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Carlo Selmi

Publications and source records attributed to Carlo Selmi.

At least 37 records · Page 2Linked to original sources
PubMed2005

Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis.

Novosphingobium aromaticivorans, a unique ubiquitous bacterium that metabolizes xenobiotics and activates environmental estrogens, has been suggested as a pathogenic factor in the development of primary biliary cirrhosis (PBC). To define the molecular basis of PBC sera reactivity, we investigated the characteristic of the bacterial antigens involved. We cloned and sequenced four genes from N. aromaticivorans coding for immunoreactive proteins, arbitrarily named Novo 1 through Novo 4. We subsequently analyzed these proteins for their homology to known mitochondrial proteins and defined their reactivity using monoclonal antibodies (mAbs), rabbit anti-lipoic acid antibody, and PBC/control sera. Moreover, we studied their phylogenetic relation with the known PBC autoantigens. Novo proteins have an extraordinary degree of amino acid homology with all of the major human mitochondrial autoantigens PDC-E2 (Novo 1 and 2), OGDC-E2 (Novo 3), and BCOADC-E2 (Novo 4). Moreover, Novo 1-4 contain a lipoylated domain, are recognized by AMA-positive sera, and react with specific mAbs to mitochondrial antigens. Interestingly, the phylogenetic relation of the proteins emphasizes the conservation of the lipoylated domain. In conclusion, our data provide a high degree of confidence that N. aromaticivorans may potentiate the breakdown of self tolerance in genetically susceptible individuals.

Acyltransferases↗
PubMed2005

Genetic polymorphisms of toll-like receptor 9 influence the immune response to CpG and contribute to hyper-IgM in primary biliary cirrhosis.

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 that the hyper-IgM is an innate immune response and can be induced with CpG-B with concurrent up-regulation of toll-like receptor 9 (TLR9). Based on these observations, we performed a two-tier study. First, we quantitated TLR9 genotypes in patients with PBC and controls and correlated these data with the B cell response to CpG-B. Second, based on these data, we performed an extensive TLR9 genotyping in a large cohort of patients and controls. We report herein that the 2848 AA TLR9 genotype is associated with enhanced gene expression and higher frequency of intracellular IgM(+) B cells following CpG stimulation. Interestingly, however, despite the functional association, there is no difference in the distribution of TLR9 genotypes between patients and controls. Our data emphasize the importance of dissecting the innate immune response in PBC.

Adult↗
PubMed2005

From bases to basis: linking genetics to causation in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a multifactorial autoimmune disease with inherited and environmental components in pathogenesis. It is exceptional among autoimmune diseases in showing strong heritability according to familial occurrence and monozygotic twins concordance, yet with weak associations with the usual genetic risk elements for autoimmunity, such as the HLA alleles. Among the latter, there is risk (at least in some populations) conferred by HLA DRB1*08 and possibly some protection by DRB1*11. However, the inconsistency among studies on HLA is surprising, given that PBC is a relatively homogenous disease entity. Among non-HLA genes, some studies implicate polymorphisms of genes for cytotoxic T-lymphocyte antigen-4, interleukin-2, or interleukin-10; polymorphisms of the vitamin D receptor could synergize with low sunlight exposure to create deficiency of the immunoregulatory factor, activated vitamin D. A new lead is available from the finding in female subjects with PBC of an increase in the degree of monosomy of the X chromosome that is presumed to carry immune response genes. A further suggested source of inquiry is the apparent protection of African-American women from PBC. Finally, data on inheritance should be sought in PBC by descent methodology, rather than by cross-sectional association studies in cases and control subjects, and based on analysis of a large number of families with an affected member through a worldwide effort.

Autoimmune Diseases↗
PubMed2005

Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology.

The etiopathogenesis of primary biliary cirrhosis (PBC), an autoimmune disease characterized by the progressive destruction of intrahepatic bile ducts, is still enigmatic. There is growing evidence that suggests that the disease results from a combination of genetic and environmental factors. PBC should be regarded as a peculiar, yet representative autoimmune disease. For example, the relative risk for siblings and the concordance rate in monozygotic twins in PBC are among the highest reported in autoimmune conditions. Association studies for specific genes have provided weak associations, which often are limited to specific geographical areas. Interestingly, PBC epidemiology also presents a geographical pattern; it is more common in the northern parts of Europe and United States. In this article, we critically review available evidence regarding genetics and geoepidemiology in PBC. We also submit possible interpretations of data, new developments and theories, and attempt to indicate directions for future research efforts.

Europe↗
PubMed2005

Antinuclear antibodies in primary biliary cirrhosis.

