TY - JOUR T1 - Antibodies reacting to mimotopes of Simian virus 40 large T antigen, the viral oncoprotein, in sera from children. JF - J Cell Physiol Y1 - 2019 A1 - Mazzoni, Elisa A1 - Frontini, Francesca A1 - Rotondo, John Charles A1 - Zanotta, Nunzia A1 - Fioravanti, Arianna A1 - Minelli, Francesca A1 - Torreggiani, Elena A1 - Campisciano, Giuseppina A1 - Marcuzzi, Annalisa A1 - Guerra, Giovanni A1 - Tommasini, Alberto A1 - Touzé, Antoine A1 - Martini, Fernanda A1 - Tognon, Mauro A1 - Comar, Manola AB -

Recent data indicate that the Simian virus 40 (SV40) infection appears to be transmitted in humans independently from early SV40-contaminated antipolio vaccines. Serum antibodies against SV40 large T antigen (Tag) were analyzed in children/adolescents and young adults. To investigate antibodies reacting to SV40 Tag antigens, serum samples ( n = 812) from children and young adults were analyzed by indirect ELISAs using specific SV40 Tag mimotopes. Mimotopes were synthetic peptides corresponding to SV40 Tag epitopes. In sera ( n = 412) from healthy children up to 17 years old, IgG antibodies against SV40 Tag mimotopes reached an overall prevalence of 15%. IgM antibodies against SV40 Tag were detected in sera of children 6-8 months old confirming and extending the knowledge that SV40 seroconversion occurs early in life. In children/adolescents affected by different diseases ( n = 180) SV40 Tag had a prevalence of 18%, being the difference no significant compared to healthy subjects ( n = 220; 16%) of the same age. Our immunological data indicate that SV40 circulates in children and young adults, both in healthy conditions and affected by distinct diseases. The IgM detection in sera from healthy children suggests that the SV40 infection/seroconversion occurs early in life (>6 months). Our immunological data support the hypothesis that SV40, or a closely related still unknown polyomavirus, infects humans. The SV40 seroprevalence is lower than common polyomaviruses, such as BKPyV and JCPyV, and other new human polyomaviruses. In addition, our immunological surveillance indicates a lack of association between different diseases, considered herein, and SV40.

VL - 234 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30362540?dopt=Abstract ER - TY - JOUR T1 - The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases. JF - Int J Mol Sci Y1 - 2018 A1 - Bernardi, Stella A1 - Marcuzzi, Annalisa A1 - Piscianz, Elisa A1 - Tommasini, Alberto A1 - Fabris, Bruno KW - Anti-Inflammatory Agents KW - Cardiovascular Diseases KW - Humans KW - Hypolipidemic Agents KW - Immune System KW - Inflammation KW - Interleukins KW - Lipid Metabolism KW - Lipids KW - Metabolic Diseases AB -

Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response-and interleukins-had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed.

VL - 19 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30558209?dopt=Abstract ER - TY - JOUR T1 - Fecal Calprotectin to Detect Inflammatory Bowel Disease in Juvenile Idiopathic Arthritis. JF - J Rheumatol Y1 - 2018 A1 - Ferrara, Giovanna A1 - Pastore, Serena A1 - Sancin, Lara A1 - Torelli, Lucio A1 - Radillo, Oriano A1 - Bramuzzo, Matteo A1 - Bibalo, Chiara A1 - Tommasini, Alberto A1 - Ventura, Alessandro A1 - Taddio, Andrea AB -

OBJECTIVE: This study aimed to test fecal calprotectin (FC) as a screening tool to identify inflammatory bowel disease (IBD) among patients with juvenile idiopathic arthritis (JIA).

METHODS: FC level < 100 g/kg was considered normal. Patients with 2 consecutive FC dosage ≥ 100 g/kg underwent endoscopic evaluation.

RESULTS: There were 113 patients with JIA enrolled. FC was raised in 7 patients out of 113. All patients had IBD. In 3/7 patients, high FC levels were the only sign consistent with IBD.

CONCLUSION: FC is a useful, economical, and noninvasive diagnostic tool to identify JIA patients with underlying IBD.

VL - 45 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29907671?dopt=Abstract ER - TY - JOUR T1 - Genetic profile of patients with early onset inflammatory bowel disease. JF - Gene Y1 - 2018 A1 - Girardelli, Martina A1 - Basaldella, Federica A1 - Paolera, Sara Della A1 - Vuch, Josef A1 - Tommasini, Alberto A1 - Martelossi, Stefano A1 - Crovella, Sergio A1 - Bianco, Anna Monica KW - Age of Onset KW - Autophagy-Related Proteins KW - Child KW - Child, Preschool KW - Computer Simulation KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Infant KW - Inflammatory Bowel Diseases KW - Interleukin-10 KW - Male KW - Nod2 Signaling Adaptor Protein KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin KW - Receptors, Interleukin-10 KW - Sequence Analysis, DNA KW - X-Linked Inhibitor of Apoptosis Protein AB -

Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract. The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway. We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate "in silico" analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range. The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).

VL - 645 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29248579?dopt=Abstract ER - TY - JOUR T1 - Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications. JF - Clin Immunol Y1 - 2018 A1 - De Rose, Domenico Umberto A1 - Giliani, Silvia A1 - Notarangelo, Lucia Dora A1 - Lougaris, Vassilios A1 - Lanfranchi, Arnalda A1 - Moratto, Daniele A1 - Martire, Baldassarre A1 - Specchia, Fernando A1 - Tommasini, Alberto A1 - Plebani, Alessandro A1 - Badolato, Raffaele AB -

Leukocyte Adhesion Deficiency type 1 (LAD-1) is a rare primary immunodeficiency due to mutations in the gene encoding for the common β-chain of the β2 integrin family (CD18). Herein, we describe clinical manifestations and long-term complications of eight LAD-1 patients. Four LAD-1 patients were treated with hematopoietic stem cell transplantation (HSCT), while the remaining four, including two with moderate LAD-1 deficiency, received continuous antibiotic prophylaxis. Untreated patients presented numerous infections and autoimmune manifestations. In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved. Other two LAD-1 patients developed type 1 diabetes and autoimmune cytopenia after HSCT, suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications.

VL - 191 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29548898?dopt=Abstract ER - TY - JOUR T1 - Low-dose sirolimus in two cousins with autoimmune lymphoproliferative syndrome-associated infection. JF - Pediatr Int Y1 - 2018 A1 - Nocerino, Agostino A1 - Valencic, Erica A1 - Loganes, Claudia A1 - Pelos, Giorgio A1 - Tommasini, Alberto KW - Anti-Bacterial Agents KW - Autoimmune Lymphoproliferative Syndrome KW - Child KW - Child, Preschool KW - Dose-Response Relationship, Drug KW - Female KW - Humans KW - Immunosuppressive Agents KW - Infant KW - Male KW - Otitis Media KW - Pneumonia, Bacterial KW - Sirolimus VL - 60 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29480551?dopt=Abstract ER - TY - JOUR T1 - Neuronal Dysfunction Associated with Cholesterol Deregulation. JF - Int J Mol Sci Y1 - 2018 A1 - Marcuzzi, Annalisa A1 - Loganes, Claudia A1 - Valencic, Erica A1 - Piscianz, Elisa A1 - Monasta, Lorenzo A1 - Bilel, Sabrine A1 - Bortul, Roberta A1 - Celeghini, Claudio A1 - Zweyer, Marina A1 - Tommasini, Alberto KW - Anticholesteremic Agents KW - Cell Line, Tumor KW - Cholesterol KW - Electron Transport KW - Humans KW - Lovastatin KW - Mitochondria KW - Neurons KW - Neuroprotective Agents KW - Organophosphorus Compounds KW - Ubiquinone AB -

Cholesterol metabolism is crucial for cells and, in particular, its biosynthesis in the central nervous system occurs in situ, and its deregulation involves morphological changes that cause functional variations and trigger programmed cell death. The pathogenesis of rare diseases, such as Mevalonate Kinase Deficiency or Smith⁻Lemli⁻Opitz Syndrome, arises due to enzymatic defects in the cholesterol metabolic pathways, resulting in a shortage of downstream products. The most severe clinical manifestations of these diseases appear as neurological defects. Expanding the knowledge of this biological mechanism will be useful for identifying potential targets and preventing neuronal damage. Several studies have demonstrated that deregulation of the cholesterol pathway induces mitochondrial dysfunction as the result of respiratory chain damage. We set out to determine whether mitochondrial damage may be prevented by using protective mitochondria-targeted compounds, such as MitoQ, in a neuronal cell line treated with a statin to induce a biochemical block of the cholesterol pathway. Evidence from the literature suggests that mitochondria play a crucial role in the apoptotic mechanism secondary to blocking the cholesterol pathway. Our study shows that MitoQ, administered as a preventive agent, could counteract the cell damage induced by statins in the early stages, but its protective role fades over time.

VL - 19 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29783748?dopt=Abstract ER - TY - JOUR T1 - Role of the Long Non-Coding RNA Growth Arrest-Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease. JF - Basic Clin Pharmacol Toxicol Y1 - 2018 A1 - Lucafò, Marianna A1 - Di Silvestre, Alessia A1 - Romano, Maurizio A1 - Avian, Alice A1 - Antonelli, Roberta A1 - Martelossi, Stefano A1 - Naviglio, Samuele A1 - Tommasini, Alberto A1 - Stocco, Gabriele A1 - Ventura, Alessandro A1 - Decorti, Giuliana A1 - De Iudicibus, Sara KW - Biomarkers KW - Cell Line, Tumor KW - Cell Proliferation KW - Child KW - Drug Resistance KW - Female KW - Gene Knockdown Techniques KW - Glucocorticoids KW - Humans KW - Inflammatory Bowel Diseases KW - Male KW - Patient Selection KW - Pharmacogenomic Testing KW - Precision Medicine KW - RNA, Long Noncoding KW - RNA, Small Interfering KW - Treatment Outcome KW - Up-Regulation AB -

Glucocorticoids (GCs) are widely employed in inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in inflammatory bowel disease (IBD). Given the high incidence of suboptimal response, associated with a significant number of side-effects, that are particularly severe in paediatric patients, the identification of subjects that are most likely to respond poorly to GCs is extremely important. Recent evidence suggests that the long non-coding RNA (lncRNA) GAS5 could be a potential marker of GC resistance. To address this issue, we evaluated the association between the lncRNA GAS5 and the efficacy of steroids, in terms of inhibition of proliferation, in two cell lines derived from colon and ovarian cancers, to confirm the sensitivity and specificity of these lncRNAs. These cells showed a different sensitivity to GCs and revealed differential expression of GAS5 after treatment. GAS5 was up-regulated in GC-resistant cells and accumulated more in the cytoplasm compared to the nucleus in response to the drug. The functions of GAS5 were assessed by silencing, and we found that GAS5 knock-down reduced the proliferation during GC treatment. Furthermore, for the first time, we measured GAS5 levels in 19 paediatric IBD patients at diagnosis and after the first cycle of GCs, and we demonstrated an up-regulation of the lncRNA in patients with unfavourable steroid response. Our preliminary results indicate that GAS5 could be considered a novel pharmacogenomic marker useful for the personalization of GC therapy.

