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Find video protocols related to scientific articles indexed in Pubmed.
Major Histocompatibility Complex Class I and Class II Alleles May Confer Susceptibility to or Protection Against Morphea: Findings From the Morphea in Adults and Children Cohort.
PUBLISHED: 07-31-2014
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To determine the HLA class I and class II alleles of the human major histocompatibility complex showing an association with morphea (localized scleroderma) in the Morphea in Adults and Children (MAC) cohort, using a nested case-control association study.
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Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis.
Am. J. Hum. Genet.
PUBLISHED: 01-07-2014
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In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
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Morphea in adults and children cohort III: nested case-control study--the clinical significance of autoantibodies in morphea.
JAMA Dermatol
PUBLISHED: 08-09-2013
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Small studies have implicated the association of specific autoantibodies with morphea subtype or severity, but no large-scale studies have been conducted. This prospective case-control study confirmed the presence of antinuclear antibodies (ANAs) and other autoantibodies in morphea but found they are of limited significance.
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A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci.
Hum. Mol. Genet.
PUBLISHED: 06-04-2013
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Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10(-11), OR = 1.20) and JAZF1 (P = 1.11 × 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.
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Can serum surfactant protein D or CC-chemokine ligand 18 predict outcome of interstitial lung disease in patients with early systemic sclerosis?
J. Rheumatol.
PUBLISHED: 04-15-2013
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To examine the predictive significance of 2 pneumoproteins, surfactant protein D (SP-D) and CC-chemokine ligand 18 (CCL18), for the course of systemic sclerosis (SSc)-related interstitial lung disease.
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New insight on the Xq28 association with systemic sclerosis.
Ann. Rheum. Dis.
PUBLISHED: 02-26-2013
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To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2).
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Right bundle branch block: a predictor of mortality in early systemic sclerosis.
PLoS ONE
PUBLISHED: 01-01-2013
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To evaluate the prognostic significance of baseline electrocardiogram (ECG) abnormalities in a multiethnic cohort of patients with early systemic sclerosis (SSc) and to determine the serological, clinical, and echocardiogram correlates of ECG findings.
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A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations.
Hum. Mol. Genet.
PUBLISHED: 11-10-2011
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A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(?2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
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Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis.
Ann. Rheum. Dis.
PUBLISHED: 09-16-2011
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Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features.
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Decreased catalytic function with altered sumoylation of DNA topoisomerase I in the nuclei of scleroderma fibroblasts.
Arthritis Res. Ther.
PUBLISHED: 06-18-2011
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Sumoylation is involved in nucleolus-nucleoplasm transport of DNA topoisomerase I (topo I), which may associate with changes of cellular and topo I functions. Skin fibroblasts of patients with systemic sclerosis (SSc) exhibit profibrotic cellular changes. The aims of this study were to examine the catalytic function and sumoylation of topo I in the nuclei of SSc fibroblasts, a major cell type involved in the fibrotic process.
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Cigarette smoking is not a risk factor for systemic sclerosis.
Arthritis Rheum.
PUBLISHED: 06-08-2011
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To investigate the association of cigarette smoking with susceptibility to systemic sclerosis (SSc) in a large, well-defined patient population.
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DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans.
