Papers by Pietro Invernizzi
Clinical Reviews in Allergy & Immunology, 2012
Serum anti-mitochondrial antibodies (AMA) are the serological hallmark of primary biliary cirrhos... more Serum anti-mitochondrial antibodies (AMA) are the serological hallmark of primary biliary cirrhosis (PBC), yet up to 15% of PBC sera are AMA negative at routine indirect immunofluorescence (IIF) while being referred to as "probable" cases. The diagnostic role of PBC-specific antinuclear antibodies (ANA) remains to be determined. We will report herein data on the accuracy of new laboratory tools for AMA and PBC-specific ANA in a large series of PBC sera that were AMA-negative at IIF. We will also provide a discussion of the history and current status of AMA detection methods. We included IIF AMA-negative PBC sera (n=100) and sera from patients with other chronic liver diseases (n=104) that had been independently tested for IIF AMA and ANA; sera were blindly tested with an ELISA PBC screening test including two ANA (gp210, sp100) and a triple (pMIT3) AMA recombinant antigens. Among IIF AMA-negative sera, 43/100 (43%) manifested reactivity using the PBC screening test. The same test was positive for 6/104 (5.8%) control sera. IIF AMA-negative/PBC screen-positive sera reacted against pMIT3 (11/43), gp210 (8/43), Sp100 (17/43), both pMIT3 and gp210 (1/43), or both pMIT3 and Sp100 (6/43). Concordance rates between the ANA pattern on HEp-2 cells and specific Sp100 and gp210 ELISA results in AMA-negative subjects were 92% for nuclear dots and Sp100 and 99% for nuclear rim and gp210. Our data confirm the hypothesis that a substantial part of IIF AMA-negative (formerly coined "probable") PBC cases manifest disease-specific autoantibodies when tested using newly available tools and thus overcome the previously suggested diagnostic classification. As suggested by the recent literature, we are convinced that the proportion of AMA-negative PBC cases will be significantly minimized by the use of new laboratory methods and recombinant antigens.
Digestive and Liver …, Jan 1, 2008
Abstract Abstract Abstract Abstract AIM: Thiazolidinediones (TZD) are a new,class of oral antidia... more Abstract Abstract Abstract Abstract AIM: Thiazolidinediones (TZD) are a new,class of oral antidiabetic drugs that have been shown,to inhibit growth of same epithelial cancer cells. Although TZD were found tobe,ligands ,for peroxisome ,proliferator-activated receptor γ(PPAR γ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism,by which TZD inhibit growth
European Journal of Heart Failure Supplements, 2006
... Department, "Ospedali Riuniti" di Trieste, Trieste, Italy; 4Cardiology Department, ... more ... Department, "Ospedali Riuniti" di Trieste, Trieste, Italy; 4Cardiology Department, Maggiore Hospital, Bologna, Italy; 5Cardiology Department, Policlinico San Matteo, Pavia, Italy ... G. Biondi-ZoccaJ 1 , G. Comerci 1 , M. Savino 1 , A. NataJe 2, F. Loperfido 1 , R Santarelli 1 1Catholic ...
Handbook of Nutrition and Immunity, 2004
Gut, Jan 7, 2015
Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (... more Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk factors for HCC development in patients with PBC. Risk factor analysis was performed in over 15 centres from North America and Europe spanning >40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates. Of 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p<0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p<0.0001), elevated serum aspartate transaminase (HR 1.24, p<0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p<0.0001), and hepatic decompensation (HR 9.89, p<0.0001). As such, non-treatment with ursodeoxyc...