VL - 122 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28722800?dopt=Abstract ER - TY - JOUR T1 - Theophylline as a precision therapy in a young girl with PIK3R1 immunodeficiency. JF - J Allergy Clin Immunol Pract Y1 - 2018 A1 - Valencic, Erica A1 - Grasso, Antonio Giacomo A1 - Conversano, Ester A1 - Lucafò, Marianna A1 - Piscianz, Elisa A1 - Gregori, Massimo A1 - Conti, Francesca A1 - Cancrini, Caterina A1 - Tommasini, Alberto VL - 6 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29510232?dopt=Abstract ER - TY - JOUR T1 - ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. JF - Ann Rheum Dis Y1 - 2017 A1 - Caorsi, Roberta A1 - Penco, Federica A1 - Grossi, Alice A1 - Insalaco, Antonella A1 - Omenetti, Alessia A1 - Alessio, Maria A1 - Conti, Giovanni A1 - Marchetti, Federico A1 - Picco, Paolo A1 - Tommasini, Alberto A1 - Martino, Silvana A1 - Malattia, Clara A1 - Gallizi, Romina A1 - Podda, Rosa Anna A1 - Salis, Annalisa A1 - Falcini, Fernanda A1 - Schena, Francesca A1 - Garbarino, Francesca A1 - Morreale, Alessia A1 - Pardeo, Manuela A1 - Ventrici, Claudia A1 - Passarelli, Chiara A1 - Zhou, Qing A1 - Severino, Mariasavina A1 - Gandolfo, Carlo A1 - Damonte, Gianluca A1 - Martini, Alberto A1 - Ravelli, Angelo A1 - Aksentijevich, Ivona A1 - Ceccherini, Isabella A1 - Gattorno, Marco KW - Adenosine Deaminase KW - Adolescent KW - Age of Onset KW - Case-Control Studies KW - Child KW - Child, Preschool KW - DNA Mutational Analysis KW - Female KW - Heterozygote KW - Homozygote KW - Humans KW - Immunoglobulins KW - Immunosuppressive Agents KW - Infant KW - Intercellular Signaling Peptides and Proteins KW - Italy KW - Livedo Reticularis KW - Male KW - Pedigree KW - Polyarteritis Nodosa KW - Stroke KW - Thalidomide KW - Tumor Necrosis Factor-alpha KW - Young Adult AB -

OBJECTIVES: To analyse the prevalence of mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study.

METHODS: Direct sequencing of was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor.

RESULTS: Biallelic homozygous or compound heterozygous mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect.

CONCLUSIONS: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.

VL - 76 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28522451?dopt=Abstract ER - TY - JOUR T1 - Curcumin Anti-Apoptotic Action in a Model of Intestinal Epithelial Inflammatory Damage. JF - Nutrients Y1 - 2017 A1 - Loganes, Claudia A1 - Lega, Sara A1 - Bramuzzo, Matteo A1 - Vecchi Brumatti, Liza A1 - Piscianz, Elisa A1 - Valencic, Erica A1 - Tommasini, Alberto A1 - Marcuzzi, Annalisa KW - Anti-Inflammatory Agents, Non-Steroidal KW - Apoptosis KW - Cell Survival KW - Curcuma KW - Curcumin KW - Cytokines KW - Epithelial Cells KW - HT29 Cells KW - Humans KW - Inflammation KW - Interferon-gamma KW - Interleukin-7 KW - Intestinal Mucosa KW - NF-kappa B KW - Phosphorylation KW - Signal Transduction AB -

The purpose of this study is to determine if a preventive treatment with curcumin can protect intestinal epithelial cells from inflammatory damage induced by IFNγ. To achieve this goal we have used a human intestinal epithelial cell line (HT29) treated with IFNγ to undergo apoptotic changes that can reproduce the damage of intestinal epithelia exposed to inflammatory cytokines. In this model, we measured the effect of curcumin (curcuminoid from ) added as a pre-treatment at different time intervals before stimulation with IFNγ. Curcumin administration to HT29 culture before the inflammatory stimulus IFNγ reduced the cell apoptosis rate. This effect gradually declined with the reduction of the curcumin pre-incubation time. This anti-apoptotic action by curcumin pre-treatment was paralleled by a reduction of secreted IL7 in the HT29 culture media, while there was no relevant change in the other cytokine levels. Even though curcumin pre-administration did not impact the activation of the NF-κB pathway, a slight effect on the phosphorylation of proteins in this inflammatory signaling pathway was observed. In conclusion, curcumin pre-treatment can protect intestinal cells from inflammatory damage. These results can be the basis for studying the preventive role of curcumin in inflammatory bowel diseases.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28587282?dopt=Abstract ER - TY - JOUR T1 - Describing Kawasaki shock syndrome: results from a retrospective study and literature review. JF - Clin Rheumatol Y1 - 2017 A1 - Taddio, Andrea A1 - Rossi, Eleonora Dei A1 - Monasta, Lorenzo A1 - Pastore, Serena A1 - Tommasini, Alberto A1 - Lepore, Loredana A1 - Bronzetti, Gabriele A1 - Marrani, Edoardo A1 - Mottolese, Biancamaria D'Agata A1 - Simonini, Gabriele A1 - Cimaz, Rolando A1 - Ventura, Alessandro KW - C-Reactive Protein KW - Child KW - Child, Preschool KW - Echocardiography KW - Female KW - Heart Failure KW - Hemoglobins KW - Humans KW - Immunoglobulins, Intravenous KW - Male KW - Mucocutaneous Lymph Node Syndrome KW - Retrospective Studies KW - Shock KW - Syndrome AB -

Kawasaki shock syndrome (KSS) is a rare manifestation of Kawasaki disease (KD) characterized by systolic hypotension or clinical signs of poor perfusion. The objectives of the study are to describe the main clinical presentation, echocardiographic, and laboratory findings, as well as the treatment options and clinical outcomes of KSS patients when compared with KD patients. This is a retrospective study. All children referred to two pediatric rheumatology units from January 1, 2012, to December 31, 2014, were enrolled. Patients were divided into patients with or without KSS. We compared the two groups according to the following variables: sex, age, type of KD (classic, with less frequent manifestations, or incomplete), clinical manifestations, cardiac involvement, laboratory findings, therapy administered, response to treatment, and outcome. Eighty-four patients with KD were enrolled. Of these, five (6 %) met the criteria for KSS. Patients with KSS had higher values of C-reactive protein (p = 0.005), lower hemoglobin levels (p = 0.003); more frequent hyponatremia (p = 0.004), hypoalbuminemia (p = 0.004), and coagulopathy (p = 0.003); and increase in cardiac troponins (p = 0.000). Among the KSS patients, three had a coronary artery involvement, but none developed a permanent aneurysm. Intravenous immunoglobulin resistance was more frequent in the KSS group, although not significantly so (3/5, 60 % vs. 23/79, 30 %, P = NS). None of the five cases was fatal, and all recovered without sequelae. KSS patients are more likely to have higher rates of cardiac involvement. However, most cardiovascular abnormalities resolved promptly with therapy.

VL - 36 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27230223?dopt=Abstract ER - TY - JOUR T1 - Action of methotrexate and tofacitinib on directly stimulated and bystander-activated lymphocytes. JF - Mol Med Rep Y1 - 2016 A1 - Piscianz, Elisa A1 - Candilera, Vanessa A1 - Valencic, Erica A1 - Loganes, Claudia A1 - Paron, Greta A1 - De Iudicibus, Sara A1 - Decorti, Giuliana A1 - Tommasini, Alberto AB -

Chronic inflammation associated with autoimmune activation is characteristic of rheumatic diseases from childhood to adulthood. In recent decades, significant improvements in the treatment of these types of disease have been achieved using disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) and, more recently, using biologic inhibitors. The recent introduction of kinase inhibitors (for example, tofacitinib; Tofa) further increases the available ARDs. However, there are patients that do not respond to any treatment strategies, for whom combination therapies are proposed. The data regarding the combined action of different drugs is lacking and the knowledge of the mechanisms of ARDs and their actions upon pathogenic lymphocytes, which are hypothesized to sustain disease, is poor. An in vitro model of inflammation was developed in the current study, in which stimulated and unstimulated lymphocytes were cultured together, but tracked separately, to investigate the action of MTX and Tofa on the two populations. By analysing lymphocyte proliferation and activation, and cytokine secretion in the culture supernatants, it was established that, due to the presence of activated cells, unstimulated cells underwent a bystander activation that was modulated by the ARDs. Additionally, varying administration schedules were demonstrated to affect lymphocytes differently in vitro, either directly or via bystander activation. Furthermore, MTX and Tofa exerted different effects; while MTX showed an antiproliferative effect, Tofa marginally effected activation, although only a slight antiproliferative action, which could be potentiated by sequential treatment with MTX. Thus, it was hypothesized that these differences may be exploited in sequential therapeutic strategies, to maximize the anti‑rheumatic effect. These findings are notable and must be accounted for, as bystander‑activated cells in vivo could contribute to the spread of autoimmune activation and disease progression.

VL - 14 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27175898?dopt=Abstract ER - TY - JOUR T1 - Carbamazepine-induced thrombocytopenic purpura in a child: Insights from a genomic analysis. JF - Blood Cells Mol Dis Y1 - 2016 A1 - Abate, Maria Valentina A1 - Stocco, Gabriele A1 - Devescovi, Raffaella A1 - Carrozzi, Marco A1 - Pierobon, Chiara A1 - Valencic, Erica A1 - Lucafò, Marianna A1 - Di Silvestre, Alessia A1 - d'Adamo, Pio A1 - Tommasini, Alberto A1 - Decorti, Giuliana A1 - Ventura, Alessandro VL - 59 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27282575?dopt=Abstract ER - TY - JOUR T1 - Clinical Characteristics of Patients Carrying the Q703K Variant of the NLRP3 Gene: A 10-year Multicentric National Study. JF - J Rheumatol Y1 - 2016 A1 - Naselli, Aldo A1 - Penco, Federica A1 - Cantarini, Luca A1 - Insalaco, Antonella A1 - Alessio, Mariolina A1 - Tommasini, Alberto A1 - Maggio, Cristina A1 - Obici, Laura A1 - Gallizi, Romina A1 - Cimmino, Marco A1 - Signa, Sara A1 - Lucherini, Orso Maria A1 - Carta, Sonia A1 - Caroli, Francesco A1 - Martini, Alberto A1 - Rubartelli, Anna A1 - Ceccherini, Isabella A1 - Gattorno, Marco AB -

OBJECTIVE: The aim of our study was to analyze the clinical and functional effect of the p.Q703K (p. Q705K, c. 2107C>A) variant of the NLRP3 gene in a population of patients screened for suspected cryopyrin-associated periodic syndrome (CAPS).

METHODS: Since 2002, 580 patients underwent molecular analysis for NLRP3. Data on clinical presentation, response to treatment, and longterm followup were collected using a uniform questionnaire. The pattern of cytokine secretion after lipopolysaccharide stimulation from isolated monocytes was analyzed in 3 patients carrying the p.Q703K variant and 1 patient with a chronic infantile neurologic, cutaneous, articular syndrome phenotype carrying both the p.M406I and p.Q703K, and compared with 7 patients with CAPS with sure pathogenic variants and 6 healthy controls.

