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The epigenetics of autoimmunity

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Cellular & Molecular Immunology 2011年第3期8卷 226-236页

作者： Francesca Meda Marco Folci Andrea Baccarelli carlo selmi Department of Medicine and Hepatobiliary Immunopathology Unit IRCCS Istituto Clinico HumanitasRozzanoMilanItaly Department of Translational Medicine University of MilanRozzanoMilanItaly Harvard School of Public Health ExposureEpidemiology&Risk ProgramBostonMAUSA

The etiology of autoimmune diseases remains largely *** rates in monozygotic twins are lower than 50% while genome-wide association studies propose numerous significant associations representing only a minority of *** lines of evidence strongly support other complementary mechanisms involved in the regulation of genes expression ultimately causing overt *** in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune *** recent years,several studies both in clinical settings and experimental models proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and *** specifically,data support the impact of epigenetic changes in systemic lupus erythematosus,rheumatoid arthritis,multiple sclerosis and other autoimmune diseases,in some cases based on mechanistical *** herein discuss what we currently know and what we expect will come in the next ***,epigenetic treatments already being used in oncology may soon prove beneficial also in autoimmune diseases.

关键词： DNA methylation histone modification microRNA tolerance breakdown

The microbiome and autoimmunity: a paradigm from the gut–liver axis

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Cellular & Molecular Immunology 2018年第6期15卷 595-609页

作者： Bo Li carlo selmi Ruqi Tang ME Gershwin Xiong Ma Division of Gastroenterology and Hepatology Key Laboratory of Gastroenterology and HepatologyMinistry of HealthState Key Laboratory for Oncogenes and Related GenesRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Institute of Digestive DiseaseShanghai 200001China Division of Rheumatology and Clinical Immunology Humanitas Research HospitalRozzanoItaly BIOMETRA Department University of Milan MilanItaly Division of Rheumatology Department of MedicineAllergy and Clinical ImmunologyUniversity of California at DavisDavisCAUSA

Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experimental data in germ-free and gnotobiotic *** understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown,as observed in rheumatic fever triggered by Streptococci via molecular mimicry,epitope spread and bystander *** availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases,including rheumatoid arthritis,type 1 diabetes,multiple sclerosis and autoimmune liver *** remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere *** fact,there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity,and microbial therapeutics is being investigated to prevent or halt autoimmune *** a putative mechanism,it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens,giving rise to the differentiation of autoreactive Th17 cells and other T helper *** comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity,with an emphasis on how dysbiosis may influence systemic *** particular,a gut–liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm,considering its anatomic and physiological connections.

关键词： autoimmunity autoimmune liver disease dysbiosis microbiome

The long and latent road to autoimmunity

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Cellular & Molecular Immunology 2018年第6期15卷 543-546页

作者： carlo selmi Bin Gao M.Eric Gershwin Division of Rheumatology and Clinical Immunology Humanitas Research HospitalRozzanoMilanItaly Department BIOMETRA University of MilanMilanItaly Laboratory of Liver Diseases National Institute for Alcohol Abuse and AlcoholismNational Institutes of HealthBethesdaMDUSA Division of Rheumatology Allergyand Clinical ImmunologyUniversity of CaliforniaDavisCAUSA

Autoimmune diseases affect nearly 5%of the general population,yet etiology remains poorly *** factors are clearly necessary but remain insufficient to explain the loss of tolerance;environmental and stochastic factors fill this *** paradigm is indicated by the concordance rates(ranging between 4 and 63%)for autoimmune diseases among monozygotic twins,who share an identical genome,compared to the invariably lower rates in dizygotic *** term“exposome”cumulatively refers to the non-hereditary(i.e.,environmental)factors that account for the remaining susceptibility and include endogenous factors such as *** evidence suggests that exposure to infections,drugs,vaccines,and chemicals may contribute to the loss of *** mechanisms by which environmental factors can shape the immune system to generate autoimmunity include molecular mimicry,self-antigen modification,bystander activation,and immune reactivity *** all cases,we should first consider the prolonged time between an environmental trigger and the appearance of autoreactivity and subsequent clinical *** this special issue,several excellent reviews discuss the potential mechanisms linking environmental factors and autoimmunity.

