Rosa Maria Dellepiane

Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.

Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. As in few reported cases, CD25 deficiency manifests with severe autoimmune enteritis and viral infections. To dissect the underlying immunological mechanisms driving these symptoms, we analyzed the regulatory and effector T cell functions in a CD25 deficient patient harboring a novel IL2RA mutation. Pronounced lymphoproliferation, mainly of the CD8+ T cells, was detected together with an increase in T cell activation markers and elevated serum cytokines. However, Ag-specific responses were impaired in vivo and in vitro. Activated CD8+STAT5+ T cells with lytic potential infiltrated the skin, even though FOXP3+ Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets. Thus, the complex pathogenesis of CD25 deficiency provides invaluable insight into the role of IL2/IL-2RA-dependent regulation in autoimmunity and inflammatory diseases.

Hyper-IgE syndrome: dental implications

Hyper-IgE syndrome (HIES) is a rare multisystem disorder with both immunologic and nonimmunological features. It is characterized by extremely elevated IgE serum levels, eczema, and recurrent skin and pulmonary infections. Dental anomalies are often included, such as retention of deciduous teeth together with ectopic eruption or noneruption of permanent teeth. Severe susceptibility to caries and mycotic infections, insufficient transversal diameter of the palate, mucosal plaques, and fissures typically located on the tongue and on the palate are often present. The aim of this study was to review the literature and to report a 6-year observation of 6 patients with HIES (aged 8-39 years) with focus on their oral problems and the treatment provided. The importance of the role of the dentist both in early diagnosis of this syndrome and in monitoring oral conditions was stressed. The dentist can prevent infective complications and intercept the development of malocclusion with a reduction of the need for complex treatment.

Invasive Aspergillus nidulans infection in a patient with chronic granulomatous disease

The patient was a 21-year-old boy affected by X-linked chronic granulomatous disease (CGD-OMIM number 3064000), with a mutation in the gene encoding gp91 phox (deletion of a single G in position 767, with loss of gp91 phox and no residual NADPH oxidase activity), diagnosed at the age of 2, because of a positive family history for CGD. He had recurrent skin abscesses, lymphadenitis, bacterial pneumonia, and lung aspergillosis with probable brain dissemination. His parents compliance was poor and they had discontinued all therapies for a number of years without notice. The patient was referred to our hospital for the first time at the age of 10 because of a multifocal pneumonia with isolation of Aspergillus fumigatus in multiple sputum cultures. He was successfully treated with intravenous conventional amphotericin B and then a prophylactic regimen with trimethoprim–sulfamethoxazole, itraconazole and interferon gamma was prescribed. At the age of 13, the patient presented another brain focus, which resolved under a treatment with liposomal amphotericin B followed by oral itraconazole. His parents admitted once again their poor compliance with prophylactic treatment. When he was 21, the patient was hospitalised because of a large popliteal abscess in the right leg (Fig. 1) and a large area of parenchymal consolidation in the right lung. Right leg magnetic resonance imaging (MRI) excluded bone damage on multiple scans and a brain MRI did not reveal any new damage, but only traces of the old parenchymal lesions. Aspergillus spp. was isolated from a sputum sample and Aspergillus nidulans was isolated in repeated popliteal abscess cultures. An in vitro antifungal susceptibility test of the A. nidulans isolate was performed with Etest (AB-Biodisk, Solna, Sweden). The minimum inhibitory concentrations resulted in the following: itraconazole 0.12 lg ml, voriconazole 0.094 lg ml, amphotericin B 0.19 lg ml. Histological examination showed granulation tissue with abscesses, a granuloma of giant plurinucleated cells and the presence of septate hyphae compatible with the morphology of the isolated A. nidulans. The presence of precipitating antibodies against somatic and metabolic A. fumigatus antigens (Microgen Bioproducts, Camberley, UK; Bio-Rad, Marnes-la Coquette, France) agreed with the isolation of Aspergillus in culture. On the contrary, no galactomannan antigen was detected using Platelia Aspergillus (Bio-Rad) in repeated serum samples. The level of total serum IgE was 8910 kIU l and anti A. fumigatus IgE Correspondence: Prof. Maria Cristina Pietrogrande, Department of Pediatrics, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Via Commenda 9, Milan 20122, Italy. Tel.: +39 2 5503 2496. Fax: +39 2 5032 0210. E-mail: mariacristina.pietrogrande@unimi.it

