9 results on '"Oksenberg JR"'
Search Results
2. Mapping gene activity in complex disorders: Integration of expression and genomic scans for multiple sclerosis.
- Author
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Fernald GH, Yeh RF, Hauser SL, Oksenberg JR, and Baranzini SE
- Subjects
- Animals, Cluster Analysis, Encephalomyelitis, Autoimmune, Experimental, Female, Genetic Linkage, Humans, Male, Mice, PubMed statistics & numerical data, Chromosome Mapping, Genetic Predisposition to Disease, Genomics, Multiple Sclerosis genetics
- Abstract
Genetic predisposition contributes to the pathogenesis of most common diseases. Genetic studies have been extremely successful in the identification of genes responsible for a number of Mendelian disorders. However, with a few exceptions, genes predisposing to diseases with complex inheritance remain unknown despite multiple efforts. In this article we collected detailed information for all genome-wide genetic screens performed to date in multiple sclerosis (MS) and in its animal model experimental autoimmune encephalomyelitis (EAE), and integrated these results with those from all high throughput gene expression studies in humans and mice. We analyzed a total of 55 studies. We found that differentially expressed genes (DEG) are not uniformly distributed in the genome, but rather appear in clusters. Furthermore, these clusters significantly differ from the known heterogeneous organization characteristic of eukaryotic gene distributions. We also identified regions of susceptibility that overlapped with clusters of DEG leading to the prioritization of candidate genes. Integration of genomic and transcriptional information is a powerful tool to dissect genetic susceptibility in complex multifactorial disorders like MS.
- Published
- 2005
- Full Text
- View/download PDF
3. Re: GAMES issue.
- Author
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Oksenberg JR and Hauser SL
- Subjects
- Europe epidemiology, Humans, Multiple Sclerosis epidemiology, International Cooperation, Multiple Sclerosis genetics
- Published
- 2004
- Full Text
- View/download PDF
4. Chromosome 7q21-22 and multiple sclerosis.
- Author
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Villoslada P, Barcellos LF, and Oksenberg JR
- Subjects
- Humans, Ireland, Italy, Spain, United States, Chromosomes, Human, Pair 7 genetics, Genetic Predisposition to Disease, Multiple Sclerosis genetics
- Published
- 2004
- Full Text
- View/download PDF
5. The HLA locus and multiple sclerosis in Spain. Role in disease susceptibility, clinical course and response to interferon-beta.
- Author
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Villoslada P, Barcellos LF, Rio J, Begovich AB, Tintore M, Sastre-Garriga J, Baranzini SE, Casquero P, Hauser SL, Montalban X, and Oksenberg JR
- Subjects
- Adult, Age Factors, Age of Onset, Cohort Studies, Disability Evaluation, Female, HLA-DR2 Antigen immunology, Humans, Lymphocytes cytology, Male, Middle Aged, Multiple Sclerosis drug therapy, Multiple Sclerosis immunology, Prospective Studies, Sex Factors, Spain, Chromosomes, Human, Pair 6 genetics, Genetic Linkage genetics, Genetic Predisposition to Disease genetics, HLA-DR2 Antigen genetics, Interferon-beta therapeutic use, Lymphocytes immunology, Multiple Sclerosis genetics
- Abstract
The HLA-DR2 haplotype (DRB1*1501, DQB1*0602) on chromosome 6p21 has consistently demonstrated both association and linkage with multiple sclerosis (MS) in case-control and family studies, particularly in Caucasians of Northern European descent. However, the role of a gene within this region in determining clinical features or response to immunotherapy remains largely unknown. A new familial MS data set from the Mediterranean Spanish Basin was collected according to rigorous ascertainment criteria. We confirm, primarily in the cohort originating from Continental Spain, that similar to other high-risk groups, there was a significant association with HLA-DR2. No other DR or DQ alleles were found to be associated with disease susceptibility nor were alleles at the class I A and B loci. Overall, the effect of HLA appears to be less substantial than that observed in a reference US population with a higher disease incidence. No effect of the HLA-DR2 haplotype on age of onset, initial clinical symptoms and disease course was observed. Similarly, no difference in the distribution of responders and nonresponders to interferon-beta (IFNB) therapy, as defined by primary and secondary end points, was observed when individuals were stratified according to HLA-DR2 status.