RESULTS: The p.Q703K variant was found in 57 screened patients with an overall allelic frequency of 5%. The frequency in normal controls was 5.5%. Clinical data at the moment of molecular analysis and at followup were available in 36 patients. Two patients displayed additional mutations of NLRP3. The mean followup was 2.5 years. Thirteen patients (39%) had a final diagnosis different from the original suspicion of CAPS. The remaining 21 patients displayed a mild phenotype mainly characterized by recurrent episodes of urticarial rash and arthralgia. Only 8 patients were treated with anti-interleukin (IL)-1 treatment, with a complete response in 5 patients. The pattern of secretion of IL-1β and other cytokines (IL-6 and IL-1 receptor antagonist) in patients did not display the aberrancies observed in patients with CAPS and was similar to that observed in healthy controls.

CONCLUSION: The present study confirms the weak clinical and functional effect of the p.Q703K variant.

VL - 43 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27036377?dopt=Abstract ER - TY - JOUR T1 - Differential expression of GAS5 in rapamycin-induced reversion of glucocorticoid resistance. JF - Clin Exp Pharmacol Physiol Y1 - 2016 A1 - Lucafò, Marianna A1 - Bravin, Vanessa A1 - Tommasini, Alberto A1 - Martelossi, Stefano A1 - Rabach, Ingrid A1 - Ventura, Alessandro A1 - Decorti, Giuliana A1 - De Iudicibus, Sara AB -

This study evaluates the association between the long noncoding RNA GAS5 levels and the anti-proliferative effect of the glucocorticoid (GC) methylprednisolone (MP) alone and in combination with rapamycin in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. The effect of MP, rapamycin, and MP plus rapamycin was determined in 17 healthy donors by labelling metabolically active cells with [methyl-3H] thymidine and the expression levels of GAS5 gene were evaluated by real-time RT-PCR TaqMan analysis. We confirmed a role for GAS5 in modulating GC response: poor responders presented higher levels of GAS5 in comparison with good responders. Interestingly, when PBMCs were treated with the combination of rapamycin plus MP, the high levels of GAS5 observed for each drug in the MP poor responders group decreased in comparison with rapamycin (P value = 0.0134) or MP alone (P value = 0.0193). GAS5 is involved in GC resistance and co-treatment of rapamycin with GCs restores GC effectiveness in poor responders through the downregulation of the long noncoding RNA. GAS5 could be considered a biomarker to personalize therapy and a novel therapeutic target useful for the development of new pharmacological approaches to restore GC sensitivity.

VL - 43 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27001230?dopt=Abstract ER - TY - JOUR T1 - Putative modifier genes in mevalonate kinase deficiency. JF - Mol Med Rep Y1 - 2016 A1 - Marcuzzi, Annalisa A1 - Vozzi, Diego A1 - Girardelli, Martina A1 - Tricarico, Paola Maura A1 - Knowles, Alessandra A1 - Crovella, Sergio A1 - Vuch, Josef A1 - Tommasini, Alberto A1 - Piscianz, Elisa A1 - Bianco, Anna Monica AB -

Mevalonate kinase deficiency (MKD) is an autosomal recessive auto‑inflammatory disease, caused by impairment of the mevalonate pathway. Although the molecular mechanism remains to be elucidated, there is clinical evidence suggesting that other regulatory genes may be involved in determining the phenotype. The identification of novel target genes may explain non‑homogeneous genotype‑phenotype correlations, and provide evidence in support of the hypothesis that novel regulatory genes predispose or amplify deregulation of the mevalonate pathway in this orphan disease. In the present study, DNA samples were obtained from five patients with MKD, which were then analyzed using whole exome sequencing. A missense variation in the PEX11γ gene was observed in homozygosis in P2, possibly correlating with visual blurring. The UNG rare gene variant was detected in homozygosis in P5, without correlating with a specific clinical phenotype. A number of other variants were found in the five analyzed DNA samples from the MKD patients, however no correlation with the phenotype was established. The results of the presents study suggested that further analysis, using next generation sequencing approaches, is required on a larger sample size of patients with MKD, who share the same MVK mutations and exhibit 'extreme' clinical phenotypes. As MVK mutations may be associated with MKD, the identification of specific modifier genes may assist in providing an earlier diagnosis.

VL - 13 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26935981?dopt=Abstract ER - TY - JOUR T1 - Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. JF - Clin Immunol Y1 - 2015 A1 - Lougaris, Vassilios A1 - Faletra, Flavio A1 - Lanzi, Gaetana A1 - Vozzi, Diego A1 - Marcuzzi, Annalisa A1 - Valencic, Erica A1 - Piscianz, Elisa A1 - Bianco, AnnaMonica A1 - Girardelli, Martina A1 - Baronio, Manuela A1 - Loganes, Claudia A1 - Fasth, Anders A1 - Salvini, Filippo A1 - Trizzino, Antonino A1 - Moratto, Daniele A1 - Facchetti, Fabio A1 - Giliani, Silvia A1 - Plebani, Alessandro A1 - Tommasini, Alberto KW - B-Lymphocytes KW - Child, Preschool KW - Female KW - Germinal Center KW - Humans KW - Hyper-IgM Immunodeficiency Syndrome KW - Infant KW - Male KW - Mutation KW - Phenotype KW - Phosphatidylinositol 3-Kinases KW - RNA Splice Sites KW - Sequence Analysis, DNA VL - 159 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25939554?dopt=Abstract ER - TY - JOUR T1 - Delayed reactivation of chronic infantile neurologic, cutaneous, articular syndrome (CINCA) in a patient with somatic mosaicism of CIAS1/NLRP3 gene after withdrawal of anti-IL-1 beta therapy. JF - Clin Exp Rheumatol Y1 - 2015 A1 - Paloni, Giulia A1 - Pastore, Serena A1 - Tommasini, Alberto A1 - Lepore, Loredana A1 - Taddio, Andrea KW - Antibodies, Monoclonal KW - Carrier Proteins KW - Cryopyrin-Associated Periodic Syndromes KW - Drug Administration Schedule KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Immunosuppressive Agents KW - Interleukin 1 Receptor Antagonist Protein KW - Interleukin-1beta KW - Mosaicism KW - Phenotype KW - Recurrence KW - Remission Induction KW - Time Factors KW - Treatment Outcome KW - Young Adult VL - 33 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26316056?dopt=Abstract ER - TY - JOUR T1 - The diagnostic challenge of very early-onset enterocolitis in an infant with XIAP deficiency. JF - BMC Pediatr Y1 - 2015 A1 - Girardelli, Martina A1 - Arrigo, Serena A1 - Barabino, Arrigo A1 - Loganes, Claudia A1 - Morreale, Giuseppe A1 - Crovella, Sergio A1 - Tommasini, Alberto A1 - Bianco, Anna Monica AB -

BACKGROUND: Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT).

CASE PRESENTATION: We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly. After several immunological, genetic and clinical investigations, subsequently a therapeutic attempt with colectomy, analysis of VEO-IBD-associated genes, revealed a causative mutation in XIAP. The genetic diagnosis of a primary immune deficiency allowed curing the boy with hematopoietic stem cell transplantation.

CONCLUSION: Our report, together with novel findings from recent literature, should contribute to increase awareness of monogenic immune defects as a cause of VEO-IBD. Comprehensive genetic analysis can allow a prompt diagnosis, resulting in the choice of effective treatments and sparing useless and damaging procedures.

VL - 15 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26671016?dopt=Abstract ER - TY - JOUR T1 - Different presentations of mevalonate kinase deficiency: a case series. JF - Clin Exp Rheumatol Y1 - 2015 A1 - De Pieri, Carlo A1 - Taddio, Andrea A1 - Insalaco, Antonella A1 - Barbi, Egidio A1 - Lepore, Loredana A1 - Ventura, Alessandro A1 - Tommasini, Alberto KW - Age Factors KW - Bacterial Infections KW - Child KW - Child, Preschool KW - Diagnosis, Differential KW - Diagnostic Errors KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Infant KW - Inflammatory Bowel Diseases KW - Male KW - Mevalonate Kinase Deficiency KW - Phenotype KW - Predictive Value of Tests KW - Recurrence KW - Risk Factors KW - Sepsis KW - Vasculitis KW - Young Adult AB -

OBJECTIVES: We aimed to raise awareness among paediatricians and physicians about this often misunderstood condition.

METHODS: We discussed the clinical profiles associated with late or wrong diagnosis of mevalonate kinase deficency (MKD) in a single centre case series.

RESULTS: We analysed the most common challenges and pitfalls that a clinician might face during the diagnostic process. Five main clinical profiles were characterised.

CONCLUSIONS: We propose a new perspective on MKD, suggesting that the presentation of this disease can vary from patient to patient.

VL - 33 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25897835?dopt=Abstract ER - TY - JOUR T1 - Failure of interferon-γ pre-treated mesenchymal stem cell treatment in a patient with Crohn's disease. JF - World J Gastroenterol Y1 - 2015 A1 - Taddio, Andrea A1 - Tommasini, Alberto A1 - Valencic, Erica A1 - Biagi, Ettore A1 - Decorti, Giuliana A1 - De Iudicibus, Sara A1 - Cuzzoni, Eva A1 - Gaipa, Giuseppe A1 - Badolato, Raffaela A1 - Prandini, Alberto A1 - Biondi, Andrea A1 - Ventura, Alessandro AB -

Mesenchymal stem cells (MSC) are cells of stromal origin which exhibit unlimited self-renewal capacity and pluripotency in vitro. It has recently been observed that MSC may also exert a profound immunosuppressive and anti-inflammatory effect both in vitro and in vivo with consequent potential use in autoimmune disorders. We present the case of a patient suffering from childhood-onset, multidrug resistant and steroid-dependent Crohn's disease who underwent systemic infusions of MSC, which led to a temporary reduction in CCR4, CCR7 and CXCR4 expression by T-cells, and a temporary decrease in switched memory B-cells, In addition, following MSC infusion, lower doses of steroids were needed to inhibit proliferation of the patient's peripheral blood mononuclear cells. Despite these changes, no significant clinical benefit was observed, and the patient required rescue therapy with infliximab and subsequent autologous hematopoietic stem cell transplantation. The results of biological and in vitro observations after MSC use and the clinical effects of infusion are discussed, and a brief description is provided of previous data on MSC-based therapy in autoimmune disorders.

VL - 21 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25892890?dopt=Abstract ER - TY - JOUR T1 - Fever tree revisited: From malaria to autoinflammatory diseases. JF - World J Clin Pediatr Y1 - 2015 A1 - Pastore, Serena A1 - Vuch, Josef A1 - Bianco, Anna Monica A1 - Taddio, Andrea A1 - Tommasini, Alberto AB -

Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today's periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin.

