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Carlo Selmi

Publications and source records attributed to Carlo Selmi.

At least 19 recordsLinked to original sources
PubMed2026

Use of synthetic data, a novel paradigm for immunopathology.

The complexity and heterogeneity of autoimmune diseases are only partially captured by current analytic tools, even when deep learning techniques are employed to intercept patterns beyond existing dogma. Synthetic data offer a newer paradigm through machine-generated reconstructions of real-world data that faithfully attempt to recapitulate biological and clinical patterns without creating duplicates and maintaining the privacy of the original ones. Synthetic data act as a magnifying lens, allowing predictions otherwise not possible on disease classification, progression, and therapeutic response. This approach has several advantages and is currently underutilized. Firstly, it provides cohort enrichment and equilibrates group imbalances. Second, it generates synthetic arms for both in vitro studies and human clinical trials, relevant to disentangle the rarity and heterogeneity of autoimmune diseases. Third, the platform allows applications beyond tabular registries, including medical images, genomics, and flow cytometry data. Last, 'digital twins' act through dynamic bidirectional links with the biological/clinical system counterpart, lending themselves to transformative opportunities for precision medicine. Herein, we discuss the current status of this fast-moving novel component of artificial intelligence and its implications for autoimmune diseases.

Humans↗
PubMed2006

European population substructure: clustering of northern and southern populations.

Using a genome-wide single nucleotide polymorphism (SNP) panel, we observed population structure in a diverse group of Europeans and European Americans. Under a variety of conditions and tests, there is a consistent and reproducible distinction between "northern" and "southern" European population groups: most individual participants with southern European ancestry (Italian, Spanish, Portuguese, and Greek) have >85% membership in the "southern" population; and most northern, western, eastern, and central Europeans have >90% in the "northern" population group. Ashkenazi Jewish as well as Sephardic Jewish origin also showed >85% membership in the "southern" population, consistent with a later Mediterranean origin of these ethnic groups. Based on this work, we have developed a core set of informative SNP markers that can control for this partition in European population structure in a variety of clinical and genetic studies.

Arthritis, Rheumatoid↗
PubMed2006

Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis.

Although there have been significant advances in understanding the clinical and biochemical features of primary biliary cirrhosis (PBC), there is still a paucity of data on the usefulness of biomarkers as prognostic indicators. This is particularly important at the time of initial diagnosis. Indeed, the widespread use of antimitochondrial antibody testing has led to an earlier diagnosis of asymptomatic PBC and it is difficult to predict which patients will experience a benign versus a rapidly progressive course. To address this issue, we examined a unique population of 127 newly diagnosed patients with PBC during a 15-year period of observation that began in January 1990. Sera from these patients were analyzed for antimitochondrial, antinuclear, and anti-smooth muscle antibodies, and immunoblotting was performed for nuclear pore complex (NPC). The patients were then followed up longitudinally using biochemical liver function tests. No patient was under any medical therapy for PBC at the time of the initial sera collection. Data were analyzed based not only on the clinical features, but also the Mayo score and specific outcome measures, including time to death, need for liver transplantation, and complication free survival. Among patients with early disease, bilirubin increased to >2 mg/dL in the anti-NPC(+) patients (26% vs. 5%, P = .019). Anti-NPC antibodies remained stable or slightly increased over the period of observation. In condusion, anti-NPC identifies patients likely to experience an unfavorable clinical course and more rapid disease progression.

Adult↗
PubMed2006

Avian models with spontaneous autoimmune diseases.

Autoimmune diseases in human patients only become clinically manifest when the disease process has developed to a stage where functional compensation by the afflicted organ or system is not possible anymore. In order to understand the initial etiologic and pathogenic events that are generally not yet accessible in humans, appropriate animal models are required. In this respect, spontaneously developing models--albeit rare--reflect the situation in humans much more closely than experimentally induced models, including knockout and transgenic mice. The present chapter describes three spontaneous chicken models for human autoimmune diseases, the Obese strain (OS) with a Hashimoto-like autoimmune thyroiditis, the University of California at Davis lines 200 and 206 (UCD-200 and -206) with a scleroderma-like disease, and the amelanotic Smyth line with a vitiligo-like syndrome (SLV). Special emphasis is given to the new opportunities to unravel the genetic basis of these diseases in view of the recently completed sequencing of the chicken genome.

Animals↗
PubMed2006

Serum islet cell autoantibodies during interferon alpha treatment in patients with HCV-genotype 4 chronic hepatitis.

Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease worldwide and HCV genotype 4 (HCV4) is predominant in African and Middle Eastern countries. It is well established that interferon-a (IFNa) treatment for HCV may trigger serum autoantibodies against pancreatic islet cells (ICA) in a subgroup of patients. Available data on the incidence of ICA during IFNa therapy for chronic HCV4 infection are not conclusive. We investigated the appearance of ICA in 40 naïve Egyptian patients (38 males, 32 +/- 6 years) with histologically defined chronic HCV4 infection undergoing IFNa treatment at a dose of 9-million U/week for 24 weeks. Serum samples were collected at baseline and following IFNa therapy and ICA were detected using indirect immunofluorescence. Baseline evaluation indicated that 2/40 (5%) patients had detectable serum ICA. After the completion of the treatment scheme, 12/38 (32%) previously ICA negative patients became ICA positive; however, no patient developed impaired glucose tolerance (IGT) or diabetes during follow-up. In conclusion, we submit that IFNa treatment for chronic hepatitis C (CHC) may induce serum ICA in one-third of Egyptian patients with HCV4. These autoantibodies, however, do not lead to alterations in glucose metabolism.

Adult↗
PubMed2006

The anti-inflammatory properties of cocoa flavanols.

Signs of chronic or acute inflammation have been demonstrated in most cardiovascular diseases of multifactorial pathogenesis, including atherosclerosis and chronic heart failure. The triggers and mechanisms leading to inflammation may vary between clinical conditions but they share many common mediators, including specific patterns of eicosanoid and cytokine production. Certain cocoa-based products can be rich in a subclass of flavonoids known as flavanols, some of which have been found in model systems to possess potential anti-inflammatory activity relevant to cardiovascular health. Indeed, experimental evidence demonstrates that some cocoa-derived flavanols can reduce the production and effect of pro-inflammatory mediators either directly or by acting on signaling pathways. However, it should be noted that the evidence for any beneficial effects of cocoa flavanols in providing a meaningful anti-inflammatory action has been gathered predominantly from in vitro experiments. Therefore, additional research in well-designed human clinical experiments, using cocoa properly characterized in terms of flavanol content, would be a welcome addition to the evidence base to determine unambiguously if this benefit does indeed exist. If so, then flavanol-rich cocoa could be a potential candidate for the treatment, or possibly prevention, of the broad array of chronic diseases that are linked to dysfunctional inflammatory responses.

Anti-Inflammatory Agents↗
PubMed2006

The X chromosome and systemic sclerosis.

PURPOSE OF REVIEW: Similar to the majority of autoimmune rheumatic diseases, systemic sclerosis is characterized by a striking female predominance superimposed on a predisposing genetic background. At least two genetic mechanisms have been proposed that play a role in susceptibility to systemic sclerosis; firstly the maintenance of immune tolerance via genes on the X chromosomes and, secondly, fetal microchimerism. Based on these lines of evidence, experimental efforts have been most recently dedicated to investigating the role of X chromosome abnormalities (i.e. monosomy rates and inactivation patterns) in autoimmunity. We will review herein the most recent data on the role of the X chromosome in systemic sclerosis onset and discuss the potential implications. RECENT FINDINGS: Women with systemic sclerosis manifest an enhanced rate of X monosomic cells in peripheral blood compared with healthy age-matched women. Furthermore, a severely skewed X chromosome inactivation pattern is found in women with systemic sclerosis. SUMMARY: These observations, reproduced in other female-predominant autoimmune diseases, strongly support the role of the X chromosome in conferring susceptibility to tolerance breakdown and open novel scenarios to emphasize the unknown etiopathogenesis of systemic sclerosis. The implications of these findings will be discussed.

Autoimmunity↗
PubMed2006

Primary biliary cirrhosis with multinucleated hepatocellular giant cells: implications for pathogenesis of primary biliary cirrhosis.

Histological and clinical features of syncytial giant cell hepatitis (GCH) are rarely observed in adults, and the disease has been associated with several autoimmune disorders and drug reactions. We describe here the case of a 62-year-old woman who presented with evidence of severe acute hepatocellular injury and cholestasis. Serum work-up demonstrated antimitochondrial antibodies specific for primary biliary cirrhosis (PBC) autoantigens, whereas markers of viral infection including hepatitis viruses, paramyxovirus and measles virus were negative. Liver histology revealed the presence of multinucleated hepatocellular giant cells in the parenchymal areas surrounding bridging necrosis. Importantly, damaged interlobular bile ducts were also observed within the lymphocyte-infiltrated portal tracts. Further study using transmission electron microscopy demonstrated the presence of filamentous strands and particles resembling paramyxovirus nucleocapsids in the cytoplasm of syncytial giant cells. To our knowledge, this is the first case of PBC with histological and clinical evidence of syncytial GCH in an adult, and we submit that it might provide novel clues in the enigma of PBC pathogenesis.

