Food-dependent exercise-induced allergic reactions in Lipid Transfer Protein (LTP) hypersensitive subjects: new data and a critical reappraisal.

Summary: Background. Lipid transfer protein is the main cause of both primary food allergy and food-dependent exercise-induced allergic reactions (FDEIAR) in Italy. What characterizes LTP-hypersensitive patients with FDEIAR is still unclear. We investigated the key characteristics of LTP-hypersensitive patients with or without FDEIAR in a large cohort of individuals sensitized to this allergen. Methods. 1,203 food-allergic patients, diagnosed on the basis of unequivocal clinical history and presence of circulating food allergen-specific IgE were studied. Serum IgE reactivity was assessed using the Allergen ExplorerALEX® system (Macroarray Diagnostics, Vienna, Austria). Association of specific IgE reactivities with FDEIAR was investigated, and patients with and without FDEIAR sensitized to LTP were compared. Results. 116 subjects (9.6%) had FDEIAR. Among these, 77 (66.3%) were LTP-reactors and 16 (13.8%) were sensitized to Tri a 19 (omega-5-gliadin). Different LTPs and omega-5-gliadin emerged as the sole allergens clearly associated with FDEIAR. Severity of allergic reactions was paralleled the level of specific IgE to LTPs. Patients with FDEIAR showed significantly lower IgE levels than their counterparts with food allergy at rest, and displayed nearly identical IgE levels regardless of the severity of allergic reactions induced by exercise. Conclusions. FDEIAR are associated with specific allergens. Specific IgE levels in LTP-hypersensitive patients with FDEIAR show an intermediate titer between those simply sensitized and those showing classic food allergy.

Investigating Novel Food Sensitization: A Real-Life Prevalence Study of Cricket, Locust, and Mealworm IgE-Reactivity in Naïve allergic Individuals.

BACKGROUND AND OBJECTIVE: With the global population on the rise, edible insects are considered a potential solution to food security, although concerns about risks such as anaphylaxis exist. METHODS: 2,014 participants underwent testing with the Allergy Explorer-ALEX-2 including extracts of three novel foods: Acheta Domesticus (Ad), Locusta migratoria (Lm), and Tenebrio molitor (Tm). The IgE-mediated sensitization status was investigated in participants who had never knowingly consumed these insects. Data was recorded using an electronic database. RESULTS: 195 individuals (9.7% of all participants) were sensitized to insects. Tropomyosin was co-recognized by 34%, and 18.5% were positive for arginine kinases. Reactivity to Sarcoplasmic-CB, Troponin-C, Paramyosin, or Myosin-light-chain was found in less than 5% of the population, whereas 108 individuals (55.4%) did not show any reactivity to invertebrate panallergens. Additionally, 33 individuals (16.9%) exhibited monosensitization exclusively to insects. Multivariate analysis revealed an inverse association between arachnid reactivity and sensitization to insect allergens, while Mollusca, Blattoidea, and tropomyosin reactivity displayed a direct relationship. Furthermore, Myosin-light-chain reactivity correlated with Ad and Lm, and Troponin-C with Ad and Tm sensitization. CONCLUSION: Edible insect extract IgE sensitization was observed in individuals without prior exposure to such foods. Mites showed a low likelihood of being primary sensitizers due to their inverse association with insect reactivity. Conversely, the direct association of insect sensitization with mollusk and cockroach extract reactivity suggests their potential as primary sensitizers in these participants. Tropomyosin consistently exhibited a positive association with reactivity to all studied insects, supporting its role as a primary sensitizer.

Clinical severity of LTP syndrome is associated with an expanded IgE repertoire, FDEIA, FDHIH, and LTP mono reactivity.