- Published
- 2002
- Full Text
- View/download PDF
6. Gene expression analysis reveals altered brain transcription of glutamate receptors and inflammatory genes in a patient with chronic focal (Rasmussen's) encephalitis.
- Author
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Baranzini SE, Laxer K, Bollen A, and Oksenberg JR
- Subjects
- Adult, Brain metabolism, Brain pathology, Chronic Disease, Cytokines genetics, Down-Regulation genetics, Down-Regulation immunology, Encephalitis metabolism, Female, Frontal Lobe immunology, Frontal Lobe metabolism, Frontal Lobe pathology, Humans, Immunoglobulins immunology, Immunoglobulins metabolism, Inflammation Mediators immunology, RNA, Messenger immunology, RNA, Messenger metabolism, Receptors, Metabotropic Glutamate genetics, Up-Regulation genetics, Up-Regulation immunology, Brain immunology, Encephalitis genetics, Encephalitis immunology, Gene Expression Regulation immunology, Inflammation Mediators metabolism, Receptors, Glutamate genetics, Transcription, Genetic immunology
- Abstract
Chronic focal encephalitis (CFE) generally presents with seizures that increase in severity and frequency as the disease progresses. Malfunction of synaptic transmission through altered glutamate signaling has been proposed as a likely mechanism triggering CFE. In addition, profuse inflammation is commonly seen in histopathological examination of resected tissue. To further explore the roles of glutamatergic activity and inflammation in this disease, we examined the expression of 52 genes by real time RT-PCR (kinetic RT-PCR or kRT-PCR) in a brain specimen from a CFE patient with active seizures, eight control specimens from patients with several other neurologic disorders, and two from individuals with no recorded history of neurological abnormalities. The CFE specimen displayed a dramatic increase in the expression of several inflammation-related genes (i.e. IL1 beta, IgVH, and IL2R gamma among others) and a striking down-regulation of several GluRs, in particular mGluR4. This type of analysis may prove useful in describing the molecular events underlying intractable epilepsy.
- Published
- 2002
- Full Text
- View/download PDF
7. Sequence variation in the transforming growth factor-beta1 (TGFB1) gene and multiple sclerosis susceptibility.
- Author
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Green AJ, Barcellos LF, Rimmler JB, Garcia ME, Caillier S, Lincoln RR, Bucher P, Pericak-Vance MA, Haines JL, Hauser SL, and Oksenberg JR
- Subjects
- Adult, Amino Acid Sequence genetics, Base Sequence genetics, Chromosome Mapping, Disability Evaluation, Female, Genetic Linkage, Genotype, Haplotypes, Humans, Interleukin-11 genetics, Male, Microsatellite Repeats, Middle Aged, Multiple Sclerosis physiopathology, Polymorphism, Genetic, Transforming Growth Factor beta1, Genetic Predisposition to Disease, Multiple Sclerosis genetics, Transforming Growth Factor beta genetics
- Abstract
Genome screenings in multiple sclerosis (MS) have identified multiple susceptibility regions supporting a polygenic model for this disease. Evidence for linkage was consistently observed at ch.19q13 suggesting the presence of an MS gene(s) in this region. Several interesting candidate genes are encoded within this region, including transforming growth factor-beta 1 (TGFB1) and interleukin-11 (IL11). Both are multifunctional cytokines with significant and well-characterized immunomodulatory properties. We performed a comprehensive evaluation of common polymorphisms within the TGFB1 and IL11 loci and three closely flanking microsatellite markers (D19S421, CEA, D19S908) in 161 stringently ascertained and clinically characterized MS multiplex families using tests of both linkage (lod score, sib-pair analysis) and association (pedigree disequilibrium test or PDT). Patients and families were stratified by HLA-DR2 status to search for two-locus interactions. Suggestive evidence for linkage and association to CEA (lod score = 1.25, theta = 0.20, p = 0.015, respectively), located 0.4 cM from TGFB1, was observed in DR2 positive families only. Distinct clinical phenotypes were also examined and an association between a TGFB1 haplotype and a mild disease course was present (p = 0.008), raising the possibility that TGFB1 or a nearby locus may influence disease expression.