关键词： endogenous latent reactivity

Clinical features and management of primary biliary cirrhosis

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World Journal of Gastroenterology 2008年第21期14卷 3313-3327页

作者： Andrea Crosignani Pier Maria Battezzati Pietro Invernizzi carlo selmi Elena Prina Mauro Podda Division of Internal Medicine and Liver Unit San Paolo Hospital School of MedicineUniversity of MilanMilano 20142Italy Division of Internal Medicine and Liver Unit San Paolo Hospital School of MedicineUniversity of MilanMilano 20142Italy Division of RheumatologyAllergyand Clinical ImmunologyUniversity of California at DavisDavisCA 95616United States

Primary biliary cirrhosis(PBC),which is characterised by progressive destruction of intrahepatic bile ducts,is not a rare disease since both prevalence and incidence are increasing during the last years mainly due to the improvement of case finding *** prognosis of the disease has improved due to both the recognition of earlier and indolent cases,and to the wide use of ursodeoxycholic acid(UDCA).New indicators of prog-nosis are available that will be useful especially for the growing number of patients with less severe *** patients are asymptomatic at ***-tus may represent the most distressing symptom and,when UDCA is ineffective,cholestyramine represents the mainstay of *** of long-standing cholestasis may be clinically relevant only in very ad-vanced *** data on the effects of UDCA on clinically relevant end points clearly indicate that the drug is able to slow but not to halt the progression of the disease while,in advanced stages,the only thera-peutic option remains liver transplantation.

关键词： Primary biliary cirrhosis Epidemiology Clinical course Natural history Treatment

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

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Cellular & Molecular Immunology 2010年第1期7卷 1-10页

作者： carlo selmi Francesca Meda Anaid Kasangian Pietro Invernizzi Zhigang Tian Zhexiong Lian Mauro Podda M Eric Gershwin Department of Translational Medicine Universitàdegli Studi di MilanoMilanItaly Department of Medicine IRCCS Istituto Clinico Humanitas RozzanoMilanItaly Divisionof Rheumatology Allergyand Clinical ImmunologyUniversity of California at DavisDavisCAUSA Institute of Immunology University of Science and Technology of ChinaHefeiChina

Primary biliary cirrhosis(PBC)is a chronic cholestatic liver disease for which an autoimmune pathogenesis is supported by clinical and experimental data,including the presence of autoantibodies and autoreactive T *** etiology remains to be determined,yet data suggest that both a susceptible genetic background and unknown environmental factors determine disease *** infectious and chemical candidates have been proposed to trigger the disease in a genetically susceptible host,mostly by molecular *** recently,several murine models have been reported,including genetically determined models as well as models induced by immunization with xenobiotics and bacteria.

关键词： pathogenesis cirrhosis biliary

The effects of Spirulina on anemia and immune function in senior citizens

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Cellular & Molecular Immunology 2011年第3期8卷 248-254页

作者： carlo selmi Patrick SC Leung Laura Fischer Bruce German Chen-Yen Yang Thomas P Kenny Gerry R Cysewski M Eric Gershwin Division of Rheumatology Allergy and Clinical ImmunologyUniversity of California at DavisDavisCAUSA Department of Medicine IRCCS Istituto Clinico HumanitasRozzanoMilanItaly Department of Food Science and Technology University of California at DavisDavisCAUSA Cyanotech Kailua-KonaHIUSA

Anemia and immunological dysfunction(***)are commonly found in older subjects and nutritional approaches are sought to counteract these *** is a filamentous and multicellular bule-green alga capable of reducing inflammation and also manifesting antioxidant *** hypothesized that Spirulina may ameliorate anemia and immunosenescence in senior citizens with a history of *** enrolled 40 volunteers of both sexes with an age of 50 years or older who had no history of major chronic *** took a Spirulina supplementation for 12 weeks and were administered comprehensive dietary questionnaires to determine their nutritional regimen during the *** cell count(CCC)and indoleamine 2,3-dioxygenase(IDO)enzyme activity,as a sign of immune function,were determined at baseline and weeks 6 and 12 of *** study participants completed the entire study and the data obtained were *** the 12-week study period,there was a steady increase in average values of mean corpuscular hemoglobin in subjects of both *** addition,mean corpuscular volume and mean corpuscular hemoglobin concentration also increased in male *** women appeared to benefit more rapidly from Spirulina ***,the majority of subjects manifested increased IDO activity and white blood cell count at 6 and 12 weeks of Spirulina *** may ameliorate anemia and immunosenescence in older *** encourage large human studies to determine whether this safe supplement could prove beneficial in randomized clinical trials.

关键词： functional food immunosenescence red blood cell IDO

Handbook of Nutrition and Immunity 1

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FoxO1 suppresses IL-10 producing B cell differentiation via negatively regulating Blimp-1 expression and aggravates allergic asthma

2004年

作者： carlo selmi Pietro Invernizzi Massimo Zuin (auth.) M. Eric Gershwin MD Penelope Nestel PhD Carl L. Keen PhD (eds.)