VL - 4 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26566482?dopt=Abstract ER - TY - JOUR T1 - Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study. JF - Pediatr Rheumatol Online J Y1 - 2015 A1 - De Pieri, Carlo A1 - Vuch, Josef A1 - De Martino, Eleonora A1 - Bianco, Anna M A1 - Ronfani, Luca A1 - Athanasakis, Emmanouil A1 - Bortot, Barbara A1 - Crovella, Sergio A1 - Taddio, Andrea A1 - Severini, Giovanni M A1 - Tommasini, Alberto KW - Adolescent KW - Carrier Proteins KW - Child KW - Cryopyrin-Associated Periodic Syndromes KW - Cytoskeletal Proteins KW - Familial Mediterranean Fever KW - Female KW - Fever KW - Gene Expression Profiling KW - Genotype KW - Hereditary Autoinflammatory Diseases KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Logistic Models KW - Male KW - Mutation KW - Phosphotransferases (Alcohol Group Acceptor) KW - Prospective Studies KW - Receptors, Tumor Necrosis Factor, Type I KW - Syndrome AB -

BACKGROUND: Periodic fever syndromes (PFS) are an emerging group of autoinflammatory disorders. Clinical overlap exists and multiple genetic analyses may be needed to assist diagnosis. We evaluated the diagnostic value of a 5-gene sequencing panel (5GP) in patients with undiagnosed PFS.

METHODS: Simultaneous double strand Sanger sequencing of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12 genes was performed in 42 patients with unexplained PFS. Clinical features were correlated with genetic results.

RESULTS: None of 42 patients analyzed displayed a causative genotype. However, single or multiple genetic variants of uncertain significance were detected in 24 subjects. Only in 5 subjects a definite diagnosis was made by taking into account both genetic and clinical data (2 TRAPS syndrome; 2 FMF; 1 FCAS). Statistical analysis showed that patients carrying genetic variants in one or more of the five selected genes displayed a significantly lower response to glucocorticoids compared with subjects who had completely negative genetic results.

CONCLUSIONS: The sequencing of multiple genes is of little help in the diagnostics of PFS and can often lead to results of uncertain interpretation, thus the clinically driven sequencing of single genes should remain the recommended approach. However, the presence of single or multiple genetic variants of uncertain significance, even if not allowing any specific diagnosis, correlated with a poorer response to glucocorticoids, possibly indicating a multifactorial subgroup of PFS with differential response to pharmacological treatment.

VL - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25866490?dopt=Abstract ER - TY - JOUR T1 - Genetics of inflammatory bowel disease from multifactorial to monogenic forms. JF - World J Gastroenterol Y1 - 2015 A1 - Bianco, Anna Monica A1 - Girardelli, Martina A1 - Tommasini, Alberto AB -

Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn's disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6(th) year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

VL - 21 IS - 43 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26604638?dopt=Abstract ER - TY - JOUR T1 - Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. JF - Ann Rheum Dis Y1 - 2015 A1 - Rusmini, Marta A1 - Federici, Silvia A1 - Caroli, Francesco A1 - Grossi, Alice A1 - Baldi, Maurizia A1 - Obici, Laura A1 - Insalaco, Antonella A1 - Tommasini, Alberto A1 - Caorsi, Roberta A1 - Gallo, Eleonora A1 - Olivieri, Alma Nunzia A1 - Marzano, AngeloValerio A1 - Coviello, Domenico A1 - Ravazzolo, Roberto A1 - Martini, Alberto A1 - Gattorno, Marco A1 - Ceccherini, Isabella AB -

OBJECTIVES: Systemic auto-inflammatory disorders (SAIDs) are a heterogeneous group of monogenic diseases sharing a primary dysfunction of the innate immune system. More than 50% of patients with SAID does not show any mutation at gene(s) tested because of lack of precise clinical classification criteria and/or incomplete gene screening. To improve the molecular diagnosis and genotype interpretation of SAIDs, we undertook the development of a next-generation sequencing (NGS)-based protocol designed to simultaneous screening of 10 genes.

METHODS: Fifty patients with SAID, already genotyped for the respective causative gene(s), were massively sequenced for the coding portions of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12, NOD2, PSTPIP1, IL1RN, LPIN2 and PSMB8. Three different bioinformatic pipelines (Ion Reporter, CLC Bio Genomics Workbench, GATK-based in-house workflow) were compared.

RESULTS: Once resulting variants were compared with the expected mutation list, no workflow turned out to be able to detect all the 79 variants known in the 50 DNAs. Additional variants were also detected, validated by Sanger sequencing and compared to assess true and false positive detection rates of the three workflows. Finally, the overall clinical picture of 34 patients was re-evaluated in the light of the new mutations found.

CONCLUSIONS: The present gene panel has resulted suitable for molecular diagnosis of SAIDs. Moreover, genotype-phenotype correlation has confirmed that the interpretation of NGS data in patients with an undefined inflammatory phenotype is remarkably difficult, thus supporting the need of evidence-based and validated clinical criteria to be used concurrently with the genetic analysis for the final diagnosis and classification of patients with SAIDs.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/26386126?dopt=Abstract ER - TY - JOUR T1 - Patients' Induced Pluripotent Stem Cells to Model Drug Induced Adverse Events: A Role in Predicting Thiopurine Induced Pancreatitis? JF - Curr Drug Metab Y1 - 2015 A1 - Stocco, Gabriele A1 - Lanzi, Gaetana A1 - Yue, Fengming A1 - Giliani, Silvia A1 - Sasaki, Katsunori A1 - Tommasini, Alberto A1 - Pelin, Marco A1 - Martelossi, Stefano A1 - Ventura, Alessandro A1 - Decorti, Giuliana AB -

Induced pluripotent stem cells (iPSC) can be produced from adult cells by transfecting them with a definite set of pluripotency-associated genes. Under adequate growth conditions and stimulation iPSC can differentiate to almost every somatic lineage in the body. Patients' derived iPSC are an innovative model to study mechanisms of adverse drug reactions in individual patients and in cell types that cannot be easily obtained from human subjects. Proof-of concept studies with known toxicants have been performed for liver, cardiovascular and central nervous system cells: neurons obtained from iPSC have been used to elucidate the mechanism of chemotherapy-induced peripheral neuropathy by evaluating the effects of neurotoxic drugs such as vincristine. However, no study has been performed yet on pancreatic tissue and drug induced pancreatitis. Thiopurines (azathioprine and mercaptopurine) are immunosuppressive antimetabolite drugs, commonly used to treat Crohn's disease. About 5% of Crohn's disease patients treated with thiopurines develop pancreatitis, a severe idiosyncratic adverse event; these patients have to stop thiopurine administration and may require medical treatment, with significant personal and social costs. Molecular mechanism of thiopurine induced pancreatitis (TIP) is currently unknown and no fully validated biomarker is available to assist clinicians in preventing this adverse event. Hence, in this review we have reflected upon the probable research applications of exocrine pancreatic cells generated from patient specific iPS cells. Such pancreatic cells can provide excellent insights into the molecular mechanism of TIP. In particular three hypotheses on the mechanism of TIP could be explored: drug biotransformation, innate immunity and adaptative immunity.

VL - 17 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26526832?dopt=Abstract ER - TY - JOUR T1 - To Extinguish the Fire from Outside the Cell or to Shutdown the Gas Valve Inside? Novel Trends in Anti-Inflammatory Therapies. JF - Int J Mol Sci Y1 - 2015 A1 - Marcuzzi, Annalisa A1 - Piscianz, Elisa A1 - Valencic, Erica A1 - Monasta, Lorenzo A1 - Vecchi Brumatti, Liza A1 - Tommasini, Alberto AB -

Cytokines are the most important soluble mediators of inflammation. Rare pediatric diseases provided exemplar conditions to study the anti-inflammatory efficacy of new generation therapies (biologics/biopharmaceuticals) selectively targeting single cytokines. Monoclonal antibodies and recombinant proteins have revolutionized anti-inflammatory therapies in the last two decades, allowing the specific targeting of single cytokines. They are very effective in extinguishing inflammation from outside the cell, even with the risk of an excessive and prolonged immunosuppression. Small molecules can enter the cell and shutdown the valve of inflammation by directly targeting signal proteins involved in cytokine release or in response to cytokines. They are orally-administrable drugs whose dosage can be easily adjusted to obtain the desired anti-inflammatory effect. This could make these drugs more suitable for a wide range of diseases as stroke, gout, or neurological impairment, where inflammatory activation plays a pivotal role as trigger. Autoinflammatory diseases, which have previously put anti-cytokine proteins in the limelight, can again provide a valuable model to measure the real potential of small inhibitors as anti-inflammatory agents.

VL - 16 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26370962?dopt=Abstract ER - TY - JOUR T1 - Two‑gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results. JF - Mol Med Rep Y1 - 2015 A1 - Bianco, Anna Monica A1 - Faletra, Flavio A1 - Vozzi, Diego A1 - Girardelli, Martina A1 - Knowles, Alessandra A1 - Tommasini, Alberto A1 - Zauli, Giorgio A1 - Marcuzzi, Annalisa AB -

Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X‑chromosome inactivation (XCI) studies on the patient's mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 µg/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient's mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X‑linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.

VL - 12 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26300074?dopt=Abstract ER - TY - JOUR T1 - Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research. JF - Acta Histochem Y1 - 2015 A1 - Frausin, Stefano A1 - Viventi, Serena A1 - Verga Falzacappa, Lucia A1 - Quattromani, Miriana Jlenia A1 - Leanza, Giampiero A1 - Tommasini, Alberto A1 - Valencic, Erica AB -

Multipotent mesenchymal stromal cells, also known as mesenchymal stem cells (MSC), can be isolated from bone marrow or other tissues, including fat, muscle and umbilical cord. It has been shown that MSC behave in vitro as stem cells: they self-renew and are able to differentiate into mature cells typical of several mesenchymal tissues. Moreover, the differentiation toward non-mesenchymal cell lineages (e.g. neurons) has been reported as well. The clinical relevance of these cells is mainly related to their ability to spontaneously migrate to the site of inflammation/damage, to their safety profile thanks to their low immunogenicity and to their immunomodulation capacities. To date, MSCs isolated from the post-natal bone marrow have represented the most extensively studied population of adult MSCs, in view of their possible use in various therapeutical applications. However, the bone marrow-derived MSCs exhibit a series of limitations, mainly related to their problematic isolation, culturing and use. In recent years, umbilical cord (UC) matrix (i.e. Wharton's jelly, WJ) stromal cells have therefore emerged as a more suitable alternative source of MSCs, thanks to their primitive nature and the easy isolation without relevant ethical concerns. This review seeks to provide an overview of the main biological properties of WJ-derived MSCs. Moreover, the potential application of these cells for the treatment of some known dysfunctions in the central and peripheral nervous system will also be discussed.

VL - 117 IS - 4-5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25747736?dopt=Abstract ER - TY - JOUR T1 - Clinical significance of hyper-IgA in a paediatric laboratory series. JF - Arch Dis Child Y1 - 2014 A1 - Copetti, Valentina A1 - Pastore, Serena A1 - De Pieri, Carlo A1 - Radillo, Oriano A1 - Taddio, Andrea A1 - Ventura, Alessandro A1 - Tommasini, Alberto KW - Adolescent KW - Child KW - Child, Preschool KW - Female KW - Hospitals, Pediatric KW - Humans KW - Hypergammaglobulinemia KW - Immunoglobulin A KW - Infant KW - Italy KW - Male KW - Tertiary Care Centers AB -

The causes of extremely elevated IgA, whether isolated or associated with an increase in other classes of immunoglobulin, are poorly defined in paediatrics. We reviewed the diagnostic significance of very high IgA levels (greater than 3 SD above the mean for age) in a cohort of patients referred to a tertiary care children's hospital. Hyper-IgA was found in 91 of 6364 subjects (1.4%) and in 68 cases was not associated with an increased IgG and/or IgM level. Most subjects with hyper-IgA (73.5%) had a severe immune defect, a chronic rheumatic disease or inflammatory bowel disease, while these conditions were very rare in a control group with normal IgA values (8%). Although our results may in part reflect the experience of a tertiary care centre, we suggest that hyper-IgA in children should always arouse suspicion of a serious disease.

