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1.  Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study 
Annals of the rheumatic diseases  2012;72(4):10.1136/annrheumdis-2012-201888.
Introduction
A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry.
Methods
4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci.
Results
Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 pMH=1.94×10−4, OR 1.19; rs4958881 pMH=3.26×10−5, OR 1.19; rs3792783 pMH=2.16×10−4, OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets.
Conclusions
These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor.
doi:10.1136/annrheumdis-2012-201888
PMCID: PMC3887516  PMID: 22896740
2.  A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility 
Introduction
A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.
Methods
Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays.
Results
We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.
Conclusion
Our results suggest a role of PPARG gene in the development of SSc.
doi:10.1186/ar4432
PMCID: PMC3978735  PMID: 24401602
3.  Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up 
Human Molecular Genetics  2012;21(12):2825-2835.
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.
doi:10.1093/hmg/dds099
PMCID: PMC3368627  PMID: 22407130
4.  In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells 
PLoS ONE  2013;8(2):e57729.
Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells. The role played by autoantibodies directed against beta cells antigens in the pathogenesis of the disease is still unclear. Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet. To clarify these issues, we screened a random peptide library with sera obtained from 58 patients with recent onset type 1 diabetes, before insulin therapy. We identified an immunodominant peptide recognized by the majority of individual patients’sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis. Antibodies against the peptide affinity-purified from patients’ sera, recognized the viral protein and autoantigens; moreover, such antibodies induced apoptosis of the beta cells upon binding the L-type calcium channels expressed on the beta cell surface, suggesting a calcium dependent mechanism. Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.
doi:10.1371/journal.pone.0057729
PMCID: PMC3585221  PMID: 23469060
5.  A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations 
Human Molecular Genetics  2011;21(4):926-933.
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 [PMH= 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 (PMH= 4.84 × 10−3 OR = 1.12). The second follow-up phase confirmed this finding (Pχ2 = 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 (PMH= 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.
doi:10.1093/hmg/ddr522
PMCID: PMC3298110  PMID: 22076442
6.  The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis 
PLoS ONE  2013;8(1):e54419.
Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P  = 1.34×10−8, OR  = 1.22, CI 95%  = 1.14–1.30; rs2004640: P  = 4.60×10−7, OR  = 0.84, CI 95%  = 0.78–0.90; rs10488631: P  = 7.53×10−20, OR  = 1.63, CI 95%  = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P  = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P  = 9.04×10−22, OR  = 1.75, CI 95%  = 1.56–1.97) better explained the observed association (likelihood P-value  = 1.48×10−4), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.
doi:10.1371/journal.pone.0054419
PMCID: PMC3553151  PMID: 23372721
7.  KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor 
Arthritis Research & Therapy  2012;14(6):R273.
Introduction
Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort.
Methods
The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay.
Results
Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients.
Conclusions
Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.
doi:10.1186/ar4124
PMCID: PMC3674598  PMID: 23270786
8.  Analysis of the association between CD40 and CD40 ligand polymorphisms and systemic sclerosis 
Arthritis Research & Therapy  2012;14(3):R154.
Introduction
The aim of the present study was to investigate the possible role of CD40 and CD40 ligand (CD40LG) genes in the susceptibility and phenotype expression of systemic sclerosis (SSc).
Methods
In total, 2,670 SSc patients and 3,245 healthy individuals from four European populations (Spain, Germany, The Netherlands, and Italy) were included in the study. Five single-nucleotide polymorphisms (SNPs) of CD40 (rs1883832, rs4810485, rs1535045) and CD40LG (rs3092952, rs3092920) were genotyped by using a predesigned TaqMan allele-discrimination assay technology. Meta-analysis was assessed to determine whether an association exists between the genetic variants and SSc or its main clinical subtypes.
Results
No evidence of association between CD40 and CD40LG genes variants and susceptibility to SSc was observed. Similarly, no significant statistical differences were observed when SSc patients were stratified by the clinical subtypes, the serologic features, and pulmonary fibrosis.