J. Am. Soc. Nephrol.
PUBLISHED: 05-26-2011
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Anti-neutrophil cytoplasmic autoantibody (ANCA) disease rarely occurs in African Americans and risk factors for the disease in this population are unknown. Here, we genotyped MHC class II alleles and found that, among African Americans, those with proteinase 3-ANCA (PR3-ANCA) had 73.3-fold higher odds of having HLA-DRB1*15 alleles than community-based controls (OR 73.3; 95% CI 9.1 to 591). In addition, a disproportionate number of African American patients carried the DRB1*1501 allelic variant of Caucasian descent rather than the DRB1*1503 allelic variant of African descent. Among Caucasians, those with PR3-ANCA had 2.2-fold higher odds of carrying DRB1*1501 than controls (OR 2.2; 95% CI 1.2 to 4.0). A validation study supported by the Vasculitis Clinical Research Consortium confirmed the strong association between the DRB1*15 allele and PR3-ANCA disease, among African Americans. Furthermore, we found that DRB1*1501 protein binds with high affinity to amino acid sequences of sense-PR3, purportedly an antigenic epitope, and to the amino acid sequence complementary to this epitope in vitro. Peptides of sense-PR3 and complementary-PR3 also bound to TNF-?-induced surface expression of DRB1*1501 on peripheral neutrophils. Taken together, these data suggest HLA-DRB1*15 alleles contribute to the pathogenesis of PR3-ANCA disease.
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Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.
PLoS Genet.
PUBLISHED: 05-25-2011
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The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P?=?2.32×10(-12), OR?=?0.75). Also, rs12540874 in GRB10 gene (P?=?1.27 × 10(-6), OR?=?1.15) and rs11047102 in SOX5 gene (P?=?1.39×10(-7), OR?=?1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P?=?1.79×10(-61), OR?=?2.48), in the HLA-DPA1/B1 loci with ATA (P?=?4.57×10(-76), OR?=?8.84), and in NOTCH4 with ACA P?=?8.84×10(-21), OR?=?0.55) and ATA (P?=?1.14×10(-8), OR?=?0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
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Anti-fibrillarin antibody in African American patients with systemic sclerosis: immunogenetics, clinical features, and survival analysis.
J. Rheumatol.
PUBLISHED: 05-15-2011
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Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc.
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Association of a functional IRF7 variant with systemic lupus erythematosus.
Arthritis Rheum.
PUBLISHED: 03-02-2011
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A previous genome-wide association study conducted in a population of European ancestry identified rs4963128, a KIAA1542 single-nucleotide polymorphism (SNP) 23 kb telomeric to IRF7 (the gene for interferon regulatory factor 7 [IRF-7]), to be strongly associated with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether genetic polymorphism within IRF7 is a risk factor for the development of SLE.
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Association study of ITGAM, ITGAX, and CD58 autoimmune risk loci in systemic sclerosis: results from 2 large European Caucasian cohorts.
J. Rheumatol.
PUBLISHED: 03-01-2011
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Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations.
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HLA-DRB1*0407 and *1304 are risk factors for scleroderma renal crisis.
Arthritis Rheum.
PUBLISHED: 02-01-2011
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To examine the predictive role of HLA genetic markers in scleroderma renal crisis (SRC), beyond the known clinical correlates, in a large population of patients with systemic sclerosis (SSc).
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Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts.
Arthritis Res. Ther.
PUBLISHED: 01-11-2011
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Increased levels of genes in the type I interferon (IFN) pathway have been observed in patients with systemic sclerosis (SSc), or scleroderma. How type I IFN regulates the dermal fibroblast and its participation in the development of dermal fibrosis is not known. We hypothesized that one mechanism by which type I IFN may contribute to dermal fibrosis is through upregulation of specific Toll-like receptors (TLRs) on dermal fibroblasts. Therefore, we investigated the regulation of TLR expression on dermal fibroblasts by IFN.
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Determinants of work disability in patients with systemic sclerosis: a longitudinal study of the GENISOS cohort.
Semin. Arthritis Rheum.
PUBLISHED: 01-01-2011
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To determine the prevalence, correlates, and predictors of work disability (WD) in the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS). We hypothesized that WD in systemic sclerosis (SSc) is a function of demographic, clinical, and psychosocial factors.
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Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of toll-like receptor 4 and 5.
J. Rheumatol.
PUBLISHED: 10-15-2010
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to identify differentially expressed genes in peripheral blood cells (PBC) of patients with ankylosing spondylitis (AS) relative to healthy controls and controls with systemic inflammation.
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Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort.
