Stephen J. Till

Background: IgE antibodies directed against cancer antigens have demonstrated potent anti‐tumour effects in pre‐clinical studies. MOv18 IgE, the first‐in‐class IgE recognising the cancer antigen folate receptor alpha (FRα), showed preliminary signs of efficacy in a Phase I trial. Treatment was well tolerated, with the most common adverse event being transient urticarial skin reactions. We investigated immunological and allergic response parameters associated with urticarial skin reactions in MOv18 IgE‐treated patients. Methods: Expression of target antigen, FRα, and MOv18 IgE reactivity with FRα or any component in human skin was studied by immunohistochemistry, immunofluorescence and immuno‐mass spectrometry. We conducted transcriptomic analyses in paired lesional and non‐lesional skin biopsies from a patient who developed an urticarial skin reaction. Systemic immunological markers including cytokines, β‐tryptase and basophil activation states were interrogated throughout the trial and contemporaneously with the skin reaction. Results: Of the 24 IgE‐treated patients, 62.5% developed transient urticarial skin reactions, with onset during the first infusion, diminishing with consecutive infusions and no β‐tryptase elevation nor clinical features indicating allergic aetiology. No FRα expression or MOv18 IgE binding to human skin was identified. Lesional skin biopsies from a patient given the highest antibody dose revealed scattered eosinophils, neutrophils and mast cell degranulation, but no increased immune cell infiltration. Transcriptomic analysis indicated pro‐inflammatory, but not allergic, pathway activation. No systemic allergic or hypersensitivity mediators or basophil activation were detected. Conclusions: Urticarial skin reactions following MOv18 IgE treatment were unlikely to result from allergic mechanisms or skin antigen recognition. The clinical presentation is consistent with infusion‐related reactions commonly observed with monoclonal antibody treatments. Trial Registration: EudraCT number: 2014‐000070‐19; ClinicalTrials.gov identifier: NCT02546921, registered 11/Sept/2015

Background: Alarmin cytokine IL‐25 promotes type 2 inflammatory responses in disorders such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) and known targets include ILC2 and Th2 cells. However, other cellular targets for IL‐25 remain poorly defined. Objective: To investigate induction and expression of IL‐25 receptor (IL‐17RB) by B cells and evaluate responsiveness of IL‐17RB‐expressing B cells to IL‐25 in vitro. Methods: IL‐17RB expression, regulation and function on B cells were evaluated in peripheral blood‐derived B cells by flow cytometry and RT‐PCR, including in response to IgE‐inducing stimuli (anti‐CD40 mAb and IL‐4). Single‐cell RNA sequencing was used to compare IL‐17RB+ and IL‐17RB‐activated peripheral blood‐derived B cells. To evaluate B cell IL‐17RB expression within type 2 inflamed tissue, B cells were compared from nasal polyps, control turbinate tissue and matched peripheral blood. Results: Activation of B cells with anti‐CD40 and IL‐4 increased IL‐17RB expression at both protein and mRNA level, which was further upregulated by IL‐25. B cells induced to express IL‐17RB responded to IL‐25 with enhanced antibody production. Single‐cell RNA‐sequencing showed that IL17RB+ activated B cells expressed higher levels of IGHE, CCL17 and CCL22 compared to IL17RB‐ B cells. B cells from nasal polyp tissue expressed higher levels of surface IL‐17RB compared with control tissue, correlating with patient‐reported CRSwNP severity (SNOT‐22). Conclusion: Peripheral blood B cells activated under IgE‐inducing conditions express surface IL‐17RB, and tissue IL‐17RB+ B cells are increased in type 2 inflammation. IL‐17RB+ cells have a distinct transcriptional profile and respond to IL‐25 with enhanced antibody production, highlighting the IL‐25/IL‐17RB pathway as a potential therapeutic target for CRSwNP and other type 2 inflammatory disorders.

Background & Aims The role of inhaled and subsequently swallowed aeroallergens in treatment outcomes of adults with eosinophilic esophagitis (EoE) is unclear. We hypothesized that the pollen season contributes to the failure of dietary therapy in EoE. In this international two-centre study, we compared six-food elimination diet (SFED) outcomes of EoE patients assessed on- versus off- pollen season. Methods Consecutive adult patients (≥18 years) with EoE who underwent SFED and skin prick test (SPT) for birch and grass pollen were included. Demographics, atopy, SPT results, endoscopy findings (EREFS), and the date of the endoscopy following SFED were retrospectively extracted. Individual sensitization profiles and historical pollen count data were scrutinized to define whether each patient had been assessed on or off pollen season following SFED. For patients without pollen sensitization, Spring (March, April, May) was considered as on-pollen season for comparison purposes. Patients were divided into group A (positive SPT for pollens) or B (negative SPT for pollens). All patients had active EoE before SFED (eosinophils ≥15/high-power field, HPF) and adhered to SFED under the supervision of a dietitian. Response to SFED (eosResults Fifty-eight patients were included, 62.0% had positive SPT for grass and/or birch (group A), while in 37.9% SPT was negative (group B). Significantly more patients from group A also had positive SPT for dust mite, cat and/or dog dander (85.7% vs 31.8%, pp=0.003). Additionally, on pollen season, patients with positive SPT for pollens had significantly lower response to SFED compared to those with negative SPT (21.4% vs 77.8%; p=0.01). Patients without pollen sensitization did not show seasonal variations in SFED response (66.7% vs 53.8%; p=0.67) (table 1). Conclusion Pollens may have a role in sustaining esophageal eosinophilia in sensitized adults with EoE despite avoidance of trigger foods. SPT for pollens may have a clinical utility in the dietary management of EoE by identifying patients less likely to respond to SFED during pollen season. Seasonal variation in six-food elimination diet (SFED) response in patients with (group A) or without (group B) sensitization to pollens