Conclusions
Our results do not suggest an important role of CD40 and CD40LG gene polymorphisms in the susceptibility to or clinical expression of SSc.
doi:10.1186/ar3890
PMCID: PMC3446540  PMID: 22731751
9.  A multicenter study confirms CD226 gene association with systemic sclerosis-related pulmonary fibrosis 
Introduction
CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population.
Methods
A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays.
Results
Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)).
Conclusion
Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis.
doi:10.1186/ar3809
PMCID: PMC3446459  PMID: 22531499
10.  Gene expression profiling in circulating endothelial cells from systemic sclerosis patients shows an altered control of apoptosis and angiogenesis that is modified by iloprost infusion 
Arthritis Research & Therapy  2010;12(4):R131.
Introduction
Circulating endothelial cells are increased in patients affected by systemic sclerosis (SSc) and their number strongly correlates with vascular damage. The effects of iloprost in systemic sclerosis are only partially known. We aimed at studying the gene expression profile of circulating endothelial cells and the effects of iloprost infusion and gene expression in patients with systemic sclerosis.
Methods
We enrolled 50 patients affected by systemic sclerosis, 37 patients without and 13 patients with digital ulcers. Blood samples were collected from all patients before and 72 hours after either a single day or five days eight hours iloprost infusion. Blood samples were also collected from 50 sex- and age-matched healthy controls. Circulating endothelial cells and endothelial progenitors cells were detected in the peripheral blood of patients with systemic sclerosis by flow cytometry with a four-colour panel of antibodies. Statistical analysis was performed with the SPSS 16 statistical package.Circulating endothelial cells were then isolated from peripheral blood by immunomagnetic CD45 negative selection for the gene array study.
Results
The number of both circulating endothelial cells and progenitors was significantly higher in patients affected by systemic sclerosis than in controls and among patients in those with digital ulcers than in patients without them. Circulating endothelial cells and progenitors number increased after iloprost infusion. Gene array analysis of endothelial cells showed a different transcriptional profile in patients compared to controls. Indeed, patients displayed an altered expression of genes involved in the control of apoptosis and angiogenesis. Iloprost infusion had a profound impact on endothelial cells gene expression since the treatment was able to modulate a very high number of transcripts.
Conclusions
We report here that circulating endothelial cells in patients with systemic sclerosis show an altered expression of genes involved in the control of apoptosis and angiogenesis. Moreover we describe that iloprost infusion has a strong effect on endothelial cells and progenitors since it is able to modulate both their number and their gene expression profile.
doi:10.1186/ar3069
PMCID: PMC2945021  PMID: 20609215
11.  Endothelial Cells' Activation and Apoptosis Induced by a Subset of Antibodies against Human Cytomegalovirus: Relevance to the Pathogenesis of Atherosclerosis 
PLoS ONE  2007;2(5):e473.
Background
Human cytomegalovirus (hCMV) is involved in the pathogenesis of atherosclerosis. We have previously shown in patients with atherosclerosis that antibodies directed against the hCMV-derived proteins US28 and UL122 are able to induce endothelial cell damage and apoptosis of non-stressed endothelial cells through cross-rection with normally expressed surface molecules. Our aim was to dissect the molecular basis of such interaction and to investigate mechanisms linking innate immunity to atherosclerosis.
Methodology/Principal Findings
We analysed the gene expression profiles in endothelial cells stimulated with antibodies affinity-purified against either the UL122 or the US28 peptides using the microarray technology. Microarray results were validated by quantitative PCR and by detection of proteins in the medium. Supernatant of endothelial cells incubated with antibodies was analysed also for the presence of Heat Shock Protein (HSP)60 and was used to assess stimulation of Toll-Like Receptor-4 (TLR4). Antibodies against UL122 and US28 induced the expression of genes encoding for adhesion molecules, chemokines, growth factors and molecules involved in the apoptotis process together with other genes known to be involved in the initiation and progression of the atherosclerotic process. HSP60 was released in the medium of cells incubated with anti-US28 antibodies and was able to engage TLR4.
