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| 1 | Genetics of inflammatory bowel disease from multifactorial to monogenic forms显示文摘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 IL23 R,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 6th 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. | Anna Monica Bianco Martina Girardelli Alberto Tommasini | 2015 | World Journal of Gastroenterology2015，21，43： | 13 |
| 2 | Failure of interferon-γ pre-treated mesenchymal stem cell treatment in a patient with crohn's disease显示文摘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 steroiddependent 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. | Andrea Taddio Alberto Tommasini Erica Valencic Ettore Biagi Giuliana Decorti Sara De Iudicibus Eva Cuzzoni Giuseppe Gaipa Raffaela Badolato Alberto Prandini Andrea Biondi Alessandro Ventura | 2015 | World Journal of Gastroenterology2015，21，14： | 2 |
| 3 | Is autophagy an elective strategy to protect neurons from dysregulated cholesterol metabolism?显示文摘The balance of autophagy, apoptosis and necroptosis is crucial to determine the outcome of the cellular response to cholesterol dysregulation. Cholesterol plays a major role in regulating the properties of cell membranes, especially as regards their fluidity, and the regulation of its biosynthesis influences the shape and functions of these membranes. Whilst dietary cholesterol can easily be distributed to most organs, the central nervous system, whose membranes are particularly rich in cholesterol, mainly relies on de novo synthesis. For this reason, defects in the biosynthesis of cholesterol can variably affect the development of central nervous system. Moreover, defective synthesis of cholesterol and its intermediates may reflect both on structural cell anomalies and on the response to inflammatory stimuli. Examples of such disorders include mevalonate kinase deficiency, and Smith-Lemli-Opitz syndrome, due to deficiency in biosynthetic enzymes, and type C Niemann-Pick syndrome, due to altered cholesterol trafficking across cell compartments. Autophagy, as a crucial pathway dedicated to the degradation of cytosolic proteins and organelles, plays an essential role in the maintenance of homeostasis and in the turnover of the cytoplasmic material especially in the presence of imbalances such as those resulting from alteration of cholesterol metabolism. Manipulating the process of autophagy can offer possible strategies for improving neuronal cell viability and function in these genetic disorders. | Elisa Piscianz Liza Vecchi Brumatti Alberto Tommasini Annalisa Marcuzzi | 2019 | Neural Regeneration Research2019，14，4： | 2 |
| 4 | Neither hereditary periodic fever nor periodic fever, aphthae, pharingitis, adenitis: Undifferentiated periodic fever in a tertiary pediatric center显示文摘AIM To describe the frequency and clinical characteristics of patients with undifferentiated periodic fever(UPF) and to investigate whether a clinical classification of UPF based on the PRINTO-Eurofever score can help predicting the response to treatment and the outcome at follow-up.METHODS Clinical and therapeutic information of patients with recurrent fever who presented at a single pediatric rheumatology center from January 2006 through April 2016 were retrospectively collected. Patients with a clinical suspicion of hereditary periodic fever(HPF) syndrome and patients with clinical picture of periodic fever, aphthae, pharingitis, adenitis(PFAPA) who were refractory to tonsillectomy underwent molecular analysis of five HPF-related genes: MEFV(NM_000243.2), MVK(NM_000431.3), TNFRSF1 A(NM_001065.3), NLRP3(NM_001079821.2), NLRP12(NM_001277126.1). All patients who had a negative genetic result were defined as UPF and further investigated. PRINTO-Eurofever score for clinical diagnosis of HPF was calculated in all cases. RESULTS Of the 221 patients evaluated for periodic fever, twelve subjects with a clinical picture of PFAPA who were refractory to tonsillectomy and 22 subjects with a clinical suspicion of HPF underwent genetic analysis. Twenty-three patients(10.4%) resulted negative and were classified as UPF. The