Patients with primary biliary cirrhosis (PBC) generate a variety of autoantibodies, which are primarily directed against mitochondrial antigens (AMA). However, a subgroup of patient sera are also positive for antibodies to nuclear components (ANAs). At indirect immunofluorescence (IIF), PBC sera mostly produce homogeneous, nuclear dot, speckled, centromere, or rim-like patterns. During the last two decades, a number of nuclear structures have been recognized as specific targets of ANA in PBC. These include Sp100 and promyelocytic leukemia proteins, which generate a nuclear dot IIF pattern, and two components of the nuclear pore complex specifically associated with a perinuclear pattern (i.e., gp210 and p62). In recent years, the clinical significance of ANA in PBC has been widely investigated and data indicate that, unlike AMAs, PBC-specific ANAs correlate with disease severity and may therefore be a marker of poor prognosis.

Antibodies, Antinuclear↗
PubMed2005

Polymorphism of the fractalkine receptor CX3CR1 and systemic sclerosis-associated pulmonary arterial hypertension.

Fractalkine (FKN) and its receptor CX3CR1 are critical mediators in the vascular and tissue damage of several chronic diseases, including systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH). Interestingly, the V249I and T280M genetic polymorphisms influence CX3CR1 expression and function. We investigated whether these polymorphisms are associated with PAH secondary to SSc. CX3CR1 genotypes were analyzed by PCR and sequencing in 76 patients with limited SSc and 204 healthy controls. PAH was defined by colorDoppler echocardiography. Homozygosity for 249II as well as the combined presence of 249II and 280MM were significantly more frequent in patients with SSc compared to controls (17 vs 6%, p = 0.0034 and 5 vs 1%, p = 0.0027, respectively). The 249I and 280M alleles were associated with PAH (odd ratio [OR] 2.2, 95% confidence interval [CI] 1.01-4.75, p = 0.028 and OR 7.37, 95%CI: 2.45-24.60, p = 0.0001, respectively). In conclusion, the increased frequencies of 249I and 280M CX3CR1 alleles in a subgroup of patients with SSc-associated PAH suggest a role for the fractalkine system in the pathogenesis of this condition. Further, the 249I allele might be associated with susceptibility to SSc.

CX3C Chemokine Receptor 1↗
PubMed2005

SNP analysis of genes implicated in T cell proliferation in primary biliary cirrhosis.

Previous studies on primary biliary cirrhosis (PBC) have focused on the role of T lymphocytes as potential effectors of tissue injury. We hypothesized that single nucleotide polymorphisms (SNPs) of genes involved in lymphocyte proliferation would be responsible for uncontrolled expansion of T cells and autoreactivity. To address this, we genotyped DNA from 154 patients with PBC and 166 ethnically matched healthy controls for SNPs of five candidate genes (60G/A CTLA-4, 1858 C/T LYP, -IVS9 C/T foxp3, p1323 C/G ICOS and -9606 T/C CD25) using a TaqMan assay. We report herein a statistically significant decrease in homozygosity rate for the 60A*CTLA-4 allele in patients with PBC compared to controls (p = 0.0411). Moreover, we found a significant association of the same allele and of the LYP*T allele with anti-mitochondrial antibody (AMA) serum negativity (p = 0.0304 and 0.0094, respectively). No association between any of the other studied SNPs and PBC susceptibility, progression, or AMA status was observed. In conclusion, given the high prevalence of SNPs in CTLA-4 detected in numerous autoimmune diseases, we encourage a more detailed genetic analysis of this candidate gene. Further, although obtained from a limited number of AMA-negative subjects, our data suggest a potential genetic heterogeneity for this specific subgroup of patients with PBC.

Aged↗
PubMed2005

Primary biliary cirrhosis: solving the enigma.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease, most commonly affecting female patients between 40 and 60 years of age. Patient sera present autoantibodies against mitochondrial antigens (AMA) and elevated serum IgM. Histologic studies demonstrate progressive destruction of small- and medium-sized intrahepatic bile ducts and, ultimately, liver cirrhosis. The precise mechanisms leading to selective destruction of such biliary epithelial cells are still unknown, although a number of immunomediated pathways have been proposed. Genetic background is critical in determining susceptibility to the disease, although no clear association with haplotypes of the major histocompatibility complex has been identified. Molecular mimicry by either infectious agents or xenobiotics has been proposed as a means of breaking tolerance in genetically predisposed individuals, thus leading to the onset of PBC. In this review, available data and current theories regarding the immunomediated pathogenesis of PBC will be described.

Antibodies, Antinuclear↗
PubMed2005

Soluble CD40L in plasma of patients with primary biliary cirrhosis.

