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PubMed2025

Epistasis of ERAP1 With 4 Major Histocompatibility Complex Class I Alleles in Frontal Fibrosing Alopecia: A Genome-Wide Association Study Meta-Analysis.

IMPORTANCE: Frontal fibrosing alopecia (FFA) is an inflammatory and scarring form of hair loss of increasing prevalence that most commonly affects women. An improved understanding of the genetic basis of FFA will support the identification of pathogenic mechanisms and therapeutic targets. OBJECTIVE: To identify novel genomic loci at which common genetic variation affects FFA susceptibility and assess nonadditive effects on genetic risk between susceptibility loci. DESIGN, SETTING, AND PARTICIPANTS: Four genome-wide association studies were combined using an SE-weighted meta-analysis. Within the major histocompatibility complex (MHC) locus, stepwise conditional analysis was undertaken to determine independently associated classical MHC class I alleles. Statistical tests for epistatic interaction were performed between risk alleles at the MHC and endoplasmic reticulum aminopeptidase 1 (ERAP1) loci. MAIN OUTCOMES AND MEASURES: Genome-wide significant locus associated with FFA and nonadditive effects on genetic risk between susceptibility loci. RESULTS: Of 6668 included patients, there were 1585 European female individuals with FFA and 5083 controls. Genome-wide significant associations were identified at 4 genomic loci, including a novel susceptibility locus at 5q15, and the association signal could be fine-mapped to a single nucleotide substitution (rs10045403) in the 5' untranslated region of ERAP1 (rs10045403; odds ratio, 1.30; 95% CI, 1.19-1.43; P = 3.6 × 10-8). Within the MHC, FFA risk was statistically independently associated with HLA-A*11:01, HLA-A*33:01, HLA-B*07:02, and HLA-B*35:01. FFA risk was affected by genetic variation at the ERAP1 locus only in individuals who carried at least 1 of the MHC class I risk alleles. CONCLUSIONS AND RELEVANCE: In this genome-wide meta-analysis, a supra-additive effect of genetic variation was found that affected peptide trimming and antigen presentation on FFA susceptibility. Patients with FFA may benefit from emerging therapeutic approaches that modulate ERAP-mediated processes.

Female↗
PubMed2000

Contributions of mass spectrometry to structural immunology.

Mass spectrometry has made important contributions to the field of immunology in the past decade. A variety of mass spectrometric-based techniques have been applied to study the structures of macromolecules that play a vital role in the immune response. These include traditional molecular mass measurements to identify post-translational modifications and structural heterogeneity, mass mapping of proteolysis products, sequencing by tandem mass spectrometry and conformational analysis. Antigen-antibody and other immune complexes have been detected by mass spectrometry, providing an avenue to study macromolecular assemblies that are important to immune function. By virtue of the ability of mass spectrometry based techniques to analyze complex biological mixtures, mass spectrometry has also been employed to identify and sequence protein epitopes important in both the humoral and cellular immune responses. This has been achieved through a combination of immunoaffinity and mass spectrometric techniques, and the coupling of high-performance chromatographs to mass spectrometers. These approaches are important for the identification of pathogens and show promise for the early diagnosis of disease associated with viral and bacterial infection and malignancy. These investigations will enable the mechanisms associated with normal and impaired immune function to be elucidated. Mass spectrometry has been utilized to characterize the structure of peptide mimics, multiple antigenic peptides and other constructs in the design of synthetic immunogens. Information derived from these studies will aid in the development of novel therapeutics and vaccines.

Allergy and Immunology↗
PubMed2001

The identification of a common pathogen-specific HLA class I A*0201-restricted cytotoxic T cell epitope encoded within the heat shock protein 65.

