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Carbone M.,Addenbrookes Hospital | Carbone M.,University of Cambridge | Lleo A.,Liver Unit and Center for Autoimmune Liver Diseases | Sandford R.N.,University of Cambridge | And 2 more authors.
European Journal of Immunology | Year: 2014

Genome-wide association studies (GWAS) have revolutionized the search for genetic influences on complex disorders, such as primary biliary cirrhosis (PBC). Recent GWAS have identified many disease-associated genetic variants. These, overall, highlighted the remarkable contribution of key immunological pathways in PBC that may be involved in the initial mechanisms of loss of tolerance and the subsequent inflammatory response and chronic bile duct damage. Results from GWAS have the potential to be translated in biological knowledge and, hopefully, clinical application. There are a number of immune pathways highlighted in GWAS that may have therapeutic implications in PBC and in other autoimmune diseases, such as the anti-interleukin-12/interleukin-23, nuclear factor-kb, tumor necrosis factor, phosphatidylinositol signaling and hedgehog signaling pathways. Further areas in which GWAS findings are leading to clinical applications either in PBC or in other autoimmune conditions, include disease classification, risk prediction and drug development. In this review we outline the possible next steps that may help accelerate progress from genetic studies to the biological knowledge that would guide the development of predictive, preventive, or therapeutic measures in PBC. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Podda M.,Liver Unit and Center for Autoimmune Liver Diseases | Selmi C.,Humanitas Clinical and Research Center | Selmi C.,University of California at Davis | Lleo A.,Liver Unit and Center for Autoimmune Liver Diseases | And 3 more authors.
Journal of Autoimmunity | Year: 2013

Epidemiology is expected to provide important clues to our understanding of the enigmatic etiopathogenesis of primary biliary cirrhosis (PBC). First, a systematic review of population based studies indicated a wide range in the yearly incidence (0.33-5.8/100.000) and point prevalence (1.91-40.2/100.000) rates. Though different ethnic representations may also contribute it is likely that methodological issues, based on the retrospective survey of diagnosed cases, and time trend play a major role, also in view of the prolonged asymptomatic period of the disease. Of note, the highest prevalence rates (35-40/100.000) were found in areas characterized by high medical awareness and easier access to healthcare. Second, the search for serum AMA in unselected population sera may identify the largest possible number of patients who have or will develop the disease. Indeed, a surprisingly high AMA prevalence rate, ranging between 0.43 and 1%, appears likely in the general population despite the lack of adequate work-up in most studies. Third, the median female to male ratio for PBC is classically accepted as 9-10:1 but is significantly lower for AMA prevalence (2.5:1), death certificates for PBC (4.3:1) and liver transplantation (6:1), thus suggesting that PBC in men may be underdiagnosed in early stages or manifest a more severe progression. Lastly, studies of both PBC and serum AMA prevalence among family members and monozygotic twins strongly support the role played by genetic factors in the etiopathogenesis of the disease. In conclusion, PBC epidemiology is far from being a closed case and the numerous open issues will be solved through a collaborative effort and powerful data mining tools. © 2013 Elsevier Ltd.


Bianchi I.,Liver Unit and Center for Autoimmune Liver Diseases | Carbone M.,Addenbrookes Hospital | Carbone M.,University of Cambridge | Lleo A.,Liver Unit and Center for Autoimmune Liver Diseases | And 2 more authors.
Seminars in Liver Disease | Year: 2014

Primary biliary cirrhosis (PBC) has been considered a multifactorial autoimmune disease presumably arising from a combination of environmental and genetic factors, with genetic inheritance mostly suggested by familial occurrence and high concordance rate among monozygotic twins. In the last decade, genome-wide association studies, new data on sex chromosome defects and instabilities, and initial evidence on the role of epigenetic abnormalities have strengthened the crucial importance of genetic and epigenetic factors in determining the susceptibility of PBC. High-throughput genetic studies in particular have revolutionized the search for genetic influences on PBC and have the potential to be translated into clinical and therapeutic applications, although more biological knowledge on candidate genes is now needed. In this review, these recent discoveries will be critically summarized with particular focus on the possible steps that may transfer genetic and epigenetic knowledge to direct health benefits in patients with PBC. Copyright © 2014 by Thieme Medical Publishers, Inc.