VL - 99 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25053738?dopt=Abstract ER - TY - JOUR T1 - F402L variant in NLRP12 in subjects with undiagnosed periodic fevers and in healthy controls. JF - Clin Exp Rheumatol Y1 - 2014 A1 - De Pieri, Carlo A1 - Vuch, Josef A1 - Athanasakis, Emmanouil A1 - Severini, Giovanni Maria A1 - Crovella, Sergio A1 - Bianco, Anna Monica A1 - Tommasini, Alberto KW - Cryopyrin-Associated Periodic Syndromes KW - Female KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Male KW - Mutation VL - 32 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25327218?dopt=Abstract ER - TY - JOUR T1 - Fate of lymphocytes after withdrawal of tofacitinib treatment. JF - PLoS One Y1 - 2014 A1 - Piscianz, Elisa A1 - Valencic, Erica A1 - Cuzzoni, Eva A1 - De Iudicibus, Sara A1 - De Lorenzo, Elisa A1 - Decorti, Giuliana A1 - Tommasini, Alberto KW - Antigens, CD KW - B-Lymphocytes KW - CD4-Positive T-Lymphocytes KW - CD8-Positive T-Lymphocytes KW - Cell Proliferation KW - Drug Administration Schedule KW - Humans KW - Janus Kinase 3 KW - Killer Cells, Natural KW - Lymphocyte Activation KW - Lymphocyte Count KW - Phytohemagglutinins KW - Piperidines KW - Primary Cell Culture KW - Protein Kinase Inhibitors KW - Pyrimidines KW - Pyrroles AB -

Tofacitinib (Tofa) is an inhibitor of Janus Kinase 3, developed for the treatment of autoimmune diseases and for the prevention of transplant rejection. Due to its selective action on proliferating cells, Tofa can offer a way to block T cell activation, without toxic effects on resting cells. However, few studies have investigated the effects of Tofa on lymphocyte activation in vitro. Our aim was to study the action of Tofa on different lymphocyte subsets after in vitro stimulation and to track the behaviour of treated cells after interruption of the treatment. Peripheral blood lymphocytes were stimulated in vitro with mitogen and treated with two concentrations of Tofa. After a first period in culture, cells were washed and further incubated for an additional time. Lymphocyte subsets, activation phenotype and proliferation were assessed at the different time frames. As expected, Tofa was able to reduce the activation and proliferation of lymphocytes in the first four days of treatment. In addition the drug led to a relative decrease of Natural Killer, B cells and CD8 T cells compared to CD4 T cells. However, treated cells were still viable after the first period in culture and begun to proliferate, strikingly, in a dose dependent manner when the drug was removed from the environment by replacing the culture medium. This novel data does not necessarily predict a similar behaviour in vivo, but can warn about the clinical use of this drug when a discontinuation of treatment with Tofa is considered for any reason.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24416411?dopt=Abstract ER - TY - JOUR T1 - Hemophagocytic lymphohistiocytosis in total parenteral nutrition dependent children: description of 5 cases and practical tips for management. JF - J Pediatr Hematol Oncol Y1 - 2014 A1 - Pastore, Serena A1 - Barbieri, Francesca A1 - Di Leo, Grazia A1 - Valencic, Erica A1 - Tommasini, Alberto A1 - Ventura, Alessandro KW - Child, Preschool KW - Fatty Acids KW - Female KW - Humans KW - Infant KW - Intestinal Diseases KW - Lymphohistiocytosis, Hemophagocytic KW - Male KW - Parenteral Nutrition, Total KW - Steroids KW - Treatment Outcome AB -

Although total parenteral nutrition (TPN) is mandatory in children with intestinal failure, this treatment is not risk free. The main complications of TPN include catheter-related sepsis, thrombosis, hepatic cholestasis and cirrhosis, metabolic bone disease, and, rarely, reactive hemophagocytic lymphohistiocytosis (HLH). The pathogenesis of HLH in patients with TPN is not known, although some authors hypothesized that it can result from the activation of macrophages because of "fat overload." We reported 5 cases of HLH that occurred in patients with 4 different underlying disorders, all requiring TPN for a long term. In our series, an underlying immunological defect or a serious infection (sepsis) can have triggered HLH. Therefore, it could be reasonable to hypothesize that besides TPN in itself, minor immune defects and infections may act together by overcoming a threshold of immune stimulation, which ultimately leads to HLH.

VL - 36 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23823121?dopt=Abstract ER - TY - JOUR T1 - In vivo detection of polyomaviruses JCV and SV40 in mesenchymal stem cells from human umbilical cords. JF - Pediatr Blood Cancer Y1 - 2014 A1 - Comar, Manola A1 - Delbue, Serena A1 - Zanotta, Nunzia A1 - Valencic, Erica A1 - Piscianz, Elisa A1 - Del Savio, Rossella A1 - Tesser, Alessandra A1 - Tommasini, Alberto A1 - Ferrante, Pasquale KW - DNA, Viral KW - Female KW - Fetal Blood KW - Humans KW - JC Virus KW - Male KW - Mesenchymal Stromal Cells KW - Polyomavirus Infections KW - Simian virus 40 KW - Tumor Virus Infections AB -

BACKGROUND: Multipotent stromal cells are present in the Wharton's jelly matrix (WJSC) of the umbilical cord and can be used as an allogeneic source of cells to treat immunological disorders. Recently it was demonstrated that adult bone marrow (BM)-derived mesenchimal stromal cells (MSC) are susceptible to infection with viruses showing potential oncogenic properties, such as the polyomavirus JC (JCV). The aim of this study was to investigate the presence of human polyomaviruses (JCV, BK Virus-BKV, SV40, and Merkel cell polyomavirus-MCPyV) in WJSC, and explore the risk of infection.

PROCEDURE: MSC samples from 35 umbilical cords were investigated by quantitative Real Time PCRs for the presence of DNA sequences of JCV, BKV, SV40, and MCPyV.

RESULTS: JCV DNA was detected in 1/35 (2.8%) of MSC samples, while SV40 DNA was found in 3/35 (8.6%) of the examined samples. None of the samples showed sequences of BKV and MCPyV.

CONCLUSIONS: The present study demonstrates the in vivo ability of polyomaviruses to infect WJSC. Since the therapeutic approach with the WJSC has high potentiality and a more intensive use can be easily hypothesized, the need to develop consensus guidelines to detect rare viral infections in MSC is pressing.

VL - 61 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24623583?dopt=Abstract ER - TY - JOUR T1 - Inhibition of mesenchymal stromal cells by pre-activated lymphocytes and their culture media. JF - Stem Cell Res Ther Y1 - 2014 A1 - Valencic, Erica A1 - Loganes, Claudia A1 - Cesana, Stefania A1 - Piscianz, Elisa A1 - Gaipa, Giuseppe A1 - Biagi, Ettore A1 - Tommasini, Alberto KW - CD4-Positive T-Lymphocytes KW - CD8-Positive T-Lymphocytes KW - Cell Proliferation KW - Cell Survival KW - Cells, Cultured KW - Coculture Techniques KW - Culture Media, Conditioned KW - Cytokines KW - Humans KW - Killer Cells, Natural KW - Lymphocyte Activation KW - Mesenchymal Stromal Cells AB -

INTRODUCTION: Despite having a proven immunosuppressive potential in vitro, human mesenchymal stromal cells (MSCs) are reported to display variable efficacy in vivo and, in fact, their proven benefit in the clinical practice is still limited and controversial.

METHODS: The interplay between clinical grade MSCs and pre-activated donor lymphocytes or selected lymphocyte subsets was studied in vitro. The kinetics of MSC growth and viability was evaluated by adhesion-dependent changes of culture plate impedance and biochemically by a colorimetric assay. Activation of natural killer (NK) cells was assessed as well, using a flow cytometry assay.

RESULTS: A strong inhibition of MSC growth was rapidly induced by the addition of pre-activated lymphocytes but not of resting lymphocytes. Inhibition seems not to be attributable to a single cell population, as similar results can be obtained by depleting NK cells or by using either selected CD4+ or CD8+ lymphocytes. In addition, conditioned medium (CM) from activated lymphocytes was able to inhibit MSC growth in a dose-dependent manner. Furthermore, licensing with IFN-γ partially protected MSCs from pre-activated lymphocytes but not from their CM. These results suggest an inhibitory role of lymphocyte-activation-derived substances. However, the identification of a single molecule responsible for MSC inhibition remained elusive, even if preliminary experiments showed that ATP and, to a lesser extent, TNF-α might play a role.

CONCLUSIONS: These results suggest that survival of MSCs can be affected by soluble mediators released by activated lymphocytes. Thus it can be hypothesized that MSC immunosuppressive action in vivo could be impaired by ongoing immune activation through the release of inflammatory mediators.

VL - 5 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24405828?dopt=Abstract ER - TY - JOUR T1 - Novel missense mutation in the NOD2 gene in a patient with early onset ulcerative colitis: causal or chance association? JF - Int J Mol Sci Y1 - 2014 A1 - Girardelli, Martina A1 - Vuch, Josef A1 - Tommasini, Alberto A1 - Crovella, Sergio A1 - Bianco, Anna Monica KW - Age of Onset KW - Amino Acid Sequence KW - Base Sequence KW - Child KW - Colitis, Ulcerative KW - Crohn Disease KW - DNA Mutational Analysis KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Interleukin-10 Receptor alpha Subunit KW - Interleukin-10 Receptor beta Subunit KW - Molecular Sequence Data KW - Mutation, Missense KW - Nod2 Signaling Adaptor Protein KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Sequence Homology, Amino Acid AB -

Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn's disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A > G p.K953E) and two already described missense variants in the IL10RA gene (S159G and G351R). The new NOD2 missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation. Although cumulative effect of these variations in the early onset of the disease can be only hypothesized, we demonstrated that family information and in silico studies can be used to predict association with the disease.