Arthritis Res. Ther.
PUBLISHED: 05-07-2010
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The objective of the present study was to examine the association of baseline demographic and clinical characteristics with sequentially obtained measurements of forced vital capacity (FVC), expressed as a percentage of the predicted value, and to identify predictors of the decline rate in FVC over time in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS).
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Separate influences of birth order and gravidity/parity on the development of systemic sclerosis.
Arthritis Care Res (Hoboken)
PUBLISHED: 04-15-2010
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Birth order has been valuable in revealing the role of environmental influences on the risk of developing certain diseases such as allergy and atopy. In addition, pregnancy has profound effects on the immune system such as short-term effects that permit fetal survival as well as longer-term effects that could influence late-onset diseases. In order to better evaluate these influences, we studied the association of birth order and gravidity/parity as risk factors for systemic sclerosis (SSc; scleroderma).
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Attenuation of fibrosis in vitro and in vivo with SPARC siRNA.
Arthritis Res. Ther.
PUBLISHED: 02-12-2010
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SPARC is a matricellular protein, which, along with other extracellular matrix components including collagens, is commonly over-expressed in fibrotic diseases. The purpose of this study was to examine whether inhibition of SPARC can regulate collagen expression in vitro and in vivo, and subsequently attenuate fibrotic stimulation by bleomycin in mouse skin and lungs.
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Systemic sclerosis and lupus: points in an interferon-mediated continuum.
Arthritis Rheum.
PUBLISHED: 01-30-2010
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To investigate peripheral blood (PB) cell transcript profiles of systemic sclerosis (SSc) and its subtypes in direct comparison with systemic lupus erythematosus (SLE).
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Autoimmune diseases and autoantibodies in the first degree relatives of patients with systemic sclerosis.
J. Autoimmun.
PUBLISHED: 01-25-2010
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To determine aggregation of autoimmune diseases in the first degree relatives (FDR) of patients with systemic sclerosis (SSc) and to investigate frequencies of antinuclear antibodies (ANA) and other autoantibodies in the FDRs and spouses of patients with SSc.
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Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.
Nat. Genet.
PUBLISHED: 01-04-2010
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Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.
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Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines.
Arthritis Rheum.
PUBLISHED: 12-02-2009
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Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility.
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Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis.
Hum. Mol. Genet.
PUBLISHED: 11-18-2009
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We describe a novel approach to genetic association analyses with proteins sub-divided into biologically relevant smaller sequence features (SFs), and their variant types (VTs). SFVT analyses are particularly informative for study of highly polymorphic proteins such as the human leukocyte antigen (HLA), given the nature of its genetic variation: the high level of polymorphism, the pattern of amino acid variability, and that most HLA variation occurs at functionally important sites, as well as its known role in organ transplant rejection, autoimmune disease development and response to infection. Further, combinations of variable amino acid sites shared by several HLA alleles (shared epitopes) are most likely better descriptors of the actual causative genetic variants. In a cohort of systemic sclerosis patients/controls, SFVT analysis shows that a combination of SFs implicating specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk.
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Association of interleukin 23 receptor polymorphisms with anti-topoisomerase-I positivity and pulmonary hypertension in systemic sclerosis.
J. Rheumatol.
PUBLISHED: 11-16-2009
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IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
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Clinical and genetic factors predictive of mortality in early systemic sclerosis.
Arthritis Rheum.
PUBLISHED: 10-01-2009
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To investigate the clinical and genetic variables at initial presentation that predict survival in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort.
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Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis.
Ann. Rheum. Dis.
PUBLISHED: 09-23-2009
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It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
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Primary biliary cirrhosis (PBC), PBC autoantibodies, and hepatic parameter abnormalities in a large population of systemic sclerosis patients.