- Published
- 2001
- Full Text
- View/download PDF
8. Multiple sclerosis: genomic rewards.
- Author
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Oksenberg JR, Baranzini SE, Barcellos LF, and Hauser SL
- Subjects
- Gene Expression, Genetic Predisposition to Disease, Genetic Variation, Genome, Humans, Major Histocompatibility Complex genetics, Models, Genetic, Multiple Sclerosis genetics
- Abstract
A large body of immunologic, epidemiologic, and genetic data indicate that tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develops in genetically susceptible individuals after exposure to an as-yet undefined causal agent. The genetic component of MS etiology is believed to result from the action of several genes of moderate effect. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, post transcriptional regulatory mechanisms, and significant nutritional and environmental influences. Equally significant, it is also likely that genetic heterogeneity exists, meaning that specific genes influence susceptibility and pathogenesis in some affects but not in others. Results in multiplex MS families confirm the genetic importance of the MHC region in conferring susceptibility of MS. Susceptibility may be mediated by the class II genes themselves (DR, DQ or both), related to the known function of these molecules in the normal immune response, e.g. antigen binding and presentation and T cell repertoire determination. The possibility that other genes in the MHC or the telomeric region of the MHC are responsible for the observed genetic effect cannot be excluded. The data also indicate that although the MHC region plays a significant role in MS susceptibility, much of the genetic effect in MS remains to be explained. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The past few years have seen real progress in the development of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and in defining the pathological basis of demyelination, setting the stage for the final characterization of the genes involved in MS susceptibility and pathogenesis. Their identification and characterization is likely to define the basic etiology of the disease, improve risk assessment and influence therapeutics.
- Published
- 2001
- Full Text
- View/download PDF
9. Gamma delta T cell receptor repertoire in brain lesions of patients with multiple sclerosis.
- Author
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Hvas J, Oksenberg JR, Fernando R, Steinman L, and Bernard CC
- Subjects
- Amino Acid Sequence, Base Sequence, Brain immunology, Gene Rearrangement, delta-Chain T-Cell Antigen Receptor, Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor, Humans, Molecular Sequence Data, Oligodeoxyribonucleotides chemistry, Receptors, Antigen, T-Cell, gamma-delta immunology, Multiple Sclerosis immunology, Receptors, Antigen, T-Cell, gamma-delta genetics, T-Lymphocytes physiology
- Abstract
The identification of activated T cells in the brains of patients with multiple sclerosis (MS) suggests that these cells are critical in the pathogenesis of this disease. Recently we have used the PCR method to analyse rearrangements of V alpha and V beta genes of the T cell receptor (TCR) in samples of MS and control brains. The results of these studies showed that TCR V gene usage in MS brains may be restricted and in particular that V beta genes may be preferentially rearranged in certain HLA haplotypes associated with susceptibility to MS. In view of the recent evidence that T lymphocytes bearing the gamma delta chains may have autoreactive potential, we have assessed whether or not such TCR-bearing lymphocytes were also present in chronic MS lesions. TCR V gamma and V delta were analysed by the PCR method using a panel of V gamma and V delta primers paired with C gamma or C delta primers in 12 MS brains, as well as in brain samples of ten normal post-mortem cases and three neurological controls. TCR V gamma-C gamma and V delta-C delta rearrangements were confirmed using Southern blotting and hybridisation of the PCR products with specific C gamma and C delta probes. Only one to four rearranged TCR V gamma and V delta transcripts were detected in each of the 23 brain samples obtained from 12 MS patients, with the majority of gamma delta T cells expressing the V gamma 2 and V delta 2 chains. In marked contrast, V gamma and V delta transcripts could only be found in one of the ten non-neurological control brains analysed. To assess the clonality of V gamma 2 and V delta 2 T cell receptor chains in the brain samples of MS patients, we have sequenced the junctional regions of the TCR V gamma-N-J gamma-C gamma and V delta-N-D delta-N-J delta-C delta segments amplified from brain tissues, CSF and spleens of two MS patients and from the spleen of two control subjects. The sequence analysis obtained so far shows no compelling evidence of an MS specific expansion of one or more clones expressing particular types of gamma delta T cell receptors. In contrast, a clonal expansion of a different population of TCR gamma delta-bearing T cells was found in the spleen of both an MS patient and one of the control individuals.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1993
- Full Text
- View/download PDF
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