Summary: Background. LTP allergy is often a challenge for clinicians. We evaluated a multiplex diagnostic approach with diverse cofactors to stratify LTP syndrome risk. Methods. Of the 1,831 participants screened with 'Allergy Explorer-ALEX-2', 426 had reactions to at least one LTP. Data was gathered and recorded via an electronic database. Results. Reactivity to peach Pru p 3 was found in 77% of individuals with LTP allergy. Higher levels of specific IgE and concurrent sensitization to more than 5 molecules (50% of all LTP-sensitised participants, 62% of symptomatic cases) were significantly associated with an increased risk of severe reactions (p = 0.001). Several cofactors, either alone or in combination, also influenced patients' clinical outcomes. Some cofactors increased the risk of severe reactions, such as mono reactivity to LTP in 44.6% of cases (p = 0.001), FDEIA in 10.8% of patients (p = 0.001), and FDNIH in 11.5% (p = 0.005). On the other hand, reactivity to PR10 (24.2%; p = 0.001), profilin hypersensitivity (10.3%; p = 0.001), and/or atopic dermatitis (16.7%; p = 0.001) had a mitigating effect on symptom severity. Conclusions. Clinical severity of LTP syndrome is associated with an expanded IgE repertoire in terms of the number of LTP components recognized and increased IgE levels in individual molecules. Ara h 9, Cor a 8, and Mal d 3 showed the strongest association with clinical severity. In addition, several cofactors may either exacerbate (FDEIA, FDHIH, and LTP monoreactivity) or ameliorate (atopic dermatitis and co-sensitization to profilin and/or PR10) individual patient outcomes. These factors may be utilized for the daily clinical management of LTP syndrome.

Factors predicting the outcome of allergen-specific nasal provocation test in children with grass pollen allergic rhinitis.

Background: Nasal provocation testing (NPT) is a reference methodology to identify the culprit allergen in patients with allergic rhinitis. Selecting the right allergen for NPT is particularly difficult in poly-sensitized patients with seasonal allergic rhinitis (SAR). Predictors of NPT outcomes may facilitate the proper use of this test or even substitute it. Objective: To identify predictors of grass pollen NPT outcome from an array of clinical data, e-diary outcomes, and allergy test results in poly-sensitized pediatric patients with SAR. Methods: Poly-sensitized, SAR patients with grass pollen allergy, participating in the @IT.2020 pilot project in Rome and Pordenone (Italy), participated in a baseline (T0) visit with questionnaires, skin prick testing (SPT), and blood sampling to measure total (ImmunoCAP, TFS, Sweden) and specific IgE antibodies to grass pollen extracts and their major allergenic molecules (ESEP, Euroimmun Labordiagnostika, Germany). During the pollen season, patients filled the AllergyMonitor® e-diary app measuring their symptoms, medication intake, and allergy-related well-being via the Visual Analogue Scale (VAS). After the pollen season (T1), patients answered clinical questionnaires and underwent a nasal provocation test (NPT) with grass pollen extract. Results: We recruited 72 patients (age 14.3 ± 2.8 years, 46 males) sensitized to grass and/or other pollens, including olive (63; 87.5%) and pellitory (49; 68.1%). Patients positive to grass pollen NPT (61; 84.7%), compared to the negative ones, had worse VAS values in the e-diary, larger SPT wheal reactions, and higher IgE levels, as well as specific activity to timothy and Bermuda grass extracts, rPhl p 5 and nCyn d 1. A positive NPT to grass pollen was predicted by an index combining the specific activity of IgE towards Phl p 5 and Cyn d 1 (AUC: 0.82; p < 0.01; best cut-off ≥7.25%, sensitivity 70.5%, specificity: 90.9%). VAS results also predicted NPT positivity, although with less precision (AUC: 0.77, p < 0.01; best cut-off ≥7, sensitivity: 60.7%, specificity: 81.8%). Conclusions: An index combining the specific activity of IgE to rPhl p 5 and nCyn d 1 predicted with moderate sensitivity and high specificity the outcome of a grass pollen NPT in complex, poly-sensitized pediatric patients with seasonal allergic rhinitis. Further studies are needed to improve the index sensitivity and to assess its usefulness for NPT allergen selection or as an alternative to this demanding test procedure.

