B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome

Background Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene-corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach. Objective Because B-cell homeostasis is perturbed in patients with WAS and restoration of immune competence is one of the main therapeutic goals, we have evaluated reconstitution of the B-cell compartment in 4 patients who received autologous hematopoietic stem cells transduced with lentiviral vector after a reduced-intensity conditioning regimen combined with anti-CD20 administration. Methods We evaluated B-cell counts, B-cell subset distribution, B cell-activating factor and immunoglobulin levels, and autoantibody production before and after gene therapy (GT). WAS gene transfer in B cells was assessed by measuring vector copy numbers and expression of Wiskott-Aldrich syndrome protein. Results After lentiviral vector-mediated GT, the number of transduced B cells progressively increased in the peripheral blood of all patients. Lentiviral vector-transduced progenitor cells were able to repopulate the B-cell compartment with a normal distribution of B-cell subsets both in bone marrow and the periphery, showing a WAS protein expression profile similar to that of healthy donors. In addition, after GT, we observed a normalized frequency of autoimmune-associated CD19+CD21-CD35- and CD21low

Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans

Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott-Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21low B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells. In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Research needs in allergy: an EAACI position paper, in collaboration with EFA

Abstract In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21 st century. The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients' Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients' organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels. Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein

Occupational allergy to food-derived allergens

Although most cases of food allergy are related to food ingestion, occupational exposure to foods by contact or inhalation may also lead to adverse reactions, inducing contact urticaria or dermatitis, asthma, rhinitis, hypersensitivity pneumonitis, and anaphylaxis. Almost 10–25% of cases of allergic occupational asthma and rhinitis are due to food products. Animal and vegetal high-molecular weight proteins derived from aerosolized foods during food processing or handling at the workplace, as well as additives used as preservatives and antioxidants, and food contaminants, are the main causal agents. Farmers who grow and harvest crops and workers employed in food processing, storage and packing, and those involved in food preparation and transport are considered at increased risk for developing food-induced occupational asthma and rhinitis. Bakers’ asthma is the most frequent type of occupational asthma all around the world. Seafood processing industry is also at higher risk for asthma and rhinitis. A proportion of cases of asthma and rhinitis in food industry is also related to latex gloves used during food processing. The diagnosis of food-related occupational asthma and rhinitis includes a careful clinical and occupational history, respiratory functional assessment and measurement of non-specific bronchial hyperresponsiveness, immunologic assessment and specific inhalation challenge. The management includes environmental interventions aimed to avoid or reduce exposure to the offending agent, pharmacologic therapy, and allergen immunotherapy when available. Only few cases of food-induced occupational anaphylaxis have been described. The management of these emergencies should follow the current guidelines on anaphylaxis. The worker should be educated in managing future possible episodes that may also occur out of the workplace, by instance after accidental ingestion of the culprit allergen, and to carry 2 pre-loaded adrenaline delivery systems and a MedicAlert bracelet

Analisi di una casistica ospedaliera di neoplasie professionali

Finalità: Verificare la frequenza con la quale le neoplasie professionali sono diagnosticate nell’attuale pratica ospedaliera e acquisire informazioni, utilizzabili in ambito preventivo, sulle loro caratteristiche eziologiche e anatomo-cliniche. Pazienti e metodi: Sono stati individuati i tumori segnalati dal nostro Istituto all’INAIL come professionali nel quinquennio 2001-2005. Dalla documentazione clinica dei singoli casi sono stati quindi ricavati i dati relativi a: sede d’insorgenza, tipo istologico, agenti causali, settori lavorativi e mansioni a rischio, durata dell’esposizione, periodo di latenza, abitudine al fumo, eventuali patologie concomitanti. Risultati: Nel periodo considerato, sono stati diagnosticati 16 tumori occupazionali in 15 soggetti maschi, in prevalenza fumatori o ex-fumatori, tutti in seguito deceduti. Tale numero è inferiore a quanto prevedibile in base ad alcune stime epidemiologiche. La casistica comprende 8 casi di carcinoma polmonare, 6 di mesotelioma pleurico maligno e 2 di urotelioma vescicale. L’amianto (tumori respiratori) è risultato l’agente eziologico più frequentemente implicato, seguito dagli idrocarburi policiclici aromatici (carcinomi polmonari e vescicali) e dalla silice cristallina (due carcinomi polmonari, di cui uno insorto in un minatore già affetto da silicosi). Edili (6 casi) e metalmeccanici (4 pazienti) sono stati i lavoratori più colpiti. I tumori sono insorti in seguito ad esposizioni reiterate negli anni e (tranne che in due soggetti) dopo lunghi periodi di latenza dall’allontanamento dal rischio. Conclusioni: Le neoplasie professionali sono probabilmente sottostimate nella pratica clinica. Un’accurata anamnesi lavorativa è fondamentale per la loro diagnosi eziologica. L’apparato respiratorio e la vescica urinaria continuano a essere bersagli preferenziali per l’oncogenesi occupazionale. L’edilizia e l’industria metalmeccanica sono le attività produttive a rischio maggiore, per le quali maggiormente si impongono migliori misure preventive. In particolare, sono necessari programmi di sorveglianza sanitaria per i soggetti con pregressa esposizione ad amianto

Rootstock effects on postharvest physiological and pathological behaviour of "Avana" mandarin

Influences of five rootstocks on "Avana" mandarin fruit yield and storage behaviour were studied. Sour Orange stock imparted the highest fruit yield. At harvest, significant differences in fruit quality were observed among the scion-rootstock combinations when pH, total acidity (TA) and ascorbic acid content were compared, while total soluble solids (TSS) were not significantly different. Ascorbic acid and pH were the only parameters not significantly different during the years. Fruit size was the most uniform on sour orange stock. Avana storage behaviour was more affected by the rootstock than by the temperature. The percentage of fruit disease was significantly affected by the rootstocks. The Sour Orange stock imparted the lowest diseases either at 2 or 8°C. Fruit grown on the sour orange rootstock evidenced the highest susceptibility to chilling injury. A triangular sensorial panel test enabled us to distinguish 3 of the 5 scion-stock combinations at harvest and during the whole experiment

[Fractional exhaled nitric oxide measurement during specific inhalation challenge tests]

The aim of the work is to evaluate the usefulness of the evaluation of the fractional exhaled nitric oxide (FeNO) in patients with suspected occupational asthma (OA) during the specific inhalation challenge (SIC). We evaluated 5 subjects with OA confirmed by SIC and 7 subjects with negative SIC result. In subjects with confirmed OA, but not in SIC negative subjects, a significant increase in FeNO values has been reported. In conclusion, FeNO measurement may be considered a useful tollfor the evaluation of bronchial inflammation during the SIC