J. Rheumatol.
PUBLISHED: 09-01-2009
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To investigate the diagnostic accuracy of antimitochondrial antibodies (AMA), sp100, and gp210 antibodies for primary biliary cirrhosis (PBC) in a large population of patients with systemic sclerosis (SSc); to examine concordance of these antibodies with subsets of SSc. Further, to assess the association of SSc-related antibodies with hepatic parameter abnormalities.
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Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.
Arthritis Rheum.
PUBLISHED: 08-01-2009
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Because studies suggest that ultraviolet (UV) radiation modulates the myositis phenotype and Mi-2 autoantigen expression, we conducted a retrospective investigation to determine whether UV radiation may influence the relative prevalence of dermatomyositis and anti-Mi-2 autoantibodies in the US.
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Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls.
Ann. Rheum. Dis.
PUBLISHED: 07-12-2009
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To determine human leucocyte antigen-class II (HLA-class II) (DRB1, DQB1, DQA1 and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis (SSc)) and its subphenotypes in a large multi-ethnic US cohort by a case-control association study.
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Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations.
J. Autoimmun.
PUBLISHED: 07-07-2009
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Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc.
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Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations.
Arthritis Res. Ther.
PUBLISHED: 06-08-2009
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Systemic sclerosis (SSc) (scleroderma) is a complex autoimmune disease that clinically manifests as progressive fibrosis of the skin and internal organs. Anti-centromere antibodies (ACAs), anti-topoisomerase antibodies (ATAs), and anti-RNA polymerase III antibodies (ARAs) are three mutually exclusive SSc-associated autoantibodies that correlate with distinct clinical subsets characterized by extent of cutaneous involvement and pattern of organ involvement. The current report sought to determine whether plasma cytokine profiles differ in SSc patients grouped according to these SSc-associated autoantibody subsets.
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A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.
Hum. Mol. Genet.
PUBLISHED: 02-28-2009
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A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.
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IRF5 polymorphism predicts prognosis in patients with systemic sclerosis.
Ann. Rheum. Dis.
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The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc.
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Independent replication and meta analysis of association studies establish TNFSF4 as a susceptibility gene preferentially associated with the subset of anticentromere-positive patients with systemic sclerosis.
J. Rheumatol.
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Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk.
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Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up.
Hum. Mol. Genet.
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Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value = 5.04 × 10(-12), odds ratio (OR) = 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10(-7), OR = 1.36) and NFKB1 (P-value = 1.03 × 10(-6), OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.
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Osteopontin in systemic sclerosis and its role in dermal fibrosis.
J. Invest. Dermatol.
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Osteopontin (OPN) is a matricellular protein with proinflammatory and profibrotic properties. Previous reports demonstrate a role for OPN in wound healing and pulmonary fibrosis. Here, we determined whether OPN levels are increased in a large cohort of patients with systemic sclerosis (SSc) and whether OPN contributes to the development of dermal fibrosis. The plasma OPN levels were increased in SSc patients, including patients with limited and diffuse disease, compared with healthy controls. Immunohistology demonstrated OPN on fibroblast-like and inflammatory cells in SSc skin and lesional skin from mice in the bleomycin (bleo)-induced dermal fibrosis model. OPN-deficient (OPN(-/-)) mice developed less dermal fibrosis compared with wild-type (WT) mice in the bleo-induced dermal fibrosis model. Additional in vivo studies have demonstrated that lesional skin from OPN(-/-)mice had fewer Mac-3-positive cells, fewer myofibroblasts, decreased transforming growth factor (TGF)-? and genes in the TGF-? pathway, and decreased numbers of cells expressing phosphorylated SMAD2 (pSMAD) and extracellular signal-regulated kinase. In vitro, OPN(-/-) dermal fibroblasts had decreased migratory capacity but similar phosphorylation of SMAD2 by TGF-?. Finally, TGF-? production by OPN-deficient macrophages was reduced compared with WT. These data demonstrate an important role for OPN in the development of dermal fibrosis and suggest that it may be a new therapeutic target in SSc.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.