Immunobiology, 2015
Regulatory T cells (Treg) influence the development of autoimmunity and their use is increasingly... more Regulatory T cells (Treg) influence the development of autoimmunity and their use is increasingly proposed for clinical applications. The well-characterized suppressive potential of Treg frequently leads to the assumption that Treg presence in prevailing numbers is indicative of immunosuppression. We hypothesized that this assumption may be false. We examined models of three different diseases caused by organ-specific autoimmune responses: primary biliary cirrhosis, atherosclerosis and rheumatoid arthritis (RA). We examined indicators of relative abundance of Treg compared to pro-inflammatory T cells, during peak inflammation. In all cases, the results were compatible with a relative enrichment of Treg at the site of inflammation or its most proximal draining lymph node. Conversely, in healthy mice or mice successfully protected from disease via a Treg-mediated mechanism, the data did not suggest that any Treg accumulation was occurring. This counter-intuitive finding may appear to be at odds with the immunosuppressive nature of Treg. Yet extensive previous studies in RA show that an accumulation of Treg occurs at peak inflammation, albeit without resulting in suppression, as the Treg suppressive function is overcome by the cytokine-rich environment. We suggest that this is a ubiquitous feature of autoimmune inflammation. Treg abundance in patient samples is increasingly used as an indicator of a state of immunosuppression. We conclude that this strategy should be revisited as it may potentially be a source of misinterpretation.
Journal of Hepatology, 2015
Clinical complexity, anatomic diversity and molecular heterogeneity of cholangiocarcinoma (CCA) r... more 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.
Molecular Mechanisms in Health and Disease, 2005
Digestive and Liver Disease, 2015
The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis is an e... more The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis is an extremely rare condition that has been reported in only six published cases so far. Here we report two cases showing the clinical manifestations of both primary biliary cirrhosis and primary sclerosing cholangitis. In one case the overlap condition was associated with psoriatric arthritis, and the patient successfully underwent dual treatment with ursodeoxycholic acid and the anti-tumour necrosis factor-alpha agent adalimumab. In the second case, the predominant condition was, initially, an antimitochondrial antibody-negative primary biliary cirrhosis with progressive course towards end-stage liver disease; the patient then developed either antimitochondrial antibody positivity or changes in the biliary tree compatible with primary sclerosing cholangitis. These two cases add information on a controversial issue in the literature, and indicate the importance of recognizing a possible overlap syndrome to optimize treatment.
Journal of Autoimmunity, 2005
The serum hallmark of primary biliary cirrhosis (PBC) is the presence of anti-mitochondrial antib... more The serum hallmark of primary biliary cirrhosis (PBC) is the presence of anti-mitochondrial antibodies (AMA), found in 95% of patients. However, nearly every patient with PBC, including those who are AMA-negative, has an elevation in serum IgM. This hyper-IgM is neither representative of other Ig isoforms, nor is due to the levels of AMA. In fact, we have recently reported
Seminars in Liver Disease, 2014
Primary biliary cirrhosis (PBC) has been considered a multifactorial autoimmune disease presumabl... more 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.
Liver Immunology, 2007
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology charac... more Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology characterized by hightiter serum antimitochondrial autoantibodies (AMAs) and an autoimmune-mediated destruction of the small and mediumsized intrahepatic bile ducts. ...
Gastroenterology, 2014
Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis... more Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points. We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death). Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;2.0 times the ULN (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .0001). Absolute levels of alkaline phosphatase 1 year after study enrollment predicted patient outcomes better than percentage change in level. One year after study enrollment, a bilirubin level 1.0 times the ULN best predicted patient transplant-free survival (C statistic, 0.79). Of patients with bilirubin levels ≤ 1.0 times the ULN, 86% survived for 10 years after study enrollment compared with 41% of those with levels…
Journal of autoimmunity, 2014
The immunobiology of FXR has attracted significant attention in immune regulation and innate immu... more The immunobiology of FXR has attracted significant attention in immune regulation and innate immunity. We have studied the mechanism of action of FXR activation on two models of acute hepatitis, inflammation mediated by Con A and α-GalCer and focused on the interactions of FXR activation and expression of PIR-B, both in vivo and in vitro using luciferase reporter and CHIP assays. In addition, based upon our data, we studied the role of FXR activation on the immunobiology of myeloid-derived suppressor cells (MDSCs). Importantly, we report herein that FXR activation reduces the inflammatory insult induced by either α-GalCer or Con A; such treatment expands CD11b(+)Ly6C(+) MDSCs. The protective effect of FXR activation is dependent on expansion of MDSCs, particularly liver CD11b(+)Ly6C(high) cells. Indeed, FXR activation enhances the suppressor function of MDSCs through upregulation of PIR-B by binding the PIR-B promoter. FXR activation drives the accumulation of MDSCs to liver through...