Pollen food syndrome (PFS) is a highly prevalent food allergy affecting pollen‐sensitized children and adults. Sufferers experience allergic symptoms when consuming raw plant foods, due to the homology between the pollen allergens and unstable proteins in these foods. The triggers involved can vary depending on the pollen sensitization, which in turn is affected by geographical location. The British Society of Allergy and Clinical Immunology (BSACI) Standards of Care Committee (SOCC) identified a need to develop a guideline for the diagnosis and management of PFS in the United Kingdom (UK). Guidelines produced by the BSACI use either the GRADE or SIGN methodology; due to a lack of high‐quality evidence these recommendations were formulated using the SIGN guidelines, which is acknowledged to be less robust than the GRADE approach. The correct diagnosis of PFS ensures the avoidance of a misdiagnosis of a primary peanut or tree nut allergy or confusion with another plant food allergy to non‐specific lipid transfer proteins. The characteristic foods involved, and rapid‐onset oropharyngeal symptoms, mean PFS can often be diagnosed from the clinical history alone. However, reactions involving tree nuts, peanuts and soya milk or severe/atypical reactions to fruits and vegetables may require additional diagnostic tests. Management is through the exclusion of known trigger foods, which may appear to be simple, but is highly problematic if coupled with a pre‐existing food allergy or for individuals following a vegetarian/vegan diet. Immunotherapy to pollens is not an effective treatment for PFS, and although oral or sublingual immunotherapy to foods seems more promising, large, controlled studies are needed. The typically mild symptoms of PFS can lead to an erroneous perception that this condition is always easily managed, but severe reactions can occur, and anxiety about the onset of symptoms to new foods can have a profound effect on quality of life.

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.

Basophils are involved in manifestations of hypersensitivity, however, the current understanding of their propensity for activation and their prognostic value in cancer patients remains unclear. As in healthy and atopic individuals, basophil populations were identified in blood from ovarian cancer patients (n = 53) with diverse tumor histologies and treatment histories. Ex vivo basophil activation was measured by CD63 expression using the basophil activation test (BAT). Irrespective of prior treatment, basophils could be activated by stimulation with IgE- (anti-FcεRI and anti-IgE) and non-IgE (fMLP) mediated triggers. Basophil activation was detected by ex vivo exposure to paclitaxel, but not to other anti-cancer therapies, in agreement with a clinical history of systemic hypersensitivity reactions to paclitaxel. Protein and gene expression analyses support the presence of basophils (CCR3, CD123, FcεRI) and activated basophils (CD63, CD203c, tryptase) in ovarian tumors. Greater numbers of circulating basophils, cells with greater capacity for ex vivo stimulation (n = 35), and gene signatures indicating the presence of activated basophils in tumors (n = 439) were each associated with improved survival in ovarian cancer. Circulating basophils in cancer patients respond to IgE- and non-IgE-mediated signals and could help identify hypersensitivity to therapeutic agents. Activated circulating and tumor-infiltrating basophils may be potential biomarkers in oncology.

Background: Although pollen‐related food allergy occurs in all European populations, lipid transfer protein (LTP) allergy is considered to manifest mainly in Mediterranean countries. We aimed to characterize adults presenting with LTP allergy in a northern European country.Method: The clinical history and sensitization patterns of subjects born and residing in the United Kingdom (UK), with a prior diagnosis of LTP allergy and sensitization to the peach LTP allergen Pru p 3, were compared to UK subjects with pollen food syndrome (PFS). The sensitization patterns were also evaluated against a matched cohort of Italian subjects diagnosed with LTP allergy.Results: None of the 15 UK PFS subjects had a positive SPT to LTP‐enriched peach reagent, compared to 91% of the 35 UK LTP subjects. The UK LTP cohort were also more likely to have positive skin prick tests to cabbage, lettuce and mustard and sensitization to the LTP allergens in peach, walnut, mugwort and plane tree These sensitization patterns to individual allergens were not significantly different to those obtained from the Italian LTP subjects, with significant correlations between Pru p 3 and the LTP allergens in peanuts, walnuts, plane tree and mugwort in both groups.Conclusion: Native UK subjects with LTP allergy are not dissimilar to those with LTP allergy in southern Europe. Testing to LTP‐enriched peach SPT reagent and/or LTP allergens in peach, walnut, mugwort and plane tree may enhance diagnostic accuracy.