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Carlo Selmi

Publications and source records attributed to Carlo Selmi.

47 records · Page 3Linked to original sources
PubMed2004

Bacteria and human autoimmunity: the case of primary biliary cirrhosis.

PURPOSE OF REVIEW: Primary biliary cirrhosis is a chronic inflammatory disease of the intrahepatic bile ducts that eventually leads to liver cirrhosis and organ failure, in which several observations suggest an autoimmune origin. Similarly to other autoimmune diseases, microbial mediated molecular mimicry is the most widely studied trigger that may break immunologic tolerance in primary biliary cirrhosis. RECENT FINDINGS: The hypothesis of a bacterial role in the cause of primary biliary cirrhosis has received recent attention, based on in vitro data and the identification of a unique xenobiotic-metabolizing bacterium that modulates naturally occurring environmental estrogens, namely, Novosphingobium aromaticivorans. SUMMARY: The evidence indicates that bacteria, through different mechanisms, may precipitate autoimmunity in primary biliary cirrhosis and other autoimmune diseases. These data have several implications.

Autoimmunity↗
PubMed2004

Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in Icelandic patients with primary biliary cirrhosis and their relatives.

OBJECTIVES: Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic disease of unknown etiology characterized by serum antimitochondrial antibodies (AMA) directed against a functionally related family of mitochondrial enzymes. We recently suggested that N. aromaticivorans might be the trigger of autoimmunity in PBC. No data are available on the specificity and crossreactivity of AMA in a genetically homogenous group of patients, such as the Icelandic population. METHODS: To address these issues and to confirm previous findings in a unique population, we obtained sera from 14 PBC patients and 85 first-degree relatives, all of Icelandic descent. We analyzed such sera for AMA specificity using recombinant mitochondrial antigens and for reactivity against N. aromaticivorans proteins. RESULTS: Thirteen of the 14 Icelandic patients with PBC (93%) were found AMA positive. We found that 5/13 AMA positive sera (38%) reacted against PDC-E2 only; 5/13 (or 38%) reacted against BCOADC-E2; and 2/13 (15%) reacted against all three antigens. There was no reactivity against OGDC-E2. Reactivities of patients' sera against N. aromaticivorans were consistent with the AMA status. One serum among the 85 first-degree relatives (1.2%) was found to be AMA-positive, as well as reactive against N. aromaticivorans. CONCLUSIONS: Interestingly, despite the homogenous genetic background, the group of Icelandic patients with PBC was heterogeneous in their AMA reactive patterns and also reacted with N. aromaticivorans proteins.

Antigen-Antibody Reactions↗
PubMed2004

Apocalypsal versus apocryphal: the role of retroviruses in primary biliary cirrhosis.

The etiology of primary biliary cirrhosis (PBC), much like that of other autoimmune diseases, remains enigmatic. In the case of PBC, several candidates have been proposed, including bacteria, chemicals, and retroviruses. The support for a retroviral etiology has led to a pilot therapeutical interventional program. However, there is limited objective data which can be used to support such a thesis. Until reproducible and mechanistically sound data can be offered, we suggest that pharmaceutical trials are unrealistic and should be discouraged.

Autoimmune Diseases↗
PubMed2003

Genetic variants of endothelial nitric oxide synthase in patients with primary biliary cirrhosis: association with disease severity.

BACKGROUND AND AIMS: Primary biliary cirrhosis (PBC) presents a wide spectrum of clinical manifestations. In experimental models of liver cirrhosis and cholestasis it has been suggested that altered nitric oxide production is involved in liver injury and portal hypertension development. The present study investigated endothelial nitric oxide synthase (eNOS) genetic polymorphisms (894G/T, -786T/C) in patients with PBC and in controls to verify whether disease susceptibility and progression are associated with a particular genotype. METHODS: Genomic DNA from 109 Italian PBC patients (65 with advanced disease, i.e. liver transplantation or histological stage III-IV) was obtained and polymorphisms determined by fluorescent probe analysis. Healthy subjects (n = 242) were used as a control group. RESULTS: The allelic frequencies of both polymorphisms did not differ significantly between PBC patients and controls. When the association between genotypes and disease severity was addressed, both the 894T and the -786T alleles were more frequently found in the 22 patients with progressing disease (894T, frequency 0.455 compared with 0.240; P = 0.032; -786T, frequency 0.682 compared with 0.460; P = 0.038). Patients with 894TT presented higher Mayo score values (6.1 +/- 1.2 compared with 5.4 +/- 1.3 in 894G/G patients; P = 0.030) but similar age and disease duration values. CONCLUSIONS: The authors suggest that genetic variants of eNOS are not associated with susceptibility to PBC, although the genotypes may lead to differences in disease severity and progression.