Bacterial antigens recognized by CD8(+) T cells in the context of MHC class I are thought to play a crucial role in protection against pathogenic intracellular bacteria. Here, we demonstrate the induction of HLA-A*0201-restricted CD8(+) T cell responses against six new high-affinity HLA-A*0201-binding CTL epitopes, encoded within an immunodominant and highly conserved antigen of Mycobacteria, the heat shock protein 65 (hsp65). One of these epitopes, Mhsp65(9(369)), is identical in a large number of pathogenic bacteria, and is recognized in a CD8-independent fashion. Mhsp65(9(369)) could be presented by either mycobacterial hsp65-pulsed target cells or BCG-infected macrophages. Interestingly, T cells specific for this epitope did not recognize the corresponding human hsp65 homologue, probably due to structural differences as revealed by modeling studies. Furthermore, in vitro proteasome digestion analyses show that, whereas the mycobacterial hsp65 epitope is efficiently generated, the human hsp65 homologue is not, thus avoiding the induction of autoreactivity. Collectively, these findings describe high-affinity HLA class I-binding epitopes that are naturally processed and are recognized efficiently by MHC class I-restricted CD8(+) T cells, providing a rational basis for the development of subunit vaccine strategies against tuberculosis and other intracellular infectious diseases.

Amino Acid Sequence↗
PubMed1989

Viral infectious complementary-DNA studies may identify nonviral genes critical to central nervous system disease.

A major interest of modern science and medicine is the delineation of genes that cause disease. In the case of cancer, the study of viral oncogenic genes led to the recognition of similar human genes that play an important role in this disease. In an analogous fashion, the identification of viral genes important in central nervous system disease may lead to the recognition of related cellular genes that are important in nonviral central nervous system disease. New molecular techniques now provide tools for identification of pathogenic viral genes and elucidation of mechanisms of disease production. Positive-strand RNA viruses such as picornaviruses provide an especially attractive model system for studies of central nervous system disease-producing genes. A limitation in molecular studies of these viruses has resulted from an inability to use restriction enzymes, since these enzymes are active against DNA and not RNA. This limitation has recently been overcome with the preparation of infectious picornavirus complementary-DNA. This review highlights the importance of infectious complementary-DNA in pathogenesis studies and provides a glimpse of the impact of such studies on neurology.

DNA↗
PubMed2002

Medical applications of Raman spectroscopy: from proof of principle to clinical implementation.

Raman spectroscopy has recently been applied ex vivo and in vivo to address various biomedical issues such as the early detection of cancers, monitoring of the effect of various agents on the skin, determination of atherosclerotic plaque composition, and rapid identification of pathogenic microorganisms. This leap in the number of applications and the number of groups active in this field has been facilitated by several technological advancements in lasers, CCD detectors, and fiber-optic probes. However, most of the studies are still at the proof of concept stage. We present a discussion on the status of the field today, as well as the problems and issues that still need to be resolved to bring this technology to hospital settings (i.e., the medical laboratory, surgical suites, or clinics). Taken from the viewpoint of clinicians and medical analysts, the potential of Raman spectroscopic techniques as new tools for biomedical applications is discussed and a path is proposed for the clinical implementation of these techniques.

Arteriosclerosis↗
PubMed2006

Identification of peptides from human pathogens able to cross-activate an HIV-1-gag-specific CD4+ T cell clone.

Antigen recognition by T cells is degenerate both at the MHC and the TCR level. In this study, we analyzed the cross-reactivity of a human HIV-1 gag p24-specific CD4(+) T cell clone obtained from an HIV-1-seronegative donor using a positional scanning synthetic combinatorial peptide library (PS-SCL)-based biometrical analysis. A number of decapeptides able to activate the HIV-1 gag-specific clone were identified and shown to correspond to sequences found in other human pathogens. Two of these peptides activated the T cell clone with the same stimulatory potency as the original HIV-1 gag p24 peptide. These findings show that an HIV-1-specific human T helper clone can react efficiently with peptides from other pathogens and suggest that cellular immune responses identified as being specific for one human pathogen (HIV-1) could arise from exposure to other pathogens.

Amino Acid Sequence↗
PubMed2003

Complex interactions in Parkinson's disease: a two-phased approach.

The identification of pathogenic mutations in the three genes alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) has elucidated the ubiquitin proteasome system (UPS) and its potential role as a causal pathway in Parkinson's disease (PD). In addition, polymorphisms of these three genes have been shown to be independently associated with PD. In a sample of 298 unrelated PD cases and 185 controls, we applied a two-phased approach of recursive partitioning and logistic regression analyses to explore complex interactions. For women only, we observed an epistatic interaction of UCHL1 and alpha-synuclein genotypes with significant effects on PD risk (odds ratio = 2.42; P = 0.003). Our findings are consistent with the hypothesis that PD is a multigenic disorder of the UPS.