median age at presentation of patients with UPF was 9.5 mo(IQR 4-24). Patients with UPF had a higher frequency of aphthae(52.2% vs 0%, P = 0.0026) and musculoskeletal pain(65.2% vs 18.2%, P = 0.0255) than patients with genetic confirmed HPF. Also, patients with UPF had a higher frequency of aphthous stomatitis(52.2% vs 10.7%, P < 0.0001), musculoskeletal pain(65.2% vs 8,0%, P < 0.0001), and abdominal pain(52.2% vs 4.8%, P < 0.0001) and a lower frequency of pharyngitis(56.6% vs 81.3%, P = 0.0127) compared with typical PFAPA in the same cohort. Twenty-one of 23 patients with UPF(91.3%) received steroids, being effective in 16; 13(56.2%) were given colchicine, which was effective in 6. Symptoms resolution occurred in 2 patients with UPF at last follow-up. Classification according to the PRINTOEurofever score did not correlate with treatment response and prognosis. CONCLUSION UPF is not a rare diagnosis among patients with periodic fever. Clinical presentation place UPF half way on a clinical spectrum between PFAPA and HPF. The PRINTOEurofever score is not useful to predict clinical outcome and treatment response in these patients. | Silvia De Pauli Sara Lega Serena Pastore Domenico Leonardo Grasso Anna Monica Rosaria Bianco Giovanni Maria Severini Alberto Tommasini Andrea Taddio | 2018 | World Journal of Clinical Pediatrics2018，7，1： | 2 |
| 5 | Heterozygous nucleotide-binding oligomerization domain-2 mutations affect monocyte maturation in Crohn's disease显示文摘瞄准:在 Crohn 的疾病(CD ) 调查单核白血球的函数病人并且相关这与联系疾病的核苷酸绑定 oligomerization domain-2 (NOD2 ) 基因变体。方法:从 47 个连续地提交的 CD 病人和 9 健康供血者的单核白血球与 interleukin (IL ) 是有教养的 -4 和 granulocyte 巨噬细胞刺激殖民地的因素(GM-CSF ) ,并且与脂肪的多糖(LPS ) 或 muramyldipeptide (MDP ) 刺激了, NOD2 的通常认为的 ligand。结果:我们发现从 CD 病人的单核白血球区分了在试管内到成熟树枝状的房间(DC ) ,由免疫显型和形态学决定了。NOD2 遗传型在所有题目被估计,并且我们观察到在 NOD2 的不成熟、刺激 LPS 的 DC 上的高 CD86 表示变异 CD 病人,作为与 wtNOD2 CD 病人和控制相比。由对比,导致到成熟, MDP 源于变异 NOD2 的题目的 DC 的 CD86 表示层次比得上正常题目的那些。在耐心房间的文化的 IL-12p70 的数量与 MDP 比在在 LPS 治疗,然而并非术后疗法以后的控制大。结论:我们的结果建议在 NOD2 基因与变化从病人获得的 DC 显示高 CD86 表示描绘的激活的显型,但是当与终端相比区别分阶段执行时,有减少的回答到 MDP。我们推测单核白血球的改变的区别可能导致在发炎和单核白血球的杀死的能力之间的不平衡,并且可能与 CD 的致病相关。 | Marilena Granzotto Elisa Fabbro Massimo Maschio Stefano Martelossi Sara Quaglia Alberto Tommasini Gianni Presani Alessandro Ventura | 2007 | World Journal of Gastroenterology2007，13，46： | 2 |
| 6 | Usefulness of Screening Program for Celiac Disease in Autoimmune Thyroiditis显示文摘 | Irene Berti Chiara Trevisiol Alberto Tommasini Angelo Città Elena Neri Onelio Geatti Alberto Giammarini Alessandro Ventura Tarcisio Not | 2000 | Digestive Diseases and Sciences2000，，2： | 1 |
| 7 | Usefulness of Screening Program for Celiac Disease in Autoimmune Thyroiditis显示文摘 | Irene Berti Chiara Trevisiol Alberto Tommasini Angelo Città Elena Neri Onelio Geatti Alberto Giammarini Alessandro Ventura Tarcisio Not | 2000 | Digestive Diseases and Sciences2000，，2： | 1 |
| 8 | Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease显示文摘 | Alessio Fasano Tarcisio Not Wenle Wang Sergio Uzzau Irene Berti Alberto Tommasini Simeon E Goldblum | 2000 | The Lancet2000，，9214： | 1 |
| 9 | Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease显示文摘 | Alessio Fasano Tarcisio Not Wenle Wang Sergio Uzzau Irene Berti Alberto Tommasini Simeon E Goldblum | 2000 | The Lancet2000，，9214： | 1 |
| 10 | The immunosuppressive effect of Wharton’s jelly stromal cells depends on the timing of their licensing and on lymphocyte activation显示文摘 | Erica Valencic Elisa Piscianz Marino Andolina Alessandro Ventura Alberto Tommasini | 2010 | Cytotherapy2010，，2： | 1 |
| 11 | Fever tree revisited:From malaria to autoinflammatory diseases显示文摘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. | Serena Pastore Josef Vuch Anna Monica Bianco Andrea Taddio Alberto Tommasini | 2015 | World Journal of Clinical Pediatrics2015，4，4： | 1 |
| 12 | Severe inflammatory bowel disease associated with congenital alteration of transforming growth factor beta signaling显示文摘 | Samuele Naviglio Serena Arrigo Stefano Martelossi Vincenzo Villanacci Alberto Tommasini Claudia Loganes Antonella Fabretto Silvia Vignola Silvia Lonardi Alessandro Ventura | 2014 | Journal of Crohn’s and Colitis2014，，： | 1 |