Frontiers in Immunology, 2014
Primary biliary cirrhosis (PBC) is an uncommon autoimmune disease with a homogeneous clinical phe... more Primary biliary cirrhosis (PBC) is an uncommon autoimmune disease with a homogeneous clinical phenotype that reflects incomplete disease concordance in monozygotic (MZ) twins. We have taken advantage of a unique collection consisting of genomic DNA and mRNA from peripheral blood cells of female MZ twins (n = 3 sets) and sisters of similar age (n = 8 pairs) discordant for disease. We performed a genome-wide study to investigate differences in (i) DNA methylation (using a custom tiled four-plex array containing tiled 50mers 19,084 randomly chosen methylation sites), (ii) copy number variation (CNV) (with a chip including markers derived from the 1000 Genomes Project, all three HapMap phases, and recently published studies), and/or (iii) gene expression (by whole-genome expression arrays). Based on the results obtained from these three approaches we utilized quantitative PCR to compare the expression of candidate genes. Importantly, our data support consistent differences in discordant twins and siblings for the (i) methylation profiles of 60 gene regions, (ii) CNV of 10 genes, and (iii) the expression of 2 interferon-dependent genes. Quantitative PCR analysis showed that 17 of these genes are differentially expressed in discordant sibling pairs. In conclusion, we report that MZ twins and sisters discordant for PBC manifest particular epigenetic differences and highlight the value of the epigenetic study of twins.
Liver Immunology, 2007
Cytokines are soluble peptides secreted by several kinds of cells, they mediate many immune and i... more Cytokines are soluble peptides secreted by several kinds of cells, they mediate many immune and inflammatory reactions, and regulate several biochemical processes in and around the cells that produce them. They may act on different cell types (pleiotropic effects ...
Autoimmunity Highlights, 2012
Primary biliary cirrhosis (PBC) is a chronic, cholestatic, autoimmune liver disease characterised... more Primary biliary cirrhosis (PBC) is a chronic, cholestatic, autoimmune liver disease characterised by the destruction of small- and medium-sized bile ducts. The serological hallmark of PBC includes antimitochondrial antibodies (AMA). The disease has a striking female predominance, and primarily affects women of middle-age. First-degree relatives, and in particular female relatives, are known to have an increased risk of developing the disease. Several studies have attempted to explain the female predominance of PBC, and autoimmune diseases in general. Two components that are of interest in PBC include monosomy X and xenobiotics. Monosomy X has been noted to be prevalent in the peripheral blood mononuclear cells of PBC patients. Xenobiotics, which are exogenous chemicals not normally found within the body, have been implicated in the modification of, and loss of, tolerance to AMA. Several cosmetics are known to contain these xenobiotics, which is of interest given the information provided in regards to known risk factors for PBC development. This review will focus on X monosomy and xenobiotics, which appear to constitute the X-factor of PBC.
World Journal of Gastroenterology, 2008
World Journal of Gastroenterology, 2008
Primary biliary cirrhosis (PBC), which is characterised by progressive destruction of intrahepati... more 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 strategies. The 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 prognosis are available that will be useful especially for the growing number of patients with less severe disease. Most patients are asymptomatic at presentation. Pruritus may represent the most distressing symptom and, when UDCA is ineffective, cholestyramine represents the mainstay of treatment. Complications of long-standing cholestasis may be clinically relevant only in very advanced stages. Available 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 therapeutic option remains liver transplantation.
Uploads
Papers by Pietro Invernizzi