Case-Control Studies↗
PubMed2005

Global protein expression analysis in apicomplexan parasites: current status.

Members of the phylum Apicomplexa are important protozoan parasites that cause some of the most serious, and in some cases, deadly diseases in humans and animals. They include species from the genus Plasmodium, Toxoplasma, Eimeria, Neospora, Cryptosporidium, Babesia and Theileria. The medical, veterinary and economic impact of these pathogens on a global scale is enormous. Although chemo- and immuno-prophylactic strategies are available to control some of these parasites, they are inadequate. Currently, there is an urgent need to design new vaccines or chemotherapeutics for apicomplexan diseases. High-throughput global protein expression analyses using gel or non-gel based protein separation technologies coupled with mass spectrometry and bioinformatics provide a means to identify new drug and vaccine targets in these pathogens. Protein identification based proteomic projects in apicomplexan parasites is currently underway, with the most significant progress made in the malaria parasite, Plasmodium falciparum. More recently, preliminary two-dimensional gel electrophoresis maps of Toxoplasma gondii and Neospora caninum tachyzoites and Eimeria tenella sporozoites, have been produced, as well as for micronemes in E. tenella. In this review, the status of proteomics in the analysis of global protein expression in apicomplexan parasites will be compared and the challenges associated with these investigations discussed.

Animals↗
PubMed1998

Diagnosis of mitochondrial disease: assessment of mitochondrial DNA heteroplasmy in blood.

Mitochondrial DNA (mtDNA) mutations are an important cause of neurological disease. The identification of causative mtDNA mutations may be particularly troublesome in blood where there are often low levels of mutant mtDNA. This is evident from a recent study in which heteroplasmic mtDNA mutations in cytochrome c oxidase genes were incorrectly thought to be linked to Alzheimer's disease. We wished to explore whether analysis of blood mtDNA, prepared by a number of DNA extraction procedures, influenced the diagnosis of mtDNA disease. DNA was extracted by different procedures from 4 patients with heteroplasmic mtDNA mutations, and the level of heteroplasmy investigated by radioactive PCR-RFLP analysis. Whilst there was no consistent decrease in the level of mtDNA heteroplasmy, we observed the coamplification of a novel mtDNA pseudogene from DNA samples extracted by a simple 'boiling' procedure using primers designed to screen for the tRNALeu(UUR) A3243G mutation. This pseudogene was readily amplified from DNA extracted from rho degrees (mtDNA-less) cells, confirming its nuclear location. We believe that mtDNA pseudogenes may therefore present significant difficulties in the accurate identification of pathogenic heteroplasmic mtDNA mutations in blood.

DNA, Mitochondrial↗
PubMed1995

Mapping of B-cell epitopes recognized by antibodies to histones in subsets of juvenile chronic arthritis.

The sera of 138 patients with juvenile chronic arthritis (JCA) were tested in ELISA with the five individual histones, 34 histone peptides covering the full length of the four core histones, and two peptides corresponding to the N- and C-terminal domains of H1. The occurrence of IgG antibodies was examined regarding the different subsets of JCA (pauciarticular, polyarticular, and systemic onset) and regarding clinical features (chronic anterior uveitis, CAU) and other serological features (antinuclear antibodies, ANA). Seventy-two percent of the 138 sera reacted with at least 1 histone peptide. The peptides 204-218 of H1, 1-25 of H2B, and 111-130 of H3 were recognized by 22-28% of JCA sera, and 42% of JCA sera reacted with one or both peptides 1-25 of H2B and 111-130 of H3. The frequency of occurrence of anti-histone antibodies (AHA) regarding the type of histone fraction (H1, H2A, H2B, H3 and H4) or the regions of histones was not significantly different in the three subsets of JCA. No obvious association was found between IgG antibodies to histone peptides and uveitis. In the subset of pauciarticular JCA, 13/31 patients (41.9%) with CAU against 14/41 patients (34.1%) without CAU possessed IgG antibodies reacting with peptides of the C-terminal domain 83-135 of H3. This difference is not statistically significant. Finally, the presence of antibodies to histones and histone peptides cannot completely explain ANA reactivity found in patients' sera. Although antibodies to histone peptides occur frequently in the serum of children with JCA, the antibody profiles seem to be highly individual and do not correlate with disease subtype or activity. Identification of AHA present not only in the circulation but also in tissue deposits may provide better insight into the identification of pathogenic antibodies.

