Dimitri Poddighe

IgE-mediated systemic anaphylaxis and impaired tolerance to food antigens in mice with enhanced IL-4 receptor signaling

BACKGROUND In atopic subjects food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays a critical role in this response, and genetic polymorphisms in its components have been linked to allergy. OBJECTIVE We sought to test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen. METHODS F709 mice, in which the IL-4Rα immunoreceptor tyrosine-based inhibitory motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses, including antibody production and T(H)2 responses, were assessed. RESULTS F709 mice, but not wild-type control animals, sensitized by means of gavage with OVA and either cholera toxin or staphylococcal enterotoxin B, displayed mast cell activation and systemic anaphylaxis on enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic T(H)2 responses, and intestinal mast cell hyperplasia compared with wild-type mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high-affinity receptor for IgE (FcεRI). CONCLUSION Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE dependent.

IgE Influences the Number and Function of Mature Mast Cells, but Not Progenitor Recruitment in Allergic Pulmonary Inflammation

Studies performed using cultured cells indicate that IgE functions not only to trigger degranulation of mast cells following allergen exposure, but also to enhance their survival. Such an influence of IgE on mast cell homeostasis during allergic responses in vivo has not been established. In this study, we show that inhalation of Aspergillus fumigatus extract in mice induced a dramatic rise in IgE accompanied by an increase in airway mast cells. These had an activated phenotype with high levels of FcεRI. Plasma mast cell protease-1 was also increased, indicating an elevated systemic mast cell load. In addition, enhanced levels of IL-5 and eosinophils were observed in the airway. Both mast cell expansion and activation were markedly attenuated in IgE−/− animals that are incapable of producing IgE in response to A. fumigatus. The recruitment of eosinophils to the airways was also reduced in IgE−/− mice. Analyses of potential cellular targets of IgE revealed that IgE Abs are not required for the induction of mast cell progenitors in response to allergen, but rather act by sustaining the survival of mature mast cells. Our results identify an important role for IgE Abs in promoting mast cell expansion during allergic responses in vivo.

Increased risk of otitis media with effusion in allergic children presenting with adenoiditis

Objective Otitis media with effusion (OME) is a common disorder in childhood. The aim of the study was to assess the association of atopy and endoscopic features with the presence of OME. Subjects and Methods This cross-sectional study evaluated 287 children presenting with acute upper-airway infections persistent for at least ten days and tested through nasal endoscopy and skin-prick test. Results Fifty-three patients had a diagnosis of OME; out of them, 23 showed acute rhinosinusitis, ten adenoiditis, and 20 both features. OME was diagnosed in 26 atopic children and in 27 nonatopic ones. On a multivariable analysis, allergic rhinitis, endoscopic pattern of adenoiditis, and younger age were all shown to be independently associated with a diagnosis of OME. Conclusions This study suggests that allergic rhinitis and adenoiditis are significant risk factors to OME development and that the risk becomes higher when these two conditions are con-comitantly present.

Passive exposure to smoke results in defective interferon-γ production by adenoids in children with recurrent respiratory infections.

There is evidence that exposure to passive smoke is associated with an increased susceptibility to respiratory infections. Indeed, cigarette smoke extracts may interfere with the immune system, even though the precise mechanism has not been fully understood yet. Recurrent respiratory infections may be sustained by a defective immune response. The aim of the present study was to evaluate whether, in a cohort of children presenting both with recurrent respiratory infections and with a history of exposure to tobacco smoke, these factors were related to a lower local production of interferon-gamma (IFN-gamma) when compared to a similar non-exposed population. The study group included 128 children undergoing adenoidectomy, presenting with more than three respiratory infections per year, independently of exposure to passive smoke at home. The intracellular cytokine profile of lymphocyte subsets in adenoids was evaluated by flow cytometry analysis. Children exposed to tobacco smoke suffered from a significantly greater number of respiratory infections and had a lower percentage of IFN-gamma-producing CD8+ cells in adenoids than non-exposed children, while other T-cell subsets were not affected. The effect of smoke exposure seems to be specific to the IFN-gamma-producing CD8+ cells in adenoids and may contribute to the increased susceptibility to the recurrence of respiratory infections.

A sudden onset of a pseudo-neurological syndrome after HPV-16/18 AS04-adjuvated vaccine: might it be an autoimmune/inflammatory syndrome induced by adjuvants (ASIA) presenting as a somatoform disorder?

In last centuries, vaccines reduced the incidence of several infectious diseases. In last decades, some vaccines aimed at preventing also some cancers, where viruses play a causative role. However, several adverse events have been described after vaccines, but a causal relationship has been established only in a minority of cases. Here, we describe a pseudo-neurological syndrome occurred shortly after the administration of the bivalent HPV vaccine. Some autoimmune disorders, including neurological demyelinating diseases, have been reported after HPV vaccines, but the patient showed no organic lesions. The patient was diagnosed as having a functional somatoform syndrome, which was supposed to be autoimmune/inflammatory syndrome induced by adjuvants (ASIA), seen the temporal link with vaccination and the presence of anti-phospholipid autoantibodies. Immunological mechanisms of vaccines—and of adjuvants—have not been completely elucidated yet, and although there is no evidence of statistical association with many post-vaccination events, a causal link with vaccine cannot be excluded in some individuals.