ISBN: (纸本)9781468498646;9781592597901

An international panel of physicians, pediatricians, immunologists, and public health nutritionists concisely review for front-line health care providers and researchers the practical aspects related to evaluating nutrition and immunology in the field. Here, the busy physician and investigator will quickly find a clear and up-to-date understanding of the essential immunological facts in adult and child nutrition. Citing the latest research findings, the authors explain the role of nutrition in the case of current health issues, such as HIV, malaria, food allergies, diarrhea, acute respiratory infections, and the impact of macro- and micronutrient deficiencies, dietary fat, and antioxidants on immune status. A compact disk accompanies the book for downloading an ebook version to the reader's PC or PDA. Comprehensive and holistic, the Handbook of Nutrition and Immunity illuminates for busy health care providers and scientists the interaction and linkages between nutrition and immunology and provides an up-to-date understanding of the practical problems associated with evaluating nutritional and immune status in the field

关键词： ImmunityNutritional aspectsHandbooks manuals etc.

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FoxO1 suppresses IL-10 producing B cell differentiation via ...

Immune-mediated bile duct injury:The case of primary biliary cirrhosis

第十四届全国免疫学学术大会

作者： Songrong Wang Rendong Hu Min Ma Xing You Haiyan Cui Yi He Damo Xu Zhibin Zhao selmi carlo Gershwin M.Eric Liang Li Zhexiong Lian Chronic Disease Laboratory School of Medicine South China University of Technology School of Biomedical Sciences and Engineering South China University of Technology Guangzhou International Campus Department of Respiratory and Critical Care Medicine The Third Affiliated Hospital of Southern Medical University Department of Rheumatology and Immunology The Third Affiliated Hospital Southern Medical University State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University Shenzhen Key Laboratory of Allergy & Immunology Shenzhen University School of Medicine Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Rheumatology and Clinical Immunology Humanitas Clinical and Research Center-IRCCS Division of Rheumatology Allergy and Clinical Immunology University of California at Davis School of Medicine National Engineering Research Center for Tissue Restoration and Reconstruction South China University of Technology Key Laboratory of Biomedical Engineering of Guangdong Province South China University of Technology Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education South China University of Technology Innovation Center for Tissue Restoration and Reconstruction South China University of Technology

IL-10-producing B cells(B10) are involved in the prevention of autoimmunity and allergy but mechanisms remain poorly understood. We took advantage of the ovalbumin-induced asthma mouse model to demonstrate that the activity of FoxO1 is upregulated in lung B cells and correlates inversely with B10 cells while showing a decreased activity in ex vivoandin vitroinduced B10 cells. We further observed that FoxO1 deficiency leads to increased B10 cells. These observations have in vivoclinical evidence, as the B cell specific FoxO1 deficiency leads to reduced lung eosinophils and asthma remission in the mouse and there are reduced regulatory B cells and increased FoxO1 activity in B cells of patients with asthma. Single cell RNA-sequencing data demonstrated a negative correlation between the expression of Foxo1and Il-10in B cells from the mouse spleen and lung and the human lung. For biology mechanism, FoxO1 inhibits B10 cell differentiation through inhibiting the expression of Prdm1, which encodes Blimp-1, a transcription factor of B10 cells. Our experimental evidence in both murine and human asthma demonstrates that FoxO1 is a negative regulator of B10 cell differentiation via negatively regulating prdm1 and its expression in B cells contributes to promote allergic disease.

关键词： FoxO1 B10 Prdm1 Asthma IL-10

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World Journal of Gastrointestinal Pathophysiology 2010年第4期1卷 118-128页

作者： carlo selmi Andrea Affronti Laura Ferrari Pietro Invernizzi Division of Internal Medicine and Hepatobiliary Immunopathology Unit IRCCS Istituto Clinico Humanitas Laura Ferrari Department of Translational MedicineUniversitàdegli Studi di Milano Department of Translational Medicine Universitàdegli Studi di Milano

Autoimmune cholangitis would be the appropriate name to define the immune-mediated bile duct injury following the breakdown of tolerance to mitochondrial proteins and the appearance of serum autoantibodies and autoreactive T ***,the conditionis universally named primary biliary cirrhosis(PBC).The disease etiology and pathogenesis remain largely unknown despite the proposed lines of *** twin study and numerous epidemiology reportssuggest that both a susceptible genetic background and environmental factors determine disease onsetwhile a recent genome-wide association study proposed highly significant associations with several commongenetic polymorphisms in subgroups of *** infectious agents and chemicals may contribute to the disease onset and perpetuation in a geneticallysusceptible host,possibly through molecular ***,several murine models have been proposed and include strains in which PBC is genetically determined or induced by immunization with chemicals and *** a pathogenetic standpoint,new exciting data have demonstrated the unique apoptotic features of bile duct cells that allow the mitochondrial autoantigens to be taken up in their intact form within apoptotic *** are convinced that the application of the most recent molecular techniques will soon pro-vide developments in PBC etiology and pathogenesis with likely implications in diagnostics and therapeutics.

关键词： Autoimmune cholangitis Anti-mitochondrial antibody Epithelial cell apoptosis Innate immunity