Amino Acid Sequence↗
PubMed2001

Gene identification in the obligate fungal pathogen Blumeria graminis by expressed sequence tag analysis.

Powdery mildew of barley is caused by the obligate fungal pathogen Blumeria graminis f. sp. hordei. Haploid conidia of B. graminis, landing on the barley leaf, germinate to form first a primary germ tube and then an appressorial germ tube. The appressorial germ tube differentiates into a mature appressorium from which direct penetration of host epidermis occurs. Here we present data on 4908 expressed sequence tags obtained from B. graminis conidia. The combined sequences represent 2676 clones describing 1669 individual genes. Comparison with sequences from other pathogenic and nonpathogenic fungi defines hypotheses on the genes required for pathogenicity and growth on the host. The putative roles of some of the identified genes are discussed.

Ascomycota↗
PubMed1997

Protective immune responses induced by the immunization of mice with a recombinant bacteriophage displaying an epitope of the human respiratory syncytial virus.

We investigated whether a recombinant bacteriophage displaying a disease-specific protective epitope could be experimentally used as a vaccine to confer protection of immunized animals against infection. We genetically engineered a recombinant phage, fd, displaying at its surface a chimeric pIII coat protein fused to the previously identified protective epitope 173-187 from the glycoprotein G of the human respiratory syncytial virus (RSV). A selected recombinant fd phage elicited a strong immune response in mice, inducing a high level of circulating RSV-specific antibodies. Mice immunized with the recombinant phage acquired a complete resistance to RSV infection as evidenced by the lack of detectable virus particles in their lungs following intranasal challenge with live RSV. In contrast, a high level of virus particles was found in the lungs of either animals immunized with the wild-type fd phage or nonimmunized mice. To our knowledge, this is the first study to report the ability of a phage presenting an immunogenic peptide to prevent infection of immunized animals by a pathogen. This finding should facilitate the identification of pathogen-specific protective epitopes selected from random phage peptide libraries, as it is simpler and less expensive than the conventional method of synthesis and coupling of phage-specific peptide ligand sequences for immunization.

Amino Acid Sequence↗
PubMed1992

In vivo models of human lymphopoiesis and autoimmunity in severe combined immune deficient mice.

The discovery of the SCID mouse mutation has been an important advance for the study of human lymphopoiesis and autoimmunity. Further work in the SCID mouse models described in this review should yield important new information related to transplantation of human hematopoietic stem cells across HLA barriers, characterization of hematopoietic development in vivo, and identification of pathogenic human T cell clones in organ-specific autoimmune diseases. If pluripotent hematopoietic stem cells and pathogenic autoimmune T cells can be defined using SCID mouse recipients, this would pave the way for development of novel strategies for bone marrow transplantation and for interventional immunotherapy of autoimmune diseases targeted at the T cell receptor (99).

Animals↗
PubMed1999

A new scoring system for the clinical diagnosis of catheter-related infections.

It is difficult to make the clinical diagnosis of catheter-related infections using the available and established definitions of the HICPAC (Hospital Infection Control Practices Advisory Committee) of the CDC (Centers for Disease Control, definitions of nosocomial infections). The scoring system shown here is a modification of these definitions and has enabled the causal relationship between the catheter and clinical episodes of systemic infections to be quantitatively graded. The scoring system included the following criteria: height and rate of rise of body temperature, attendant shivering, identification of pathogens in blood and/or catheter tip cultures, improvement in the clinical course after catheter removal, signs of catheter exit site inflammation and results of diagnostic tests for other possible sources of infection. These criteria were graded using points and weighted according to their specificity. The comparative evaluation of 65 episodes of systemic infections using the scoring system and the diagnostic criteria of HICPAC showed agreement in 85%. No case was graded "false-negative." In nine of ten false-positive cases additional findings supported the presence of a catheter-associated infection. This scoring system appears, therefore, to be more sensitive than existing diagnostic criteria, without loss of specificity.