| 13 | Druggable monogenic immune defects hidden in diverse medical specialties:Focus on overlap syndromes显示文摘In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies:An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections.Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors,providing innovative precision treatments that can change the natural history of diseases.In this article we review some of these“druggable”inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties.Since the availability of precision treatments can dramatically impact the course of these diseases,preventing the development of organ damage,it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure. | Valentina Boz Chiara Zanchi Laura Levantino Guglielmo Riccio Alberto Tommasini | 2022 | World Journal of Clinical Pediatrics2022，11，2： | 0 |
| 14 | Ages of celiac disease: From changing environment to improved diagnostics显示文摘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. | Alberto Tommasini Tarcisio Not Alessandro Ventura | 2011 | World Journal of Gastroenterology2011，17，32： | 0 |
| 15 | Innovation for rare diseases and bioethical concerns: A thin thread between medical progress and suffering显示文摘@Alberto Tommasini@Andrea Magnolato@Irene | Alberto Tommasini ANDrea Magnolato Irene Bruno | 2018 | World Journal of Clinical Pediatrics2018，7，3： | 0 |
| 16 | Altered pattern of tumor necrosis factor-alpha production in peripheral blood monocytes from Crohn's disease显示文摘AIM To evaluate the inflammatory state in Crohn's disease(CD) patients and correlate it with genetic background and microbial spreading.METHODS By means of flow cytometry, production of tumor necrosis factor-alpha(TNF-α) was measured in peripheral blood monocytes from patients suffering from CD, ulcerative colitis(UC) and in healthy subjects after stimulation of the NOD2 and TLR pathways. CD patients were genotyped for the three most common NOD2 variants(R702W, G908 R and L1007Pfs*2) and basal production of TNF-α was correlated to NOD2 genotype. Also, production of TNF-α was correlated to plasmatic levels of LPS Binding Protein(LBP), soluble(s) CD14 and to the activity state of the disease.RESULTS The patients with CD were characterized by a significantly higher monocyte basal expression of TNF-αcompared with healthy subjects and UC patients, and after stimulation with Pam3CSK4(ligand of TLR2/1) and MDP-L18(ligand of NOD2) this difference was maintained, while other microbial stimuli(LPS, ligand of TLR4 and Poly I:C, ligand of TLR3) induced massive activation in CD monocytes as well as in UC and in healthy control cells. There was no significant difference in the production of TNF- α between patients who carried CD-associated heterozygous or homozygous variants in NOD2 and patients with wild type NOD2 genotype. Although serum LBP levels have been shown to correlate positively with the state of activity of the disease, TNF-α production did not show a clear correlation with either LBP or s CD14 levels in plasma. Moreover, no clear correlation was seen between TNF-α production and activity indices in either CD or UC.CONCLUSION Peripheral monocytes from CD express higher basal and stimulated TNF-α than controls, regardless of NOD2 genotype and without a clear correlation with disease activity. | Claudia Loganes Alessia Pin Samuele Naviglio Martina Girardelli Anna Monica Bianco Stefano Martelossi Alberto Tommasini Elisa Piscianz | 2016 | World Journal of Gastroenterology2016，22，41： | 0 |
| 17 | Hydroxychloroquine modulates immunological pathways activated by RNA:DNA hybrids in Aicardi–Goutières syndrome patients carrying RNASEH2 mutations显示文摘Aicardi–Goutières syndrome(AGS)is a rare genetic disease caused by mutations in nine genes that are all involved in nucleic acid metabolism or sensing.1,2 The three RNASEH2 subunits represent the most frequently mutated genes in AGS patients,1,3 and mutations in RNASEH2 subunits lead to the accumulation of endogenous RNA:DNA hybrids that may trigger an interferon-α-mediated immune response4 through the activation of pattern recognition receptors(PRRs).5 PRRs perform surveillance on extracellular,endosomal,and