CD40 ligand (CD40L) is expressed by activated T cells and interacts with the CD40 molecule present on B cells and endothelial cells, promoting immunoglobulin switching in the former and cytokine upregulation in the latter. CD40L exists in both a soluble (sCD40L) and a membrane-bound form. Because primary biliary cirrhosis (PBC) is characterized by targeting of small intrahepatic bile ducts by autoreactive T cells, plasma concentrations of sCD40L were investigated using enzyme-linked immunosorbent assay (ELISA) to measure plasma concentrations of sCD40L in 12 patients with PBC and 12 healthy controls. No difference could be detected between plasma concentrations of sCD40L in patients versus controls (P = 0.977). No correlation between age and plasma levels of sCD40L could be identified (P = 0.24). We concluded that PBC patients do not exhibit higher plasma concentrations of sCD40L than age-matched controls, a finding common to several autoimmune diseases. Further investigation of the CD40-CD40L system is strongly encouraged.

Adult↗
PubMed2005

Decreased serum leptin levels in primary biliary cirrhosis: a link between metabolism and autoimmunity?

Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology resulting in the progressive destruction of the intrahepatic bile ducts and leading to chronic cholestasis and ultimately liver cirrhosis and failure. The immune response in PBC seems to be mediated by autoantibodies as well as autoreactive T lymphocytes directed against mitochondrial antigens in biliary epithelial cells, primarily PDC-E2. Experimental evidence suggests a role of the hormone/cytokine leptin in autoimmune diseases. Leptin is an adipocyte-derived molecule that acts as a hormone influencing food intake and energy metabolism as well as a cytokine with pro-inflammatory, immune-regulatory functions. To study serum leptin in PBC and its association with disease severity, we evaluated serum levels in 37 patients with PBC (27 with no signs of fibrosis or cirrhosis at histologic examination) and 37 age- and sex-matched healthy controls using a validated ELISA method. We found that patients with PBC had significantly lower leptin serum levels compared with healthy controls (13.6 +/- 13.8 vs. 17.6 +/- 11.6; P < 0.05). No correlation between disease severity and serum leptin levels was found. This study has demonstrated that leptin levels are decreased in the serum of patients with PBC but do not seem to be associated with disease severity. Data do not seem to indicate a direct role of leptin in the perpetuation of the autoimmune response in PBC. However, further studies are warranted to further characterize the functions of leptin during the natural history of autoimmunity.

Adult↗
PubMed2005

The enigma of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by a striking predominance in female patients (with most cases diagnosed between ages 40 and 60 yr) as well as serum auto-antibodies to mitochondrial antigens, elevated serum immunoglobulin M,progressive destruction of intrahepatic bile ducts, and, ultimately, liver cirrhosis and failure(1). The precise mechanisms leading to selective destruction of biliary epithelial cells lining intrahepatic bile ducts are still unknown, although numerous immunomediated pathways have been proposed. Genetic background appears to be important in determining susceptibility to the disease (2), but no clear association with alleles in the major histocompatibility complex has been identified. Molecular mimicry either by infections (3) or xenobiotics (4) has been proposed to be capable of breaking tolerance in genetically predisposed individuals, thus leading to onset of PBC. This article describes and discusses the available data regarding the immunomediated pathogenesis of PBC (with particular attention to auto-antibodies and autoreactive T-cells) and presents the recent evidence indicating a role for either xenobiotic chemicals or novel infectious agents in the induction of the disease.

Animals↗
PubMed2005

Mitochondrial antigens as targets of cellular and humoral auto-immunity in primary biliary cirrhosis.

Several factors point toward an auto-immune pathogenesis for primary biliary cirrhosis(PBC), mostly based on the presence of serum auto-antibodies to mitochondrial antigens(AMAs) and autoreactive T cells (both helper and cytotoxic). Interestingly, epitopes recognized by AMA and T-cell clones are located within overlapping areas of the antigens. Moreover,a role for an imbalance in cytokine pattern and for natural-killer lymphocytes has also been proposed. Despite several experimental reports, no clear evidence is available regarding the interaction of these factors leading to bile duct destruction. This article reviews the current reports regarding the auto-immune reaction against mitochondrial auto-antigens in PBC.

Antigen-Presenting Cells↗
PubMed2004

Frequency of monosomy X in women with primary biliary cirrhosis.

The mechanisms that cause the female predominance of primary biliary cirrhosis (PBC) are uncertain, but the X chromosome includes genes involved in immunological tolerance. We assessed the rate of X monosomy in peripheral white blood cells from 100 women with PBC, 50 with chronic hepatitis C, and 50 healthy controls, by fluorescence in-situ hybridisation. Frequency of X monosomy increased with age in all groups, but was significantly higher in women with PBC than in controls (p<0.0001); age-adjusted back-transformed mean frequencies were 0.050 (95% CI 0.046-0.055) in women with PBC, 0.032 (0.028-0.036) in those with chronic hepatitis C, and 0.028 (0.025-0.032) in controls. We suggest that haploinsufficiency for specific X-linked genes leads to female susceptibility to PBC.