Lleo A.,Liver Unit and Center for Autoimmune Liver Diseases | Zhang W.,University of California at Davis | Mcdonald W.H.,Vanderbilt University | Seeley E.H.,Vanderbilt University | And 8 more authors.
Hepatology | Year: 2014

Shotgun proteomics is a powerful analytic method to characterize complex protein mixtures in combination with multidimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used this platform for proteomic characterization of apoptotic bodies in an effort to define the complex protein mixtures found in primary cultures of human intrahepatic biliary epithelial cells (HiBEC), human renal proximal tubular epithelial cells, human bronchial epithelial cells, isolated intrahepatic biliary epithelial cells from explanted primary biliary cirrhosis (PBC), and control liver using a total of 24 individual samples. Further, as additional controls and for purposes of comparison, proteomic signatures were also obtained from intact cells and apoptotic bodies. The data obtained from LC-MS/MS, combined with database searches and protein assembly algorithms, allowed us to address significant differences in protein spectral counts and identify unique pathways that may be a component of the induction of the signature inflammatory cytokine response against BECs, including the Notch signaling pathway, interleukin (IL)8, IL6, CXCR2, and integrin signaling. Indeed, there are 11 proteins that localize specifically to apoptotic bodies of HiBEC and eight proteins that were specifically absent in HiBEC apoptotic bodies. Conclusion: Proteomic analysis of BECs from PBC liver compared to normal liver are significantly different, suggesting that an immunological attack affects the repertoire of proteins expressed and that such cells should be thought of as living in an environment undergoing continuous selection secondary to an innate and adaptive immune response, reflecting an almost "Darwinian" bias. (Hepatology 2014;60:1314-1323). © 2014 by the American Association for the Study of Liver Diseases.


Invernizzi P.,Liver Unit and Center for Autoimmune Liver Diseases | Invernizzi P.,University of California at Davis
Journal of Autoimmunity | Year: 2013

The study of the liver as a lymphoid organ is a growing field fueled by our better knowledge of the different component of the immune system and how they orchestrate an immune-related response. The liver have highly specialized mechanisms of immune tolerance, mainly because is continuously exposed to microbial and environmental antigens, and dietary components from the gut. Accordingly, the liver contains specialized lymphoid subpopulations acting as antigen-presenting cells. Growing evidences show that the liver is also associated with obesity-associated diseases because of its immune-related capacity to sense metabolic stress induced by nutritional surplus. Finally, the liver produces a pletora of neo-antigens being the primary metabolic organ of the body. Common immune mechanisms play a key pathogenetic role in most of acute and chronic liver diseases and in the rejection of liver allografts. Any perturbations of liver-related immune functions have important clinical implications. This issue of the Journal of Autoimmunity is focused on the more recent advances in our knowledge related to the loss of liver tolerance, a paradox for a tolerogenic organ, that leads to overactivation of the innate and adaptive immune response and the development of autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. The invited expert review articles capture the underlying immunomolecular mechanisms of the development and progression of autoimmune liver diseases, the novel field of the immune-related "liver-gut" axis influences to the development of liver autoimmunity, the predominant role of genetic factors, and the increasingly effective immuno-therapeutic possibilities. © 2013 Elsevier Ltd.


Zhang H.,Liver Unit and Center for Autoimmune Liver Diseases | Zhang H.,Shanghai JiaoTong University | Bernuzzi F.,Liver Unit and Center for Autoimmune Liver Diseases | Lleo A.,Liver Unit and Center for Autoimmune Liver Diseases | And 2 more authors.
Mediators of Inflammation | Year: 2015

Emerging evidence reveals that various cytokines and tissue microenvironments contribute to liver inflammation and autoimmunity, and IL-17 family is one of highlights acknowledged. Although the implication of IL-17 family in most common autoimmune diseases (such as psoriasis, inflammatory bowel disease, and rheumatoid arthritis) has been extensively characterized, the role of this critical family in pathophysiology of autoimmune liver diseases (AILD) still needs to be clarified. In the review, we look into the intriguing biology of IL-17 family and further dissect on the intricate role of IL-17-mediated pathway in AILD. Considering encouraging data from preclinical and clinical trials, IL-17 targeted therapy has shown promises in several certain autoimmune conditions. However, blocking IL-17-mediated pathway is just beginning, and more fully investigation and reflection are required. Taking together, targeting IL-17-mediated responses may open up new areas of potential clinical treatment for AILD. © 2015 Haiyan Zhang et al.