VL - 15 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24595243?dopt=Abstract ER - TY - JOUR T1 - Severe inflammatory bowel disease associated with congenital alteration of transforming growth factor beta signaling. JF - J Crohns Colitis Y1 - 2014 A1 - Naviglio, Samuele A1 - Arrigo, Serena A1 - Martelossi, Stefano A1 - Villanacci, Vincenzo A1 - Tommasini, Alberto A1 - Loganes, Claudia A1 - Fabretto, Antonella A1 - Vignola, Silvia A1 - Lonardi, Silvia A1 - Ventura, Alessandro KW - Child, Preschool KW - Colon KW - Colonoscopy KW - Female KW - Humans KW - Infant KW - Inflammatory Bowel Diseases KW - Loeys-Dietz Syndrome KW - Male KW - Signal Transduction KW - Transforming Growth Factor beta AB -

Transforming growth factor beta is a pleiotropic cytokine which plays a central role in the homeostasis of the immune system. A complex dysregulation of its signaling occurs in Loeys-Dietz syndrome, a monogenic disorder caused by mutations of transforming growth factor beta receptors type 1 or type 2, characterized by skeletal involvement, craniofacial abnormalities, and arterial tortuosity with a strong predisposition for aneurysm and dissection. In addition, several immunologic abnormalities have been described in these patients, including an increased risk of allergic disorders as well as eosinophilic gastrointestinal disorders. The occurrence of inflammatory bowel disorders has been also reported, but it is poorly documented. We describe two unrelated children with Loeys-Dietz syndrome affected by severe chronic inflammatory colitis appearing at an early age. The intestinal disease presented similar features in both patients, including a histopathological picture of non-eosinophilic chronic ulcerative colitis, striking elevation of inflammatory markers, and a distinctly severe clinical course leading to failure to thrive, with resistance to multiple immunosuppressive treatments. One of the patients also presented autoimmune thyroiditis. Our report confirms that chronic ulcerative colitis may be associated with Loeys-Dietz syndrome. This finding suggests that an alteration of transforming growth factor beta signaling may by itself predispose to inflammatory colitis in humans, and represent an invaluable model to understand inflammatory bowel diseases.

VL - 8 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24486179?dopt=Abstract ER - TY - JOUR T1 - TNF-α SNP rs1800629 and risk of relapse in childhood acute lymphoblastic leukemia: relation to immunophenotype. JF - Pharmacogenomics Y1 - 2014 A1 - Franca, Raffaella A1 - Rebora, Paola A1 - Athanasakis, Emmanouil A1 - Favretto, Diego A1 - Verzegnassi, Federico A1 - Basso, Giuseppe A1 - Tommasini, Alberto A1 - Valsecchi, Maria Grazia A1 - Decorti, Giuliana A1 - Rabusin, Marco KW - Adolescent KW - Antineoplastic Agents KW - Child KW - Child, Preschool KW - Drug Resistance, Neoplasm KW - Female KW - Genotype KW - Humans KW - Infant KW - Leukemia, Lymphocytic, Chronic, B-Cell KW - Male KW - Phenotype KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma KW - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma KW - Recurrence KW - Risk Assessment KW - Steroids KW - Tumor Necrosis Factor-alpha AB -

AIM: In the AIEOP-BFM ALL (Associazione Italiana Ematologia Oncologia Pediatrica-Berlin Frankfurt Münster acute lymphoblastic leukemia) 2000 protocol, 70% of relapsed patients had favorable prognostic features and fell within less intensive polychemotherapeutic regimens, suggesting the need for better assessing lower risk stratification.

MATERIALS & METHODS: A novel two-phase study design selected 614 children to be genotyped for TNF-α SNP rs1800629 (-308G>A). A weighted Cox model was applied to evaluate the SNP effect on hazard of relapse, adjusting for immunophenotype, risk group, age and gender and including interaction terms.

RESULTS: Significant interaction was found with immunophenotypes (p = 0.0007, with minor allele genotypes being adverse genetic markers in B-cell acute lymphoblastic leukemia and protective ones in T-cell acute lymphoblastic leukemia), and also with risk protocols (p = 0.0041, with minor allele genotypes as prognostic factor of relapse for standard risk patients [only one T-cell acute lymphoblastic leukemia in the subgroup analyzed]).

CONCLUSION: The presence of at least one A allele in TNF-α SNP rs1800629 should suggest a closer monitoring in B-cell acute lymphoblastic leukemia standard risk patients.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24798719?dopt=Abstract ER - TY - JOUR T1 - A common genetic background could explain early-onset Crohn's disease. JF - Med Hypotheses Y1 - 2012 A1 - Bianco, Anna Monica A1 - Zanin, Valentina A1 - Girardelli, Martina A1 - Magnolato, Andrea A1 - Martelossi, Stefano A1 - Martellossi, Stefano A1 - Tommasini, Alberto A1 - Marcuzzi, Annalisa A1 - Crovella, Sergio KW - Crohn Disease KW - Genetic Linkage KW - Genetic Predisposition to Disease KW - Humans KW - Models, Biological AB -

Crohn's disease (CD) is a multifactorial disease, in which environmental, microbial and genetic factors play important roles. CD is characterized by a chronic granulomatous inflammation by necrotic scarring with aspects of full-thickness wall. In spite of affecting mainly young adults, sometimes, CD can be present in the first year of life (early onset Crohn disease, EOCD) showing an unpredictable course and being often more severe than at older ages. In this paper we propose the hypothesis that EOCD patients should be analyzed using a Mendelian approach with family studies aimed to identify new loci directly involved in the early onset Crohn's disease. So we will leave the classic association study approach used until now for the identification of genes responsible for susceptibility to CD and propose linkage family analysis as alternative and powerful tool for the identification of new genetic variants associated with familiar cases of EOCD.

VL - 78 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22309886?dopt=Abstract ER - TY - JOUR T1 - Defective and excessive immunities in pediatric diseases. JF - Curr Pharm Des Y1 - 2012 A1 - Notarangelo, Luigi Daniele A1 - Tommasini, Alberto KW - Autoimmune Diseases KW - Child KW - Drug Design KW - Humans KW - Immunologic Deficiency Syndromes KW - Inflammation KW - Lymphocyte Activation KW - Severity of Illness Index AB -

Inflammatory and autoimmune diseases are classically considered as disorders arising from hyper-activation of immunity and hence are treated with drugs that suppress the lymphocyte activation and inflammation. Although this strategy has proven useful to cure symptoms, it rarely can heal the disease and long-term treatments are usually needed. Inflammatory and autoimmune diseases frequently occur also in patients with primary immune deficiency disease, proving that immune hyper-activation may paradoxically arise from defective function of immune genes. In these cases, the phenotype of hyper-activation is believed to reflect the attempts of the immune system to compensate for immune defects. Recent data suggest that similar mechanisms could be involved also in the pathogenesis of some multifactorial disorders, such as Crohn's disease and systemic lupus erythematosus. Based on these considerations, novel therapies could be developed to cure severe autoimmune and inflammatory disorders, not only by aiming to hyper-activation but as well by focusing on the possible underlying immune defects.

VL - 18 IS - 35 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22726115?dopt=Abstract ER - TY - JOUR T1 - Immunomodulatory drugs in autoimmune lymphoproliferative syndrome (ALPS). JF - Pediatr Blood Cancer Y1 - 2012 A1 - Tommasini, Alberto A1 - Valencic, Erica A1 - Piscianz, Elisa A1 - Rabusin, Marco KW - Antineoplastic Agents KW - Autoimmune Lymphoproliferative Syndrome KW - Diseases in Twins KW - Humans KW - Male KW - Pentostatin VL - 58 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21674759?dopt=Abstract ER - TY - JOUR T1 - Inflammation profile of four early onset Crohn patients. JF - Gene Y1 - 2012 A1 - Marcuzzi, Annalisa A1 - Girardelli, Martina A1 - Bianco, Anna Monica A1 - Martelossi, Stefano A1 - Magnolato, Andrea A1 - Tommasini, Alberto A1 - Crovella, Sergio KW - Crohn Disease KW - Cytokines KW - Humans KW - Inflammation KW - Monocytes KW - Nod2 Signaling Adaptor Protein KW - Polymorphism, Genetic KW - Receptors, Interleukin-10 KW - Tumor Necrosis Factor-alpha AB -

Crohn disease (CD) is a multifactorial disorder affecting mainly young adults. Sometimes, however, it can present in the first year of life (Early onset Crohn disease (EOCD)) showing an unpredictable course and can often be more severe than at older ages. Some cases have been associated to an underlying primary immunodeficiency such as IL10R deficiency. We studied the functional response to IL-10 and the genotype of IL-10 receptor in four patients with early onset crohn-like colitis. We found an IL10R variant, which may be associated with a decreased response to the cytokine in one patient. Further studies to determine its pathogenic effect should be performed. In addition IL-10 mediated inhibition of LPS-induced TNFα expression was measured in patient's monocytes.

VL - 493 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22155628?dopt=Abstract ER - TY - JOUR T1 - JCV+ Patients with Inflammatory bowel disease show elevated plasma levels of MIG and SCF. JF - Inflamm Bowel Dis Y1 - 2012 A1 - Comar, Manola A1 - Secchiero, Paola A1 - De Lorenzo, Elisa A1 - Martelossi, Stefano A1 - Tommasini, Alberto A1 - Zauli, Giorgio KW - Adolescent KW - Adult KW - Chemokine CXCL9 KW - Child KW - DNA, Viral KW - Female KW - Humans KW - Inflammatory Bowel Diseases KW - JC Virus KW - Leukoencephalopathy, Progressive Multifocal KW - Male KW - Stem Cell Factor KW - Young Adult VL - 18 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22467521?dopt=Abstract ER - TY - JOUR T1 - The MDM2 inhibitor Nutlin-3 modulates dendritic cell-induced T cell proliferation. JF - Hum Immunol Y1 - 2012 A1 - Gasparini, Chiara A1 - Tommasini, Alberto A1 - Zauli, Giorgio KW - Dendritic Cells KW - Humans KW - Imidazoles KW - Immunologic Factors KW - Immunophenotyping KW - Lymphocyte Activation KW - Piperazines KW - Proto-Oncogene Proteins c-mdm2 KW - T-Lymphocytes AB -

Nutlin-3, a small molecule inhibitor of the MDM2/p53 interaction, has been recently taken into consideration as a promising therapeutic tool for tumor treatment based on its ability to stabilize and activate the p53 transcription factor pathway. Since Nutlin-3 displays non cell-autonomous tumor-suppressor activities, we wanted to investigate its effect on dendritic cell functions, given the central role of these cells in the modulation of the immune response. We found that Nutlin-3 alone slightly affected the levels of major histocompatibility complex and costimulatory molecules and significantly promoted the ability of dendritic cells to stimulate T cells in the mixed lymphocyte reaction. Taken together, our findings suggest that the ability of Nutlin-3 to modulate dendritic cell functions and therefore lymphocyte proliferation might represent an additional important mechanism by which Nutlin-3 exerts its non cell-autonomous tumor-suppression function.

VL - 73 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22374325?dopt=Abstract ER - TY - JOUR T1 - A red baby should not be taken too lightly. JF - Acta Paediatr Y1 - 2012 A1 - Faletra, Flavio A1 - Bruno, Irene A1 - Berti, Irene A1 - Pastore, Serena A1 - Pirrone, Angela A1 - Tommasini, Alberto KW - Child, Preschool KW - Dermatitis KW - Ectodermal Dysplasia KW - Female KW - Humans KW - Immunologic Deficiency Syndromes KW - Infant KW - Male KW - Netherton Syndrome KW - Severe Combined Immunodeficiency KW - Skin AB -

AIM: To identify clinical and laboratory features that can drive the differential diagnosis of a primary immunodeficiency diseases in patients with ectodermal defects.

METHODS: Analysis of selected teaching cases.

RESULTS: We identified four exemplary cases that allowed to point out specific clues.