Adult↗
PubMed2004

Primary biliary cirrhosis: does X mark the spot?

Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology leading to progressive destruction of intrahepatic bile duct, with cholestasis, cirrhosis, and eventually liver failure. Epidemiological data indicate that environmental factors trigger autoimmunity in genetically susceptible individuals, although no definitive association of PBC with specific genes has been found. Further, no convincing explanation has been provided for the strong female predominance observed in the prevalence of PBC. However, we recently suggested that the enhanced monosomy X in peripheral white blood cells, and particularly in lymphocytes, of affected women might play a role in the induction of PBC. Such observations appear independent from the degree of cholestasis and specific for PBC. In this review we discuss the implications of these findings and their immunological implications.

Autoimmune Diseases↗
PubMed2004

Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment.

BACKGROUND & AIMS: There is growing evidence that the interplay of genetic susceptibility and environmental factors leads to primary biliary cirrhosis (PBC). In particular, family members of an infected individual have up to a 100-fold higher risk of developing PBC. Although concordant rates for identical twins in other autoimmune diseases range between 25% and 50%, there are no such data on PBC. Accordingly, we evaluated the concordance of PBC in a genetically defined population of twin sets and evaluated the clinical characteristics between concordant subjects. METHODS: We identified 16 pairs of twins within a 1400-family cohort followed up by several centers worldwide, evaluated the diagnosis of PBC in all individuals, and determined the zygosity of sets reported as identical by the analysis of 2 highly variable HLA class II regions and 5 short tandem repeats. RESULTS: Eight of 16 sets of twins were monozygotic. In 5 of 8 monozygotic twin sets, both individuals had PBC (pairwise concordance rate, 0.63). Among the dizygotic twins (n = 8), no set was found to be concordant for PBC. Interestingly, the age at onset of disease was similar in 4 of 5 concordant sets of monozygotic pairs; however, there were differences in natural history and disease severity. CONCLUSIONS: The concordance rate of PBC in identical twins is among the highest reported in autoimmunity. However, discordant pairs were identified. The data show not only the role of genetics but also emphasize that either epigenetic factors and/or environment play a critical role.

Adult↗
PubMed2004

Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis.

BACKGROUND & AIMS: Recent observations, including a pilot clinical trial, have suggested that a human mouse mammary tumor virus (MMTV) causes primary biliary cirrhosis (PBC). We attempted to confirm such data. METHODS: We obtained sera from 101 patients (53 with PBC and 48 controls), fixed liver sections from 10 patients (8 PBC and 2 controls), fresh liver specimens (6 PBC and 6 controls), and fresh peripheral blood lymphocytes (PBLs) (10 PBC and 10 controls). We studied sera for reactivities against 3 different strains of MMTV virions, MMTV(C3H), MMTV(FM), and MMTV(LA), including goat polyclonal antibodies against MMTV virions, gp52, and p27 as positive controls. We stained liver specimens using polyclonal antibodies against MMTV and gp52 and further examined tissue samples and PBLs for specific MMTV genome sequences. RESULTS: By Western blot analysis, no detectable reactivity in any of the PBC sera against any of the 3 MMTV strains or MMTV gp52 or p27 was observed. However, viral proteins were recognized by our control positive polyclonal antibodies. We note that 13%-60% of PBC sera presented low reactivity against 2 proteins of approximately 57 and 74 kilodaltons. Such reactivity is related to the trace amounts of mitochondrial antigens in the virus preparations derived from murine mammary tumor tissue. No detectable immunohistochemical or molecular evidence for MMTV was found in the liver specimens or PBLs. CONCLUSIONS: We were unable to recapitulate the data on this specific retroviral etiology of PBC and suggest that such data could be the result of contamination.

Aged↗
PubMed2004

Epidemiology and pathogenesis of primary biliary cirrhosis.

Primary biliary cirrhosis is an autoimmune disease of unknown etiology leading to progressive destruction of small intrahepatic bile ducts and eventually to liver cirrhosis and failure. It is characterized by female predominance (with most cases observed between the ages of 40 and 60) and serum autoantibodies to mitochondrial antigens as highly specific hallmarks. Epidemiologic data indicate a variable incidence and prevalence of the disease. A number of genetic factors have been indicated as playing a role in determining disease susceptibility or progression, although no definitive conclusion has been reached so far. However, as suggested by some epidemiologic observations, a number of environmental factors, including molecular mimicry by either microorganisms or xenobiotics, have also been proposed. A hypothesis gaining support is that environmental factors may trigger disease in genetically predisposed individuals. In this review, the available data regarding the epidemiology and pathogenesis of primary biliary cirrhosis will be described and discussed.

Humans↗