Lleo A.,Liver Unit and Center for Autoimmune Liver Diseases | Maroni L.,Marche Polytechnic University | Glaser S.,Texas A&M University | Alpini G.,Texas A&M University | Marzioni M.,Marche Polytechnic University
Seminars in Liver Disease | Year: 2014

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by selective destruction of intrahepatic cholangiocytes. Mechanisms underlying the development and progression of the disease are still controversial and largely undefined. Evidence suggests that PBC results from an articulated immunologic response against an immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2); characteristics of the disease are also the presence of disease-specific antimitochondrial autoantibodies (AMAs) and autoreactive CD4 and CD8 T cells. Recent evidence suggests that cholangiocytes show specific immunobiological features that are responsible for the selective targeting of those cells by the immune system. The immune reaction in PBC selectively targets small sized, intrahepatic bile ducts; although a specific reason for that has not been defined yet, it has been established that the biliary epithelium displays a unique heterogeneity, for which the physiological and pathophysiological features of small and large cholangiocytes significantly differ. In this review article, the authors provide a critical overview of the current evidence on the role of cholangiocytes in the immune-mediated destruction of the biliary tree that characterizes PBC. Copyright © 2014 by Thieme Medical Publishers, Inc.


Raggi C.,Liver Unit and Center for Autoimmune Liver Diseases | Mousa H.S.,Liver Unit and Center for Autoimmune Liver Diseases | Correnti M.,Liver Unit and Center for Autoimmune Liver Diseases | Sica A.,Humanitas Clinical and Research Center | And 2 more authors.
Oncogene | Year: 2016

The idea that tumor initiation and progression are driven by a subset of cells endowed with stem-like properties was first described by Rudolf Virchow in 1855. 'Cancer stem cells', as they were termed more than a century later, represent a subset of tumor cells that are able to generate all tumorigenic and nontumorigenic cell types within the malignancy. Although their existence was hypothesized >150 years ago, it was only recently that stem-like cells started to be isolated from different neoplastic malignancies. Interestingly, Virchow, in suggesting a correlation between cancer and the inflammatory microenvironment, also paved the way for the 'Seed and Soil' theory proposed by Paget a few years later. Despite the time that has passed since these two important concepts were suggested, the relationships between Virchow's 'stem-like cells' and Paget's 'soil' are far from being fully understood. One emerging topic is the importance of a stem-like niche in modulating the biological properties of stem-like cancer cells and thus in affecting the response of the tumor to drugs. This review aims to summarize the recent molecular data concerning the multilayered relationship between cancer stem cells and tumor-associated macrophages that form a key component of the tumor microenvironment. We also discuss the therapeutic implications of targeting this synergistic interplay. © 2016 Macmillan Publishers Limited All rights reserved.


Sica A.,Humanitas Clinical and Research Center | Sica A.,University of Piemonte Orientale | Invernizzi P.,Liver Unit and Center for Autoimmune Liver Diseases | Mantovani A.,Humanitas Clinical and Research Center | Mantovani A.,University of Milan
Hepatology | Year: 2014

Resident and recruited macrophages are key players in the homeostatic function of the liver and in its response to tissue damage. In response to environmental signals, macrophages undergo polarized activation to M1 or M2 or M2-like activation states. These are extremes of a spectrum in a universe of activation states. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of mononuclear phagocytes. Resident and recruited macrophages are a key component of diverse homeostatic and pathological responses of hepatic tissue. Polarized macrophages interact with hepatic progenitor cells, integrate metabolic adaptation, mediate responses to infectious agents, orchestrate fibrosis in a yin-yang interaction with hepatic stellate cells, and are a key component of tumor-promoting inflammation. Conclusion: A better understanding of macrophage diversity and plasticity in liver homeostasis and pathology may pave the way to innovative diagnostic and therapeutic approaches. © 2014 by the American Association for the Study of Liver Diseases.


Raggi C.,Liver Unit and Center for Autoimmune Liver Diseases | Invernizzi P.,Liver Unit and Center for Autoimmune Liver Diseases | Andersen J.B.,Copenhagen University
Journal of Hepatology | Year: 2015

Summary Clinical complexity, anatomic diversity and molecular heterogeneity of cholangiocarcinoma (CCA) represent a major challenge in the assessment of effective targeted therapies. Molecular and cellular mechanisms underlying the diversity of CCA growth patterns remain a key issue of clinical concern. Crucial questions comprise the nature of the CCA-origin, the initial target for cellular transformation as well as the relationship with the cancer stem cells (CSC) concept. Additionally, since CCA often develops in the context of an inflammatory milieu (cirrhosis and cholangitis), the stromal compartment or tumour microenvironment (TME) likely promotes initiation and progression of this malignancy, contributing to its heterogeneity. This review will emphasize the dynamic interplay between stem-like intrinsic and TME-extrinsic pathways, which may represent novel options for multi-targeted therapies in CCA.

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