cytosolic compartments to identify signs of infection:endogenous nucleic acids that are inappropriately cleared may enter and accumulate in the cytoplasm,driving inflammation and autoimmune diseases.6 This accumulation may be the cause of the clinical autoimmune phenotype of AGS patients carrying RNASEH2 mutations.A proven effective cure for AGS has not been discovered,and targeting these two pathways may lead to a treatment that improves patients’immunological symptoms.Hydroxychloroquine(HCQ)interferes with normal antigen processing and presentation and is widely used in the clinical treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.7 HCQ is also a well-known inhibitor of autophagy that prevents the degradation of autolysosomes.This drug inhibits acidification and maturation of endosomes and increases the pH in lysosomes,resulting in the inhibition of their main functions,such as downstream cell signaling through TLRs.7 Therefore,the aim of our work was to investigate whether HCQ is able to modulate the abnormal inflammatory response driven by RNA:DNA hybrids. | Jessica Garau Daisy Sproviero Francesca Dragoni Elisa Piscianz Carolina Santonicola Davide Tonduti Stephana Carelli Alessandra Tesser Gian Vincenzo Zuccotti Alberto Tommasini Simona Orcesi Orietta Pansarasa Cristina Cereda | 2021 | Cellular & Molecular Immunology2021，18，6： | 0 |
| 18 | Ex vivo response to mucosal bacteria and muramyl dipeptide in inflammatory bowel disease显示文摘AIM To evaluate how mucosal bacteria impact on the spontaneous and muramyl dipeptide(MDP)-induced inflammation in Crohn's disease(CD) and ulcerative colitis(UC).METHODS Colonic mucosal biopsies were collected from children with active or remissive CD, UC and controls. Two tissue samples were taken from inflamed mucosal segments(in patients with active disease) or from noninflamed mucosa [in patients in remission or in healthy controls(HC)]. Experiments were performed in the presence or absence of antibiotics, to assess whether the disease-associated microbiota can modulate the cytokine response ex vivo. For this purpose, each specimen was half-cut to compare spontaneous and MDP-induced inflammation in the presence of live bacteria(LB) or antibiotics. After 24 h of culture, an array of 17 cytokines was assessed in supernatants. Statistical analyses were performed to find significant differences in single cytokines or in patterns of cytokine response in the different groups. RESULTS We demonstrated that subjects with CD display a spontaneous production of inflammatory cytokines including granulocyte-colony stimulating factor(G-CSF), interleukin(IL) 6, IL8, IL10 and IL12, that was not significantly influenced by the addition of antibiotics. UC specimens also displayed a trend of increased spontaneous secretion of several cytokines, which however was not significant due to broader variability among patients. After the addition of antibiotics, spontaneous IL8 secretion was significantly higher in UC than in controls. In HC, a trend towards the weakening of spontaneous IL8 production was observed in the presence of live mucosal bacteria with respect to the presence of antibiotics. In contrast, in the presence of LB UC showed an increasing trend of spontaneous IL8 production, while MDP stimulation resulted in lower IL8 production in the presence of antibiotics. We also showed that subjects with CD seem to have a lowered production of IL8 in response to MDP in the presence of LB. Only with the addition of antibiotics, likely reducing the contribution of LB, multivariate statistical analysis could identify the combination of measures of G-CSF, tumor necrosis factor alpha, IL4 and IL17 as a good discriminator between CD and UC.CONCLUSION We showed that the presence of LB or antibiotics can significantly influence the inflammatory response ex vivo in inflammatory bowel diseases. | Claudia Loganes Erica Valencic Alessia Pin Elisa Marini Stefano Martelossi Samuele Naviglio Luigina De Leo Tarcisio Not Lorenzo Monasta Alberto Tommasini Annalisa Marcuzzi | 2016 | World Journal of Gastroenterology2016，22，44： | 0 |
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