Entity

Time filter

Source Type


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. Source


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. Source


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. Source


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. Source


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. Source

Discover hidden collaborations