CONCLUSIONS: A careful evaluation of immune and ectodermal signs is the key to the diagnosis. Therefore, a multidisciplinary approach can lead to diagnosis and to an appropriate treatment in most of the cases.

VL - 101 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22946961?dopt=Abstract ER - TY - JOUR T1 - Ages of celiac disease: from changing environment to improved diagnostics. JF - World J Gastroenterol Y1 - 2011 A1 - Tommasini, Alberto A1 - Not, Tarcisio A1 - Ventura, Alessandro KW - Autoantibodies KW - Celiac Disease KW - Diet, Gluten-Free KW - Gliadin KW - Glutens KW - History, 19th Century KW - History, 20th Century KW - History, 21st Century KW - History, Ancient KW - History, Medieval KW - Humans KW - Transglutaminases AB -

From the time of Gee's landmark writings, the recent history of celiac disease (CD) can be divided into many ages, each driven by a diagnostic advance and a deeper knowledge of disease pathogenesis. At the same time, these advances were paralleled by the identification of new clinical patterns associated with CD and by a continuous redefinition of the prevalence of the disease in population. In the beginning, CD was considered a chronic indigestion, even if the causative food was not known; later, the disease was proven to depend on an intolerance to wheat gliadin, leading to typical mucosal changes in the gut and to a malabsorption syndrome. This knowledge led to curing the disease with a gluten-free diet. After the identification of antibodies to gluten (AGA) in the serum of patients and the identification of gluten-specific lymphocytes in the mucosa, CD was described as an immune disorder, resembling a chronic "gluten infection". The use of serological testing for AGA allowed identification of the higher prevalence of this disorder, revealing atypical patterns of presentation. More recently, the characterization of autoantibodies to endomysium and to transglutaminase shifted the attention to a complex autoimmune pathogenesis and to the increased risk of developing autoimmune disorders in untreated CD. New diagnostic assays, based on molecular technologies, will introduce new changes, with the promise of better defining the spectrum of gluten reactivity and the real burden of gluten related-disorders in the population. Herein, we describe the different periods of CD experience, and further developments for the next celiac age will be proposed.

VL - 17 IS - 32 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21990947?dopt=Abstract ER - TY - JOUR T1 - Differential action of 3-hydroxyanthranilic acid on viability and activation of stimulated lymphocytes. JF - Int Immunopharmacol Y1 - 2011 A1 - Piscianz, Elisa A1 - Cuzzoni, Eva A1 - De Iudicibus, Sara A1 - Valencic, Erica A1 - Decorti, Giuliana A1 - Tommasini, Alberto KW - 3-Hydroxyanthranilic Acid KW - Boronic Acids KW - Cell Survival KW - Cells, Cultured KW - Humans KW - Lymphocyte Activation KW - Lymphocytes KW - Manganese KW - Pyrazines AB -

Lymphocytes proliferation after antigen-driven activation leads to an increase in cell count, which could last some week, until apoptosis mechanisms allow the homeostatic control of the system. During the first days of this stimulation, activated lymphocytes display high resistance to apoptosis and to most immunosuppressive drugs. According to the literature, few compounds have been described to kill recently activated cells, by inhibiting metabolic processes fundamental to proliferation. The aim of our work was to evaluate comparatively these different compounds, in order to identify the best strategy to kill cells that have undergone proliferation, while sparing the repertoire of resting cells. After preliminary experiments, 3-HAA and bortezomib were selected as the most suitable compounds for our purposes. The possible synergic effect of 3-HAA with bortezomib or with manganese ions was also assessed. 3-HAA was confirmed to be the most reliable pharmacologic approach to inhibit proliferation with acceptable toxicity on resting cells. While in the case of PHA stimulation 3-HAA led to death of most lymphocytes, only a minor percentage of cells were killed after allo-stimulation, suggesting that the effect is proportional to the percentage of stimulated lymphocytes. Manganese ions further enhanced this effect, while results with bortezomib seemed to be less consistent. These results deserve further investigations to develop new procedures for targeting activated cells with pharmacological approaches.

VL - 11 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21979495?dopt=Abstract ER - TY - JOUR T1 - The farnesyltransferase inhibitors tipifarnib and lonafarnib inhibit cytokines secretion in a cellular model of mevalonate kinase deficiency. JF - Pediatr Res Y1 - 2011 A1 - Marcuzzi, Annalisa A1 - De Leo, Luigina A1 - Decorti, Giuliana A1 - Crovella, Sergio A1 - Tommasini, Alberto A1 - Pontillo, Alessandra KW - Alendronate KW - Animals KW - Anti-Inflammatory Agents KW - Cell Line KW - Child KW - Child, Preschool KW - Cholesterol KW - Cytokines KW - Dose-Response Relationship, Drug KW - Enzyme Inhibitors KW - Farnesyltranstransferase KW - Humans KW - Inflammation Mediators KW - Lovastatin KW - Male KW - Mevalonate Kinase Deficiency KW - Mice KW - Monocytes KW - Phosphotransferases (Alcohol Group Acceptor) KW - Piperidines KW - Polyenes KW - Polyisoprenyl Phosphates KW - Polyunsaturated Alkamides KW - Pyridines KW - Quinolones KW - Terpenes AB -

The shortage of geranylgeranyl-pyrophosphate (GGPP) was associated to an increased IL-1β release in the autoinflammatory syndrome mevalonate kinase deficiency (MKD), a rare inherited disease that has no specific therapy. Farnesyltransferase inhibitors (FTIs) act at the end of mevalonate pathway. Two FTIs, tipifarnib (Tip) and lonafarnib (Lon), were therefore evaluated as possible therapeutical choices for the treatment of MKD. FTIs could lead to a redirection of the limited available number of mevalonate intermediates preferentially to GGPP synthesis, eventually preventing the uncontrolled inflammatory response. The effect of Tip and Lon on intracellular cholesterol level (ICL) and on proinflammatory cytokines secretion was evaluated in a cellular model of MKD, chemically obtained treating RAW 264.7 cells with lovastatin (Lova) and alendronate (Ald). The combination of FTIs with the isoprenoid geraniol (GOH) was also tested both in this model and in monocytes isolated from MKD patients. Tip and Lon proved to revert the ICL lowering and to significantly reduce the lipopolysaccharide-induced cytokines secretion in Ald-Lova -RAW 264.7 cells. This anti-inflammatory effect was amplified combining the use of GOH with FTIs. The effect of GOH and Tip was successfully replicated in MKD patients' monocytes. Tip and Lon showed a dramatic anti-inflammatory effect in monocytes where mevalonate pathway was chemically or genetically impaired.

VL - 70 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21430599?dopt=Abstract ER - TY - JOUR T1 - Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability. JF - J Allergy Clin Immunol Y1 - 2011 A1 - Passerini, Laura A1 - Olek, Sven A1 - Di Nunzio, Sara A1 - Barzaghi, Federica A1 - Hambleton, Sophie A1 - Abinun, Mario A1 - Tommasini, Alberto A1 - Vignola, Silvia A1 - Cipolli, Marco A1 - Amendola, Mario A1 - Naldini, Luigi A1 - Guidi, Luisa A1 - Cecconi, Massimiliano A1 - Roncarolo, Maria G A1 - Bacchetta, Rosa KW - Forkhead Transcription Factors KW - Gene Expression Regulation KW - Genetic Diseases, X-Linked KW - Humans KW - Immunologic Deficiency Syndromes KW - Intestinal Diseases KW - Male KW - Mutation KW - Polyendocrinopathies, Autoimmune VL - 128 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22000569?dopt=Abstract ER - TY - JOUR T1 - Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome. JF - Eur J Immunol Y1 - 2011 A1 - Passerini, Laura A1 - Di Nunzio, Sara A1 - Gregori, Silvia A1 - Gambineri, Eleonora A1 - Cecconi, Massimiliano A1 - Seidel, Markus G A1 - Cazzola, Giantonio A1 - Perroni, Lucia A1 - Tommasini, Alberto A1 - Vignola, Silvia A1 - Guidi, Luisa A1 - Roncarolo, Maria G A1 - Bacchetta, Rosa KW - Cell Differentiation KW - Cell Lineage KW - Cells, Cultured KW - Enteritis KW - Forkhead Transcription Factors KW - Genetic Diseases, X-Linked KW - Humans KW - Immunity, Innate KW - Interleukin-2 Receptor alpha Subunit KW - Mutation KW - Polyendocrinopathies, Autoimmune KW - Syndrome KW - T-Lymphocytes, Regulatory AB -

Mutations of forkhead box p3 (FOXP3), the master gene for naturally occurring regulatory T cells (nTregs), are responsible for the impaired function of nTregs, resulting in an autoimmune disease known as the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. The relevance of other peripheral tolerance mechanisms, such as the presence and function of type 1 regulatory T (Tr1) cells, the major adaptive IL-10-producing Treg subset, in patients with IPEX syndrome remains to be clarified. FOXP3(mutated) Tr1-polarized cells, differentiated in vitro from CD4(+) T cells of four IPEX patients, were enriched in IL-10(+) IL-4(-) IFN-γ(+) T cells, a cytokine production profile specific for Tr1 cells, and expressed low levels of FOXP3 and high levels of Granzyme-B. IPEX Tr1 cells were hypoproliferative and suppressive, thus indicating that FOXP3 mutations did not impair their function. Furthermore, we isolated Tr1 cell clones from the peripheral blood of one FOXP3(null) patient, demonstrating that Tr1 cells are present in vivo and they can be expanded in vitro in the absence of WT FOXP3. Overall, our results (i) show that functional Tr1 cells differentiate independently of FOXP3, (ii) confirm that human Tr1 and nTregs are distinct T-cell lineages, and (iii) suggest that under favorable conditions Tr1 cells could exert regulatory functions in IPEX patients.

VL - 41 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21400500?dopt=Abstract ER - TY - JOUR T1 - Gastrointestinal Foxp3 expression in normal, inflammatory and neoplastic conditions. JF - Pathology Y1 - 2011 A1 - Villanacci, Vincenzo A1 - Not, Tarcisio A1 - Nascimbeni, Riccardo A1 - Ferrara, Fortunato A1 - Tommasini, Alberto A1 - Manenti, Stefania A1 - Antonelli, Elisabetta A1 - Bassotti, Gabrio KW - Adult KW - Aged KW - Celiac Disease KW - Cell Count KW - Disease Progression KW - Esophagitis KW - Female KW - Forkhead Transcription Factors KW - Gastric Mucosa KW - Gastritis KW - Humans KW - Inflammatory Bowel Diseases KW - Lymphocytes KW - Male KW - Middle Aged KW - Precancerous Conditions KW - Stomach Diseases KW - Stomach Neoplasms KW - Young Adult AB -

BACKGROUND: Foxp3(+) regulatory T lymphocytes (T-regs) represent an important regulatory cell subset in inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract.

METHODS: Inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract (189 cases) were studied with the evaluation of Foxp3 regulatory T cells based on immunohistochemistry.

RESULTS: Few Foxp3(+) cells were found in controls and inflammatory conditions (oesophagitis, gastritis, coeliac disease, inflammatory bowel disease); in preneoplastic and neoplastic conditions the number of Foxp3(+) cells was significatively increased.