Acute acalculous cholecystitis associated with severe EBV hepatitis in an immunocompetent child.

Acute acalculous cholecystitis (AAC) is an inflammation of the gallbladder in the absence of demonstrated stones, which is rarely seen in paediatric population. The diagnosis is accomplished mainly through abdominal ultrasonography in the appropriate but usually non-specific clinical picture. Complicated cases need surgical intervention; the medical management is mainly constituted by supportive and antibiotic therapy, as most AAC are observed in the setting of systemic bacterial or parasitic infections. However, AAC has been rarely reported in association with Epstein–Barr virus (EBV) infection, where the gastrointestinal involvement is often mild and thus unrecognised. We report a case of EBV-related AAC associated with unusually severe hepatitis in an immunocompetent and otherwise healthy patient. We describe its benign clinical course, despite the serious liver impairment, by a medical management characterised by the prompt discontinuation of broad-spectrum antibiotics, as soon as EBV aetiology is ascertained, and by the appropriate analgesia and fluid resuscitation.

Response to long-term growth hormone therapy in short children with reduced GH bioactivity

Background/Aims: The aim of the present study was to investigate whether short children with normal growth hormone (GH) immunoreactivity, but reduced bioactivity (bioinactive GH) could benefit from rhGH treatment as GH deficient (GHD) patients. Methods: We evaluated 12 pre-pubertal children (8 M, 4 F), with GH deficiency-like phenotype showing normal serum GH peak levels (>10 ng/ml), measured by immunofluorimetric assay (IFMA-GH), in contrast with a reduced GH bioactivity (bio-GH), evaluated using the Nb2 cells. We also evaluated 15 age-matched GHD pre-pubertal children (11 M, 4 F) with serum GH peak <5 ng/ml. Both groups were treated with rhGH therapy at the dose of 0.23 mg/kg/week s.c. Results: Serum bio-GH/IFMA-GH ratio at peak time for each patient during the provocative test was significantly lower in bioinactive GH than in GHD children (0.29 vs. 2.05, p = 0.00001). Recombinant human GH therapy induced a significant (p < 0.001) increase in growth rate in both groups during the first 2 years. In the third year of treatment, while growth rate in GHD children is maintained, in bioinactive GH patients it decreases remaining, however higher compared to the pre-treatment one. Conclusions:Short rhGH therapy given to selected bioinactive GH children improve growth rate and might result in greater final adult height.

Sublingual immunotherapy for pediatric allergic rhinitis: The clinical evidence

Allergic rhinitis is estimated to affect 10%-20% of pediatric population and it is caused by the IgE-sensitization to environmental allergens, most importantly grass pollens and house dust mites. Allergic rhinitis can influence patients daily activity severely and may precede the development of asthma, especially if it is not diagnosed and treated correctly. In addition to subcutaneous immunotherapy, sublingual immunotherapy (SLIT) represents the only treatment being potentially able to cure allergic respiratory diseases, by modulating the immune system activity. This review clearly summarizes and analyzes the available randomized, double-blinded, placebo-controlled trials, which aimed at evaluating the effectiveness and the safety of grass pollen and house dust mite SLIT for the specific treatment of pediatric allergic rhinitis. Our analysis demonstrates the good evidence supporting the efficacy of SLIT for allergic rhinitis to grass pollens in children, whereas trials regarding pediatric allergic rhinitis to house dust mites present lower quality, although several studies supported its usefulness.

Acalculous Acute Cholecystitis in Previously Healthy Children: General Overview and Analysis of Pediatric Infectious Cases

Acute acalculous cholecystitis (AAC) is an inflammation of the gallbladder, which does not appear to be associated with the presence of gallstones. AAC is estimated to represent more than 50% of cases of acute cholecystitis in the pediatric population. Although this pathology was initially described in critically ill patients, actually most pediatric cases have been observed during several infectious diseases. Particularly, here we reviewed pediatric infectious acute acalculous cholecystitis and analyzed the pathophysiological and clinical aspects of bacterial and viral forms.

The role of upper airway pathology as a co-morbidity in severe asthma

ABSTRACT Introduction: Severe asthma is a complex heterogeneous disease that is refractory to standard treatment and is complicated by multiple co-morbidities and risk factors. Several co-morbidities may contribute to worsen asthma control and complicate diagnostic and therapeutic management of severe asthmatic patients. Areas covered: A prevalent cluster of chronic upper airway co-morbid diseases is recognized in severe asthma. Evaluation for these disorders should always be considered in clinical practice. The aim of this review is to provide an updated overview of the prevalence, the pathogenetic mechanisms, the clinical impact and the therapeutic options for upper airway pathology in severe asthma, focusing on chronic rhinosinusitis and allergic rhinitis. Expert commentary: In the context of severe asthma, the clinical significance of upper airway co-morbidities is based on mutual interactions complicating diagnosis and management. A better analysis and understanding of phenotypes and endotypes of both upper and lower airway diseases are crucial to further develop targeted treatment.