Eosinophilic granulomatosis with polyangiitis (EGPA) and PRES: a case-based review of literature in ANCA-associated vasculitides.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-sized vessel systemic necrotizing vasculitis and belongs to the family of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. The involvement of central nervous system in this condition is pretty rare. Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity described for the first time by Hinchey et al. (N Engl J Med 334(8):494-500, 1996) and characterized by MRI findings of reversible subcortical vasogenic edema predominantly in the white matter of posterior cerebral lobes. There are few case reports describing the concurrence of PRES with ANCA-associated vasculitides. We describe a case of PRES in a patient with a diagnosis of EGPA with a concise review of the literature. The exact cause of this syndrome is unknown. It has been related to eclampsia, drug-induced hypertension, renal insufficiency and also to rheumatologic diseases. Endothelial injury, hypertension and immunosuppressive medications can compromise the regulation of cerebral blood flow. In ANCA-associated vasculitides, patients presenting with symptoms of PRES represent a challenge to treatment with immunosuppressive medications. However, since an inflammatory process might be implicated, judicious use of these agents along with tight control of blood pressure and a supportive therapy may contribute to the resolution of the encephalopathic syndrome treating at the same time other manifestation related to the rheumatologic disease. Larger clinical studies are warranted to optimize the management of vasculitis-associated PRES.

Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator.

Mismanaged protein trafficking by the proteostasis network contributes to several conformational diseases, including cystic fibrosis, the most frequent lethal inherited disease in Caucasians. Proteostasis regulators, as cystamine, enable the beneficial action of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators in ΔF508-CFTR airways beyond drug washout. Here we tested the hypothesis that functional CFTR protein can sustain its own plasma membrane (PM) stability. Depletion or inhibition of wild-type CFTR present in bronchial epithelial cells reduced the availability of the small GTPase Rab5 by causing Rab5 sequestration within the detergent-insoluble protein fraction together with its accumulation in aggresomes. CFTR depletion decreased the recruitment of the Rab5 effector early endosome antigen 1 to endosomes, thus reducing the local generation of phosphatidylinositol-3-phosphate. This diverts recycling of surface proteins, including transferrin receptor and CFTR itself. Inhibiting CFTR function also resulted in its ubiquitination and interaction with SQSTM1/p62 at the PM, favoring its disposal. Addition of cystamine prevented the recycling defect of CFTR by enhancing BECN1 expression and reducing SQSTM1 accumulation. Our results unravel an unexpected link between CFTR protein and function, the latter regulating the levels of CFTR surface expression in a positive feed-forward loop, and highlight CFTR as a pivot of proteostasis in bronchial epithelial cells.

TBP-1 protects the human oncosuppressor p14ARF from proteasomal degradation.

The p14ARF tumor suppressor is a key regulator of cellular proliferation, frequently inactivated in human cancer. The mechanisms that regulate alternative reading frame (ARF) turnover have been obscure for long time, being ARF a relatively stable protein. Recently, it has been described that its degradation depends, at least in part, on the proteasome and that it can be subjected to N-terminal ubiquitination. We have previously reported that ARF protein levels are regulated by TBP-1 (Tat-Binding Protein 1), a multifunctional protein, component of the regulatory subunit of the proteasome, involved in different cellular processes. Here we demonstrate that the stabilization effect exerted by TBP-1 requires an intact N-terminal 39 amino acids in ARF and occurs independently from N-terminal ubiquitination of the protein. Furthermore, we observed that ARF can be degraded in vitro by the 20S proteasome, in the absence of ubiquitination and this effect can be counteracted by TBP-1. These observations seem relevant in the comprehension of the regulation of ARF metabolism as, among the plethora of cellular ARF's interactors already identified, only NPM/B23 and TBP-1 appear to be involved in the control of ARF intracellular levels.