Adult↗
PubMed2003

Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium.

Infectious and environmental agents have been proposed as immunologic triggers for primary biliary cirrhosis (PBC). Recently, a ubiquitous organism that metabolizes organic compounds and estrogens, Novosphingobium aromaticivorans, has been defined. Importantly, 2 bacterial proteins have homology with the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Sera from 97 patients with PBC, 46 first-degree relatives, 10 spouses, and 195 controls were studied for reactivity against N. aromaticivorans and Escherichia coli. The reactivity was defined by absorption, affinity purification, and using monoclonal antibodies to PDC-E2. Stool samples from 20 patients with PBC and 34 controls were analyzed by polymerase chain reaction (PCR) for the presence of N. aromaticivorans. Sera from 100% of anti-PDC-E2 positive (77/77), 33% of anti-BCOADC E2 positive (1/3), and 12% of antimitochondrial antibody (AMA) negative patients with PBC (2/17) reacted with titers up to 10(-6) against two known lipoylated bacterial proteins (47 and 50 kd) from N. aromaticivorans, including patients with early disease. This titer was approximately 100- to 1,000-fold higher than against E. coli and verified by absorption, use of affinity-purified sera, and monoclonal antibody reagents. Moreover, 78 of 80 AMA-positive and 5 of 17 AMA-negative patients with PBC had antibodies against 3 other N. aromaticivorans proteins. In contrast, 0 of 195 control sera reacted against N. aromaticivorans. Approximately 25% of patients and controls had N. aromaticivorans in their fecal specimens. In conclusion, based on protein homology, capacity to metabolize xenobiotics as well as modulate estrogens, its presence in feces, and specific immunologic response, we propose that N. aromaticivorans is a candidate for the induction of PBC.

Alphaproteobacteria↗
PubMed2002

Presence of fetal DNA in maternal plasma decades after pregnancy.

Cells of fetal origin and cell-free fetal DNA can be detected in the maternal circulation during pregnancy, and it has recently been shown that fetal cells can persist long after delivery. Given the various biological and clinical implications of this fact, we tested the hypothesis that cell-free fetal DNA can be present in maternal plasma decades after pregnancy. We extracted DNA from plasma samples and nucleated blood cells of 160 healthy women with male offspring at different time intervals after delivery (range 1-60 years). All of the samples were tested by means of a real-time quantitative PCR assay for a specific Y chromosome sequence (the SRY gene). Y chromosome-specific DNA was detected in 16 peripheral blood cell samples (10%) and 35 plasma samples (22%). The women with male sequences in the cell fraction had significantly greater total parity ( P=0.018). The proportion of women with detectable Y sequences in the plasma or cell samples was not related to the time since delivery. The fetal DNA concentrations in the genomic material extracted from plasma samples were significantly higher than those extracted from the Y-positive cell samples (149+/-140 vs 20+/-13 genome-equivalents/ml; P<0.001). There was no relationship between the concentration of fetal DNA and the time since delivery. Not only fetal cells, but also fragments of fetal DNA can be present in the maternal circulation indefinitely after pregnancy. This finding has practical implications for non-invasive prenatal diagnoses based on maternal blood, and may be considered for possible pathophysiological correlations.

Adult↗
PubMedDate not supplied

Geographic clusters of primary biliary cirrhosis.

