pathogen recognition receptor expression profiles in human DC subsets, the most promising cell surface receptors that are currently being explored as possible targets for the induction of tolerance in DCs will be discussed. We also review the different strategies that are being tested to target DC receptors such as antigen-carbohydrate conjugates, antibody-antigen fusion proteins and antigen-adjuvant conjugates.

The topic of standardization in relation to allergen products has been discussed by allergists, regulators, and manufacturers for a long time. In contrast to synthetic medicinal products, the natural origin of allergen products makes the necessary comparability difficult to achieve. This holds true for both aspects of standardization: Batch-to-batch consistency (or product-specific standardization) and comparability among products from different manufacturers (or cross-product comparability). In this review, we focus on how the United States and the European Union have tackled the topic of allergen product standardization in the past, covering the early joint standardization efforts in the 1970s and 1980s as well as the different paths taken by the two players thereafter until today. So far, these two paths have been based on rather classical immunological methods, including the corresponding benefits like simple feasability. New technologies such as mass spectrometry present an opportunity to redefine the field of allergen standardization in the future.

Allergies arise from aberrant T helper type 2 responses to allergens. Several respiratory allergens possess proteolytic activity, which has been recognized to act as an adjuvant for the development of a Th2 response. Allergen source-derived proteases can activate the protease-activated receptor-2, have specific effects on immune cells by cleaving cell membrane-bound regulatory molecules, and can disrupt tight junctions. The protease activity can induce a non-allergen-specific inflammatory response in the airways, which will set the stage for an allergen-specific Th2 response. In this review, we will discuss the evidence for the induction of oxidative stress as an underlying mechanism in Th2 sensitization to proteolytic allergens. We will discuss recent data linking the proteolytic activity of an allergen to its potential to induce oxidative stress and how this can facilitate allergic sensitization. Based on experimental data, we propose that a less proficient anti-oxidant response to allergen-induced oxidative stress contributes to the susceptibility to allergic sensitization. Besides the effect of oxidative stress on the immune response, we will also discuss how oxidative stress can increase the immunogenicity of an allergen by chemical modification.

Background Discovered and described 40 years ago, non‐specific lipid transfer proteins (nsLTP) are present in many plant species and play an important role protecting plants from stressors such as heat or drought. In the last 20 years, sensitization to nsLTP and consequent reactions to plant foods has become an increasing concern. Aim The aim of this paper is to review the evidence for the structure and function of nsLTP allergens, and cross‐reactivity, sensitization, and epidemiology of nsLTP allergy. Materials and Methods A Task Force, supported by the European Academy of Allergy & Clinical Immunology (EAACI), reviewed current evidence and provide a signpost for future research. The search terms for this paper were “Non‐specific Lipid Transfer Proteins”, “LTP syndrome”, “Pru p 3”, “plant food allergy”, “pollen‐food syndrome”. Results Most nsLTP allergens have a highly conserved structure stabilised by 4‐disulphide bridges. Studies on the peach nsLTP, Pru p 3, demonstrate that nsLTPs are very cross‐reactive, with the four major IgE epitopes of Pru p 3 being shared by nsLTP from other botanically related fruits. These nsLTP allergens are to varying degrees resistant to heat and digestion, and sensitization may occur through the oral, inhaled or cutaneous routes. In some populations, Pru p 3 is the primary and sole sensitizing allergen, but many are poly‐sensitised both to botanically un‐related nsLTP in foods, and non‐food sources of nsLTP such as Cannabis sativa, Platanus acerifolia, (plane tree), Ambrosia artemisiifolia (ragweed) and Artemisia vulgaris (mugwort). Initially, nsLTP sensitization appeared to be limited to Mediterranean countries, however more recent studies suggest clinically relevant sensitization occurs in North Atlantic regions and also countries in Northern Europe, with nsLTP sensitisation profiles being broadly similar. Discussion These robust allergens have the potential to sensitize and provoke symptoms to a large number of plant foods, including those which are raw, cooked or processed. It is unknown why some sensitized individuals develop clinical symptoms to foods whereas others do not, or indeed what other allergens besides Pru p 3 may be primary sensitising allergens. It is clear that these allergens are also relevant in non‐Mediterranean populations and there needs to be more recognition of this. Conclusion Non‐specific LTP allergens, present in a wide variety of plant foods and pollens, are structurally robust and so may be present in both raw and cooked foods. More studies are needed to understand routes of sensitization and the world‐wide prevalence of clinical symptoms associated with sensitization to these complex allergens.

Dendritic cells (DCs) are paramount in initiating and guiding immunity towards a state of activation or tolerance. This bidirectional capacity of DCs sets them at the center stage for treatment of cancer and autoimmune or allergic conditions. Accordingly, many clinical studies use ex vivo DC vaccination as a strategy to boost anti-tumor immunity or to suppress immunity by including vitamin D3, NF-κB inhibitors or retinoic acid to create tolerogenic DCs. As harvesting DCs from patients and differentiating these cells in vitro is a costly and cumbersome process, in vivo targeting of DCs has huge potential as nanoparticulate platforms equipped with activating or tolerogenic adjuvants can modulate DCs in their natural environment. There is a rapid expansion of the choices of nanoparticles and activation- or tolerance-promoting adjuvants for a therapeutic vaccine platform. In this review we highlight the most recent nanomedical approaches aimed at inducing immune activation or tolerance via targeting DCs, together with novel fundamental insights into the mechanisms inherent to fostering anti-tumor or tolerogenic immunity.