Catheterization, Central Venous↗
PubMed2006

[Improving the diagnosis of septic arthritis by use of a pediatric blood culture system].

BACKGROUND: Prognosis and outcome of bacterial joint infections are dependent on the fast and reliable identification of pathogens in the synovial fluid. Previous studies have suggested the possible advantage of using a blood culture system in contrast to conventional culture methods. PATIENTS AND METHODS: A total of 101 synovial specimens from patients presenting with symptoms suggesting septic arthritis were taken by aspiration with a sterile syringe. We compared the diagnostic results of automated analysis in a blood culture system against conventional culture on solid agar plates. RESULTS: Some 67 specimens (66.3%) were found to be negative in both preparations, while samples from 21 patients (20.8%) yielded the same microorganisms. In 13 cases (12.9%), the isolation of a pathogen was possible only with the blood culture method, whereas the conventional method never yielded a positive result when the blood culture was negative. Thus, the diagnostic yield was significantly improved by use of the blood culture system (P <0.001). CONCLUSION: The use of a commonly available blood culture system offers a fast, reliable and cost-effective approach for the diagnosis of septic arthritis and should therefore be considered as an useful alternative to conventional culture methods.

Adolescent↗
PubMed2025

Unveiling the Genomic Landscape of Escherichia coli O1:K1:H7 ST59 in Non-complicated Urinary Infections from Colombia Through Whole-Genome Sequencing.

Escherichia coli (E. coli) is a Gram-negative bacterium known for causing both intestinal and extraintestinal infections in humans. Among extraintestinal infections, urinary tract infections (UTIs) are particularly prevalent and impactful. In Colombia, limited information is available regarding the molecular epidemiology of E. coli. This lack of data hinders the understanding of the local epidemiological landscape and the identification of pathogenic lineages that may contribute to public health concerns. This study aimed to characterize an E. coli strain isolated from a 24-year-old female patient with a community-acquired lower UTI, focusing on genotypic analysis through whole-genome shotgun sequencing (WGSS) and subsequent bioinformatics investigations. The identified strain belongs to phylogroup F, with serotype O1:H7 and sequence type (ST) 59. Several virulence factors, including traT and afimbrial adhesins (afaC), were identified, with afaC being notably uncommon in ST59 phylogroup F. In addition, an antibiotic susceptibility test was performed, and the isolate was found to be sensitive to all the antibiotics tested. This work contributes to the understanding of E. coli phylogroup F in Colombia and provides valuable genomic data, shedding light on the virulence profile of this strain in lower urinary tract infections.

Female↗
PubMed1999

Identification and localization of differences between Escherichia coli and Salmonella typhimurium genomes by suppressive subtractive hybridization.

The availability of bacterial genome sequences raises an important new problem - how can one move from completely sequenced microorganisms as a reference to the hundreds and thousands of other strains or isolates of the same or related species that will not be sequenced in the near future? An efficient way to approach this task is the comparison of genomes by subtractive hybridization. Recently we developed a sensitive and reproducible subtraction procedure for comparison of bacterial genomes, based on the method of suppression subtractive hybridization (SSH). In this work we demonstrate the applicability of subtractive hybridization to the comparison of the related but markedly divergent bacterial species Escherichia coli and Salmonella typhimurium. Clone libraries representing sequence differences were obtained and, in the case of completely sequenced E. coli genome, the differences were directly placed in the genome map. About 60% of the differential clones identified by SSH were present in one of the genomes under comparison and absent from the other. Additional differences in most cases represent sequences that have diverged considerably in the course of evolution. Such an approach to comparative bacterial genomics can be applied both to studies of interspecies evolution - to elucidate the "strategies" that enable different genomes to fit their ecological niches - and to development of diagnostic probes for the rapid identification of pathogenic bacterial species.

Base Sequence↗