Cholestasis↗
PubMed2006

Interferon alpha and its contribution to autoimmunity.

It is now well accepted that interferon (IFN)alpha plays a critical role in the pathogenesis and perpetuation of specific autoimmune diseases, including systemic lupus erythematosus (SLE), autoimmune thyroid disease and type 1 diabetes. IFNalpha-based treatments are widely used for the treatment of chronic viral infections, particularly chronic hepatitis C virus infection; however, several case reports have emerged describing autoimmune conditions that have developed during IFNalpha therapy. The data support the pathogenic potential of IFNalpha in autoimmunity, although it is clear that genetic and environmental factors are also key to the development of autoimmune conditions. Several points of interaction between IFNalpha and immune effector cells have been experimentally defined, the functional consequences of many of which remain poorly understood. This review describes the most recent data in support of an important role for IFNalpha in autoimmunity, particularly SLE, and the potential mechanisms by which IFNalpha contributes to immune dysfunction. Future approaches to IFNalpha modulation as a therapeutic strategy for use in the treatment of autoimmune diseases are also discussed.

Animals↗
PubMed2005

Juvenile idiopathic arthritis.

One of the most enigmatic problems in rheumatology has been juvenile idiopathic arthritis (JIA). Firstly, the classification has often depended on clinical features that have variations between patients. Secondly, there are different classification schemes in usage and there are few objective serologic tests that help to resolve the differences between the criteria sets. Thirdly, only recently have significant advances been made in understanding the immunology and immunopathology of JIA and, in particular, new treatment options. In this review, we will define the historical basis of JIA and emphasize not only the clinical features, but also the immunological characteristics, the pathogenesis, and treatment options. We will also discuss, in particular, quality of life, psychosocial functioning, socioeconomic outcomes and the difficult area of mortality. Finally, this review will attempt to bridge genetic observations with clinical presentation. JIA represents a relatively common syndrome of pediatric onset rheumatologic disease and a better understanding of the clinical definition, the relationship to autoimmunity, and novel treatments with biologic agents are critical for improved patient care.

Adolescent↗
PubMed2005

X chromosome monosomy: a common mechanism for autoimmune diseases.

The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y alpha-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 +/- 0.3% and 4.3 +/- 0.3%, respectively, vs 2.9 +/- 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.

Adult↗
PubMed2005

Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis.

Epidemiological data suggest that environmental factors may trigger autoimmunity in genetically susceptible individuals. In primary biliary cirrhosis (PBC), it has been postulated that halogenated xenobiotics can modify self-molecules, facilitating the breakdown of tolerance to mitochondrial antigens. The transport and metabolism of xenobiotics is highly dependent on key genetic polymorphisms that alter enzymatic phenotype. We analyzed genomic DNA from 169 patients with PBC and 225 geographically and sex-matched healthy subjects for polymorphisms of genes coding for cytochromes P450 (CYPs) 2D6 (CYP2D6*4, CYP2D6*3, CYP2D6*5, and CYP2D6*6) and 2E1 (cl/c2), multidrug resistance 1 (MDR1 C3435T) P-glycoprotein, and pregnane X receptor (PXR C-25385T, C8055T, and A7635G). We compared the genotype frequencies in patients and controls and also correlated polymorphisms with PBC severity. The distributions of the studied genotypes did not significantly differ between patients and controls. However, when clinical characteristics of patients with PBC were compared according to genotype, the CYP2E1 c2 allele was associated with signs of more severe disease. In conclusion, genetic polymorphisms of CYP 2D6 and 2E1, PXR, and MDR1 do not appear to play a role in the onset of PBC.

Aged↗
PubMed2005

Small ubiquitin-related modifiers: A novel and independent class of autoantigens in primary biliary cirrhosis.