Genetic and environmental factors have been widely suggested to contribute to the pathogenesis of primary biliary cirrhosis (PBC), an autoimmune disease of unknown etiology leading to destruction of small bile ducts. Interestingly, epidemiologic data indicate a variable prevalence of the disease in different geographical areas. The study of clusters of PBC may provide clues as to possible triggers in the induction of immunopathology. We report herein four such unique PBC clusters that suggest the presence of both genetic and environmental factors in the induction of PBC. The first cluster is represented by a family of ten siblings of Palestinian origin that have an extraordinary frequency of PBC (with 5/8 sisters having the disease). Second, we describe the cases of a husband and wife, both having PBC. A family in which PBC was diagnosed in two genetically unrelated individuals, who lived in the same household, represents the third cluster. Fourth, we report a high prevalence of PBC cases in a very small area in Alaska. Although these data are anedoctal, the study of a large number of such clusters may provide a tool to estimate the roles of genetics and environment in the induction of autoimmunity.

Adult↗
PubMedDate not supplied

Serum reactivity against bacterial pyruvate dehydrogenase: increasing the specificity of anti-mitochondrial antibodies for the diagnosis of primary biliary cirrhosis.

Antimitochondrial antibodies (AMA) are the serum hallmark of primary biliary cirrhosis (PBC). However, AMA-positivity can be found in non-PBC sera when lower dilutions are used, thus raising issues about the specificity and sensitivity of the test. AMA reacts primarily with the lipoylated domains of pyruvate dehydrogenase-E2 (PDC-E2) which is highly conserved across species, including bacteria. We studied 77 serum samples, including 24 from patients with anti-PDC-E2-positive PBC and 53 controls (16 with autoimmune hepatitis (AIH), 10 with primary sclerosing cholangitis (PSC), and 27 healthy individuals) for their reactivities at serial dilutions (1:10, 1:20 and 1:40) against Escherichia coli DH5 alpha lysate overexpressing human PDC-E2 using immunoblotting (IB). A murine anti-human PDC-E2 monoclonal antibody (mAB) was used as control. We further studied positive sera using adsorption with a synthetic E. coli peptide sharing similarity with human PDC-E2. Finally, we verified whether a unique buffer for E. coli preparation could reduce non-specific serum reactivity. Results demonstrated that 100% of anti-PDC-E2-positive PBC and up to 38% of control sera at 1:10 dilution recognized E. coli PDC-E2 at IB while dilution tests indicated that the overall potency of PBC reactivity was 100-fold higher compared to controls. In fact, a subgroup (20-38%) of non-PBC sera were positive at low titers but lost the reactivity when absorbed with the synthetic E. coli peptide. Finally, our unique buffer reduced the reactivity of non-PBC sera as measured by ELISA. In conclusion, we demonstrated that weak cross-reactivity with E. coli PDC-E2 occurs in non-PBC sera at lower dilutions and that such reactivity is not due to AMA-positivity. The use of a specific buffer might avoid the risk of false positive AMA determinations when E. coli-expressed recombinant antigens are used.

Autoantibodies↗
PubMedDate not supplied

T-cell receptor polymorphism in primary biliary cirrhosis.

T-cell receptor (TCR) plays a key role in immune regulation and polymorphisms of its genes have been found in association with several autoimmune diseases. No data are available for primary biliary cirrhosis, an autoimmune liver disease the natural history of which is highly variable. We studied a TCR constant beta-2 chain polymorphism in 70 patients affected by primary biliary cirrhosis and in 70 healthy controls. The DNA chains of patients and controls were amplified by means of polymerase chain reaction using primers designed around a Bgl II polymorphic restriction site and digested for restriction fragment length polymorphism analysis. We found a slight increase of the heterozygous genotype in patients compared with controls (49 vs 40%), which became higher if only patients with early disease were considered (60 vs 40%). Heterozygous patients had less severe disease as indicated by a lower Mayo score (5.1 +/- 1.2 vs 5.7 +/- 1.2 in non-heterozygous). Our data suggest that TCR constant beta-2 polymorphism does not play a key role in modulating the multifactorial etiopathogenesis of primary biliary cirrhosis.

Female↗