CONCLUSIONS: In normal conditions the number of mucosal lymphocytes is very low throughout the gastro-intestinal tract; in active coeliac disease patients or on a gluten-free diet, only a slight increase in Foxp3(+) cells may be found. Gastrointestinal cancers are associated with higher Foxp3(+) cell proportion, compared with microscopically normal tissue and with precancerous conditions. However, it is uncertain whether the increase in these regulatory cells is a cause or a consequence of tumour progression.

VL - 43 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21670722?dopt=Abstract ER - TY - JOUR T1 - Decreased cholesterol levels reflect a consumption of anti-inflammatory isoprenoids associated with an impaired control of inflammation in a mouse model of mevalonate kinase deficiency. JF - Inflamm Res Y1 - 2010 A1 - Marcuzzi, Annalisa A1 - Decorti, Giuliana A1 - Pontillo, Alessandra A1 - Ventura, Alessandro A1 - Tommasini, Alberto KW - Animals KW - Anti-Inflammatory Agents KW - Cholesterol KW - Disease Models, Animal KW - Inflammation KW - Interleukin-1beta KW - Male KW - Mevalonate Kinase Deficiency KW - Mice KW - Mice, Inbred BALB C KW - Random Allocation KW - Terpenes AB -

OBJECTIVE: The aim of this study was to evaluate, in a mouse model of mevalonate kinase deficiency (MKD), the possible link between inflammatory symptoms and serum cholesterol levels.

MATERIALS AND METHODS: Balb/c mice were treated with alendronate and bacterial muramyl dipeptide. Body temperature, interleukin-1 beta (IL-1 beta) secretion and serum cholesterol levels were measured.

RESULTS: An increased production of the pro-inflammatory cytokine IL-1 beta (p < 0.05) and a rise in body temperature (p < 0.05) was observed, while, in parallel, serum cholesterol concentration significantly decreased (p < 0.05). These effects were completely reversed when animals were treated with exogenous isoprenoids.

CONCLUSIONS: In the mouse model of MKD, the inflammatory response is associated with a reduction in cholesterol levels, and hence this parameter could be used as an indicator of isoprenoid consumption. In addition, plant derived isoprenoids could represent candidate treatments for this disease.

VL - 59 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20174853?dopt=Abstract ER - TY - JOUR T1 - Follow-up and quality of life of patients with cryopyrin-associated periodic syndromes treated with Anakinra. JF - J Pediatr Y1 - 2010 A1 - Lepore, Loredana A1 - Paloni, Giulia A1 - Caorsi, Roberta A1 - Alessio, Maria A1 - Rigante, Donato A1 - Ruperto, Nicola A1 - Cattalini, Marco A1 - Tommasini, Alberto A1 - Zulian, Francesco A1 - Ventura, Alessando A1 - Martini, Alberto A1 - Gattorno, Marco KW - Adolescent KW - Adult KW - Case-Control Studies KW - Child KW - Child, Preschool KW - Cryopyrin-Associated Periodic Syndromes KW - Female KW - Follow-Up Studies KW - Humans KW - Inflammation KW - Interleukin 1 Receptor Antagonist Protein KW - Interleukin-1 KW - Male KW - Phenotype KW - Quality of Health Care KW - Quality of Life KW - Questionnaires KW - Syndrome KW - Treatment Outcome AB -

OBJECTIVE: To evaluate the quality of life and long-term follow-up of patients enrolled in the Italian registry of cryopyrin-associated periodic syndromes (CAPS).

STUDY DESIGN: Since 2004, 20 patients with CAPS were enrolled in a common registry from different Italian Centers of Pediatric Rheumatology; 14 patients were treated with Anakinra in an open fashion. Both treated and untreated patients were routinely followed according to standard of care. The Child Health Questionnaire (CHQ-PF 50) was used to assess the health-related quality of life.

RESULTS: The mean duration of follow-up was 37.5 months. In all treated patients, a complete and persistent control of the inflammatory manifestations was observed with no further progression of the disease. At enrollment in the registry, patients showed a poorer health-related quality of life than healthy children in both physical and the psychosocial summary scores. Treatment was associated with a dramatic and sustained amelioration of a variety of measures of poor quality of life, particularly in those concerning the global health perception, bodily pain-discomfort, and other physical domains.

CONCLUSIONS: Long-term IL-1 blockade produces a significant and persistent improvement in the clinical manifestations associated with the disease and on the overall quality of life.

VL - 157 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20472245?dopt=Abstract ER - TY - JOUR T1 - Natural isoprenoids inhibit LPS-induced-production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes. JF - Int Immunopharmacol Y1 - 2010 A1 - Marcuzzi, Annalisa A1 - Tommasini, Alberto A1 - Crovella, Sergio A1 - Pontillo, Alessandra KW - Animals KW - Cell Line KW - Cells, Cultured KW - Child KW - Child, Preschool KW - Cytokines KW - Diphosphonates KW - Humans KW - Inflammation KW - Interleukin-1beta KW - Lipopolysaccharides KW - Male KW - Mevalonate Kinase Deficiency KW - Mice KW - Monocytes KW - Nitric Oxide KW - Terpenes AB -

The inhibition of mevalonate pathway through genetic defects (mevalonate kinase deficiency, MKD) or pharmacologic drugs (aminobisphosphonates) causes a shortage of intermediate compounds and, in particular, of geranylgeranyl-pyrophosphate (GGPP) associated to the activation of caspase-1 and IL-1beta release. Geraniol (GOH), farnesol (FOH), geranylgeraniol (GGOH) and menthol (MOH), due to their isoprenoid structure, are supposed to enter the mevalonate pathway and to by-pass the biochemical block, reconstituting the pathway. Considering the already known side effects of aminobisphosphonates, and the lack of a specific treatment for MKD, we evaluated the impact of these natural isoprenoids compounds in a RAW cell lines chemically treated with the aminobisphosphonate alendronate, and in monocytes isolated from 2 patients affected by MKD. GOH, FOH, GGOH and MOH were all capable to diminish inflammatory marker levels induced by LPS. These natural isoprenoids could be proposed as novel therapeutic approach for the still orphan drug MKD, but also considered for the evaluation of possible inflammatory side effects of aminobisphosphonates.

VL - 10 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20304105?dopt=Abstract ER - TY - JOUR T1 - Targeting farnesyl-transferase as a novel therapeutic strategy for mevalonate kinase deficiency: in vitro and in vivo approaches. JF - Pharmacol Res Y1 - 2010 A1 - De Leo, Luigina A1 - Marcuzzi, Annalisa A1 - Decorti, Giuliana A1 - Tommasini, Alberto A1 - Crovella, Sergio A1 - Pontillo, Alessandra KW - Adult KW - Animals KW - Anti-Inflammatory Agents KW - Cells, Cultured KW - Child, Preschool KW - Enzyme Inhibitors KW - Farnesyltranstransferase KW - Female KW - Humans KW - Male KW - Mevalonate Kinase Deficiency KW - Mevalonic Acid KW - Mice KW - Mice, Inbred BALB C KW - Monocytes KW - Polyenes KW - Polyisoprenyl Phosphates KW - Polyunsaturated Alkamides KW - Young Adult AB -

Mevalonate kinase deficiency (MKD) is a rare inborn auto-inflammatory disease due to the impairment of the pathway for the biosynthesis of cholesterol and non-sterol isoprenoids. The shortage of isoprenoids compounds and in particular of geranylgeranylpyrophosphate (GGPP) was recently associated to the MKD characteristic inflammatory attacks. The aim of this study is to demonstrate that the normalization of the mevalonate pathway intermediates levels and in particular of GGPP, through the specific inhibition of farnesyl-transferase (FT) with Manumycin A could ameliorate the inflammatory phenotype of MKD patients. The effect of Manumycin A was first evaluated in MKD mouse and cellular models, chemically obtained using the aminobisphosphonate alendronate (ALD), and then in monocytes isolated from 2 MKD patients. Our findings were compared to those obtained by using natural exogenous isoprenoids (NEIs). Manumycin A was able to significantly reduce the inflammatory marker serum amyloid A in ALD-treated Balb/c mice, as well as IL-1 beta secretion in ALD-monocytes and in MKD patients. These results clearly showed that, through the inhibition of FT, an increased number of mevalonate pathway intermediates could be redirected towards the synthesis of GGPP diminishing the inflammatory response. The importance in limiting the shortage of GGPP was emphasized by the anti-inflammatory effect of NEIs that, due to their biochemical structure, can enter the MKD pathway. In conclusion, manumycin A, as well as NEIs, showed anti-inflammatory effect in MKD models and especially in MKD-monocytes, suggesting novel approaches in the treatment of MKD, an orphan disease without any efficacious treatment currently available.

VL - 61 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20206266?dopt=Abstract ER - TY - JOUR T1 - Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease. JF - J Allergy Clin Immunol Y1 - 2010 A1 - Freudenberg, Folke A1 - Wintergerst, Uwe A1 - Roesen-Wolff, Angela A1 - Albert, Michael H A1 - Prell, Christine A1 - Strahm, Brigitte A1 - Koletzko, Sibylle A1 - Ehl, Stephan A1 - Roos, Dirk A1 - Tommasini, Alberto A1 - Ventura, Alessandro A1 - Belohradsky, Bernd H A1 - Seger, Reinhard A1 - Roesler, Joachim A1 - Güngör, Tayfun KW - Age of Onset KW - Anti-Bacterial Agents KW - Antibodies, Monoclonal KW - Child KW - Drug Therapy, Combination KW - Gene Deletion KW - Granulomatous Disease, Chronic KW - Humans KW - Inflammatory Bowel Diseases KW - Male KW - NADPH Oxidase KW - Steroids KW - Treatment Outcome KW - Vidarabine VL - 125 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20371400?dopt=Abstract ER - TY - JOUR T1 - The universe of immune deficiencies in Crohn's disease: a new viewpoint for an old disease? JF - Scand J Gastroenterol Y1 - 2010 A1 - Tommasini, Alberto A1 - Pirrone, Angela A1 - Palla, Gabriella A1 - Taddio, Andrea A1 - Martelossi, Stefano A1 - Crovella, Sergio A1 - Ventura, Alessandro KW - Biological Markers KW - Crohn Disease KW - Cytokines KW - Evidence-Based Medicine KW - Granulomatous Disease, Chronic KW - Hematopoietic Stem Cell Transplantation KW - Humans KW - Immunosuppressive Agents KW - Phagocytes KW - Treatment Outcome KW - Wiskott-Aldrich Syndrome AB -

Crohn's disease (CD) is generally considered a multifactorial disorder, since different genetic and environmental factors are thought to play a role in its pathogenesis. Recently, genome wide linkage studies allowed to identify the association of several loci with the increased risk of CD, although it is still unclear how they interact with environmental factors in causing the disease. The fact that many CD-risk-related genes are involved in the function of phagocytes seems in agreement with the well known role of these cells in CD histopathology. Functional defects in cytokine production or in clearance of bacteria in CD patients have recently been reported. Growing evidence that CD could arise from primary phagocyte immunodeficiency is also coming from the study of cases with early onset in infancy. We review such evidences starting from selected cases and discuss the clinical implications of these findings.

VL - 45 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20497046?dopt=Abstract ER -