Serum autoantibodies against components of nuclear dots (anti-NDs), namely PML and Sp100, are specifically detected in 20% to 30% of patients with primary biliary cirrhosis (PBC). Although anti-ND antibodies are nonpathogenic, the mechanisms that lead to this unique reactivity are critical to understanding the loss of immune tolerance in PBC. Importantly, Sp100 and PML are both covalently linked to small ubiquitin-related modifiers (SUMOs). Therefore, we investigated whether SUMO proteins are independent autoantigens in PBC and studied 99 PBC sera samples for reactivity against NDs, PML, and Sp100, as well as against SUMO-2 and SUMO-1 recombinant proteins. Autoantibodies against SUMO-2 and SUMO-1 were found in 42% and 15% of anti-ND-positive PBC sera, respectively. Anti-SUMO reactivity was not observed in anti-ND-negative sera. Anti-SUMO-2 autoantibodies were found in 58% of sera containing autoantibodies against both PML and Sp100 and were detected exclusively in sera containing anti-Sp100 autoantibodies. In conclusion, SUMO proteins constitute a novel and independent class of autoantigens in PBC. Furthermore, we believe our data emphasize the post-translational modification of lysine by either lipoylation in the case of AMA or SUMOylation in the case of specific anti-ND autoantibodies as the pivotal site for autoantibody generation in PBC.

Animals↗
PubMed2005

Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis.

The role of the adaptive immune response, with regard to the development of autoantibodies, has been extensively studied in primary biliary cirrhosis (PBC). However, the importance of innate immunity has been noted only recently. Based on the proposed role of microorganisms in the pathogenesis of the disease, we hypothesize that patients with PBC possess a hyper-responsive innate immune system to pathogen-associated stimuli that may facilitate the loss of tolerance. To address this issue, we isolated peripheral blood monocytes from 33 patients with PBC and 26 age-matched healthy controls and stimulated such cells in vitro with defined ligands for toll-like receptor (TLR) 2 (lipoteichoic acid; LTA), TLR3 (polyIC), TLR4 (lipopolysaccharide; LPS), TLR5 (flagellin), and TLR9 (CpG-B). Supernatant fluids from the cultures were analyzed for levels of 5 different pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6, IL-8, IL-12p70, and TNF-alpha. After in vitro challenge with TLR ligands, PBC monocytes produced higher relative levels of pro-inflammatory cytokines, particularly IL-1beta, IL-6, IL-8, and TNF-alpha, compared with controls. In conclusion, monocytes from patients with PBC appear more sensitive to signaling via select TLRs, resulting in secretion of selective pro-inflammatory cytokines integral to the inflammatory response that may be critical in the breakdown of self-tolerance.

Adult↗
PubMed2005

Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients.

Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology, often associated with other autoimmune conditions. Controlled studies have so far provided conflicting data on risk factors and comorbidity rates in PBC. We enrolled patients with PBC (n = 1032) from 23 tertiary referral centers for liver diseases in the United States and random-digit-dialed controls (n = 1041) matched for sex, age, race, and geographical location. Patients and controls were administered a modified version of the US National Health and Nutrition Examination Study (NHANES III) questionnaire by trained personnel to evaluate associations between PBC and social, demographic, personal and family medical histories, lifestyle, and reproductive factors and the rates of comorbidity in affected individuals. Data indicate that having a first-degree relative with PBC (adjusted odds ratio [AOR] 10.736; 95% confidence interval 4.227-27.268), history of urinary tract infections (AOR 1.511, 95% CI 1.192-1.915), past smoking (AOR 1.569, 95% CI 1.292-1.905), or use of hormone replacement therapies (AOR 1.548, 95% CI 1.273-1.882) were significantly associated with increased risk of PBC. The frequent use of nail polish slightly increased the risk of having PBC. Other autoimmune diseases were found in 32% of cases and 13% of controls (P<0.0001). In conclusion, environmental factors, possibly including infectious agents through urinary tract infections or chemicals contained in cigarette smoke, may induce PBC in genetically susceptible individuals. Exogenous estrogens may also contribute to explain the female predominance of the disease.

Aged↗
PubMed2005

Genes and goals: an approach to microarray analysis in autoimmunity.

A significant body of data on gene expression patterns in autoimmune diseases has been generated by microarray analysis. Although results are very promising, there are many factors that have detracted from the data. Indeed, no common methodological directions are available. Similarly, collection techniques, processing methods, and statistical approaches are often different. The impact of future studies will depend on the comparison of large datasets to validate results and must include rigorous statistical analysis. To better illustrate the issue we review herein the gene expression patterns observed in five representative autoimmune diseases, i.e. systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, dermatomyositis, and primary biliary cirrhosis. We also emphasize how, once potential chromosome regions or pathways are identified, specific array design will be a powerful resource when used on large and representative populations.

Animals↗