The Emerging Role of Innate Lymphoid Cells (ILCs) and Alarmins in Celiac Disease: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications.

Celiac disease (CD) is an intestinal disease that develops in genetically predisposed individuals and is triggered by the ingestion of gluten. CD was considered a Th1-disease. Today, the role of Th17, IL-21, and IL-17A lymphocytes is well known. Inflammation is regulated by the activity of gluten-specific CD4+ T lymphocytes that produce pro-inflammatory cytokines, including IFN-γ, TNF-α, and IL-21, perpetuating the Th1 response. These cytokines determine an inflammatory state of the small intestine, with consequent epithelial infiltration of lymphocytes and an alteration of the architecture of the duodenal mucosa. B cells produce antibodies against tissue transglutaminase and against deamidated gliadin. Although the role of the adaptive immune response is currently known, the evidence about the role of innate immunity cells is still poorly understood. Epithelial damage determines the release of damage-associated molecular patterns (DAMPs), also known as alarmins. Together with the intestinal epithelial cells and the type 1 innate lymphoid cells (ILC1s), alarmins like TSLP, IL-33, and HMGB1 could have a fundamental role in the genesis and maintenance of inflammation. Our study aims to evaluate the evidence in the literature about the role of ILCs and alarmins in celiac disease, evaluating the possible future diagnostic and therapeutic implications.

Emerging Role of Alarmins in Food Allergy: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications.

Food allergies are immuno-mediated adverse reactions to ingestion or contact with foods, representing a widespread health problem. The immune response can be IgE-mediated, non-IgE-mediated, or with a mixed mechanism. The role of innate immunity and alarmins in the pathogenesis of diseases such as asthma and atopic dermatitis is well known. Some authors have investigated the correlation between alarmins and food allergies, often obtaining interesting results. We analyzed articles published in English from the last 22 years present on PubMed concerning the role of alarmins in the pathogenesis of food allergies and their potential use as disease biomarkers, response biomarkers to therapy, or potential therapeutic targets. Nuclear alarmins (TSLP, IL-33, IL-25) appear to have a critical role in IgE-mediated allergies but are also implicated in entities such as eosinophilic esophagitis. Calprotectin and defensins may play a role as disease biomarkers and could help predict response to therapy, although results in the literature are often conflicting. Despite the promising results, more studies on humans still need to be conducted. Deepening our knowledge regarding alarmins and their involvement in food allergies could lead to the development of new biological therapies, significantly impacting patients' quality of life.

Datterino Trial: A Double Blind, Randomized, Controlled, Crossover, Clinical Trial on the Use of Hydroponic Cultivated Tomato Sauce in Systemic Nickel Allergy Syndrome.

A low-nickel (Ni) diet, a key treatment for Systemic Nickel Allergy Syndrome (SNAS), is difficult in the long term and strongly impacts quality of life (QoL). Hydroponic agriculture could be an alternative to allow the reintroduction of tomato, an essential food in the global diet. In a first interventional, randomized, double-blind, single-center crossover study, we compared the possible effects of eating tomato puree deriving from hydroponic agriculture versus tomato puree from conventional cultivation, collecting data on subjective control of SNAS symptoms, adherence to treatment, and impact on QoL. Thirty subjects were randomly assigned to one of the following treatment groups: (1) a 12-week low-Ni diet plus 100% Italian Datterino tomato puree deriving from hydroponic technology; (2) a 12-week low-Ni diet plus 100% Italian Datterino tomato puree deriving from conventional cultivation. Then, after a 2-week washout period on the low-Ni diet, each patient crossed over to the other treatment. Patients reported lower symptom scores after eating Datterino tomato puree deriving from hydroponic technology; specifically, bloating (p = 0.0111, p = 0.0060), flatulence (p = 0.0090), abdominal cramps (p = 0.0207), constipation (p = 0.0395), and diarrhea (p = 0.0105). Overall, the adherence rate was high for both treatment arms. At baseline, QoL was poor, but significant improvement was observed after two treatments. In our study, precision medicine and precision agriculture merge in a holistic approach to the challenges of food allergies.

Diet Intervention Study through Telemedicine Assistance for Systemic Nickel Allergy Syndrome Patients during the COVID-19 Pandemic.