Nutritional Status in Agammaglobulinemia: An Italian Multicenter Study

Rosa Maria Dellepiane & Laura Dell’Era & Lorena Vanesa Beilis & Paola Pavesi & Micol Raimondi & Annarosa Soresina & Vassilios Lougaris & Maria Carrabba & Baldassarre Martire & Silvana Martino & Giovanna Russo & Giuseppe Patuzzo & Claudio Pignata & Giuseppe Spadaro & Romina Gallizzi & Marzia Duse & Fernando Giuseppe Specchia & Viviana Moschese & Gian Luigi Marseglia & Maria Cristina Pietrogrande & Giorgio Bedogni & Carlo Agostoni

Kawasaki disease: guidelines of Italian Society of Pediatrics, part II - treatment of resistant forms and cardiovascular complications, follow-up, lifestyle and prevention of cardiovascular risks

This second part of practical Guidelines related to Kawasaki disease (KD) has the goal of contributing to prompt diagnosis and most appropriate treatment of KD resistant forms and cardiovascular complications, including non-pharmacologic treatments, follow-up, lifestyle and prevention of cardiovascular risks in the long-term through a set of 17 recommendations.Guidelines, however, should not be considered a norm that limits the treatment options of pediatricians and practitioners, as treatment modalities other than those recommended may be required as a result of peculiar medical circumstances, patient’s condition, and disease severity or individual complications.

Kawasaki disease: guidelines of the Italian Society of Pediatrics, part I - definition, epidemiology, etiopathogenesis, clinical expression and management of the acute phase

The primary purpose of these practical guidelines related to Kawasaki disease (KD) is to contribute to prompt diagnosis and appropriate treatment on the basis of different specialists’ contributions in the field. A set of 40 recommendations is provided, divided in two parts: the first describes the definition of KD, its epidemiology, etiopathogenetic hints, presentation, clinical course and general management, including treatment of the acute phase, through specific 23 recommendations.Their application is aimed at improving the rate of treatment with intravenous immunoglobulin and the overall potential development of coronary artery abnormalities in KD. Guidelines, however, should not be considered a norm that limits treatment options of pediatricians and practitioners, as treatment modalities other than those recommended may be required as a result of peculiar medical circumstances, patient’s condition, and disease severity or complications.

Circulating Follicular Helper and Follicular Regulatory T Cells Are Severely Compromised in Human CD40 Deficiency: A Case Report

Mutations in genes that control class switch recombination and somatic hypermutation during the germinal center (GC) response can cause diverse immune dysfunctions. In particular, mutations in CD40LG, CD40, AICDA, or UNG cause hyper-IgM (HIGM) syndrome, a heterogeneous group of primary immunodeficiencies. Follicular helper (Tfh) and follicular regulatory (Tfr) T cells play a key role in the formation and regulation of GCs, but their role in HIGM pathogenesis is still limited. Here, we found that compared to CD40 ligand (CD40L)- and activation-induced cytidine deaminase (AICDA)-deficient patients, circulating Tfh and Tfr cells were severely compromised in terms of frequency and activation phenotype in a child with CD40 deficiency. These findings offer useful insight for human Tfh biology, with potential implications for understanding the molecular basis of HIGM syndrome caused by mutations in CD40.

An immune-molecular hypothesis supporting infectious aetiopathogenesis of Kawasaki disease in children

The competitive binding between CpG-ODN (single-stranded DNA from pathogens) and HLA-B and HLA-A ligands for the inhibitory Killer Immunoglobulin-like Receptors (KIR)3DL1/2 may lead to possible hypo-sensing of pathogens and ineffective clearance. We observed an overabundance of HLA ligands for inhibitory KIR with three domains in KD subjects.