BACKGROUND: Restrictions due to the COVID-19 pandemic limited patients' access to hospital care. The aims of this study were to assess dietary nutritional status, quality of life (QoL), and adherence to dietary therapy before and after 30-day personalized diet therapy through telenutrition tools in patients with systemic nickel allergic syndrome (SNAS). METHODS: Each SNAS patient underwent the following allergological procedures: (a) face-to-face visit (nutritional visit and QoL evaluation) with prescription of one out of five personalized and balanced dietary plans different for calorie intake, (b) video call visit for dietary evaluation and assessment of adherence to diet after 15 days, and (c) video call visit for dietary and QoL evaluation and assessment of adherence to diet therapy after 30 days (end of study). RESULTS: We enrolled 20 SNAS patients. After 15 and 30 days, we found a statistically significant improvement in anthropometric findings after diet therapy, a significant adherence rate to low-nickel diet (60% and 80%, respectively), and an improvement in QoL with an increase in almost all psychometric indices. CONCLUSIONS: Our study demonstrates that telenutrition can be a valid tool to monitor nutritional status and adherence to balanced low-Ni diet positively affecting QoL in SNAS patients during the COVID-19 pandemic.

Immediate allergic reaction to thiocolchicoside confirmed by skin testing and basophil activation test: A case report and literature review.

BACKGROUND: Thiocolchicoside is a muscle relaxant, anti-inflammatory, and analgesic. Administered orally, intramuscularly, or topically, this drug is used in the symptomatic treatment of muscular spasms and rheumatologic disorders. Despite its extensive use, thiocolchicoside is a very rare sensitizer. OBJECTIVE: To evaluate IgE-mediated reaction to thiocolchicoside by basophil activation test. METHODS: Allergological work-up with skin prick tests, intradermal tests and basophil activation test with thiocolchicoside. RESULTS: We report the first case of immediate reaction to thiocolchicoside confirmed by basophil activation test in addition to positive skin tests. CONCLUSIONS: BAT can be considered a complementary diagnostic tool to demonstrate an IgE-mediated reaction also for muscle relaxant drugs.

Nickel allergy in lipid transfer protein sensitized patients: Prevalence and clinical features.

Nickel (Ni), the main responsible for allergic contact dermatitis worldwide, is also involved in systemic condition called "Systemic Nickel Sulfate Allergy Syndrome (SNAS)." Likewise, IgE-mediated reactivity to Lipid Transfer Protein (LTP) represents the main cause of primary food allergy in adults of Mediterranean countries. We evaluated the prevalence of SNAS in LTP allergic patients and investigated patients' clinical features with double sensitization (LTP and Ni). A retrospective, single-center, observational study was conducted performing a complete allergological work-up including: (1) skin prick tests; (2) serum specific IgE for plant food allergens and rPru p3 (LTP); (3) patch test with 5% Ni sulfate in petrolatum. We enrolled 140 LTP allergic patients of which 36 patients (25.7% of sample) showed additional positivity to Ni patch test. Patients with double sensitization were more frequently females and reported fewer cutaneous symptoms. Higher values of sIgE for peach, apple, peanut, walnut, grain, corn, and garlic were found in LTP allergic patients, while higher values for hazelnut in the other subgroup. The prevalence of SNAS in the LTP allergic population is clinically relevant. Moreover, the clinical and immunological profiles of patients with double sensitization were different from patients monosensitized to LTP.

Eosinophilic oesophagitis (in nickel-allergic patient) regressed after nickel oral desensitization: A case report.

The eosinophilic oesophagitis (EoE) is a chronic immune/antigen disorder of the oesophagus clinically characterized by dysphagia and pathologically by mucosa eosinophilic infiltration. Th2-type allergic reactions are considered having important roles in the aetiopathogenesis of EoE. Avoidance of food allergens, administration of steroidal anti-inflammatory medications and dilation of the oesophagus are the most important treatments. 'Systemic nickel allergy syndrome' (SNAS) interests about 20% of patients with nickel contact allergy which could present systemic cutaneous manifestations (urticaria, oedema, etc.) and also respiratory and digestive symptoms (meteorism, abdominal pain, diarrhoea, etc.). In the literature, it is demonstrated that nickel oral immunotherapy is effective in reducing symptoms of SNAS and in modulating inflammatory parameters. We describe the case of a 48-year-old woman suffering from EoE not responsive to the topical steroid administration and diagnosis of SNAS. The patient started nickel oral desensitization according to the literature protocol continuing nickel-free diet. After 1 year from the beginning of the treatment, during the maintenance dose (500 ng three times a week), she decreased gradually the dosage of immunotherapy and reintroduced all the culprit foods. After the immunotherapy interruption, during the free diet, she repeated the oesophagogastroscopy with a complete macroscopic and histological resolution. We showed the first case of an EoE in a patient affected by SNAS responsive to the nickel-free diet and the oral immunotherapy.