Conclusions/Significance
Antibodies directed against hCMV modulate the expression of genes coding for molecules involved in activation and apoptosis of endothelial cells, processes known to play a pivotal role in the pathogenesis of atherosclerosis. Moreover, endothelial cells exposed to such antibodies express HSP60 on the cell surface and release HSP60 in the medium able to activate TLR4. These data confirm that antibodies directed against hCMV-derived proteins US28 and UL122 purified from patients with coronary artery disease induce endothelial cell damage and support the hypothesis that hCMV infection may play a crucial role in mediating the atherosclerotic process.
doi:10.1371/journal.pone.0000473
PMCID: PMC1868596  PMID: 17534423
12.  In Celiac Disease, a Subset of Autoantibodies against Transglutaminase Binds Toll-Like Receptor 4 and Induces Activation of Monocytes 
PLoS Medicine  2006;3(9):e358.
Background
Celiac disease is a small intestine inflammatory disorder with multiple organ involvement, sustained by an inappropriate immune response to dietary gluten. Anti-transglutaminase antibodies are a typical serological marker in patients with active disease, and may disappear during a gluten-free diet treatment. Involvement of infectious agents and innate immunity has been suggested but never proven. Molecular mimicry is one of the mechanisms that links infection and autoimmunity.
Methods and Findings
In our attempt to clarify the pathogenesis of celiac disease, we screened a random peptide library with pooled sera of patients affected by active disease after a pre-screening with the sera of the same patients on a gluten-free diet. We identified a peptide recognized by serum immunoglobulins of patients with active disease, but not by those of patients on a gluten-free diet. This peptide shares homology with the rotavirus major neutralizing protein VP-7 and with the self-antigens tissue transglutaminase, human heat shock protein 60, desmoglein 1, and Toll-like receptor 4. We show that antibodies against the peptide affinity-purified from the sera of patients with active disease recognize the viral product and self-antigens in ELISA and Western blot. These antibodies were able to induce increased epithelial cell permeability evaluated by transepithelial flux of [3H] mannitol in the T84 human intestinal epithelial cell line. Finally, the purified antibodies induced monocyte activation upon binding Toll-like receptor 4, evaluated both by surface expression of activation markers and by production of pro-inflammatory cytokines.
Conclusions
Our findings show that in active celiac disease, a subset of anti-transglutaminase IgA antibodies recognize the viral protein VP-7, suggesting a possible involvement of rotavirus infection in the pathogenesis of the disease, through a mechanism of molecular mimicry. Moreover, such antibodies recognize self-antigens and are functionally active, able to increase intestinal permeability and induce monocyte activation. We therefore provide evidence for the involvement of innate immunity in the pathogenesis of celiac disease through a previously unknown mechanism of engagement of Toll-like receptor 4.
A subset of anti-transglutaminase IgA antibodies recognize the viral protein VP-7, suggesting a possible involvement of rotavirus infection in the pathogenesis of celiac disease through a mechanism of molecular mimicry.
Editors' Summary
Background.
Celiac disease is an autoimmune, digestive disorder in which the small intestine (the part of the gut that absorbs nutrients from food) is damaged. In autoimmune diseases, the immune system, which normally provides protection against foreign invaders, attacks a person's own tissues. In celiac disease, this attack is triggered by eating food containing gluten, a mixture of proteins found in wheat, barley, and rye. To avoid malnutrition, people with celiac disease—about one in 100 people of north European descent—must follow a strict, lifelong gluten-free diet, one that avoids baked products, wheat, pasta, and many other foods. If they fail to do this, their immune system may attack not only their gut but also their brain, skin, joints, and other tissues, in part through the production of antibodies (autoantibodies) that recognize a protein (self-antigen) called tissue transglutaminase. Celiac disease is diagnosed also by looking for these autoantibodies in patients' blood when they are on a gluten-containing diet; they rapidly disappear when a gluten-free diet is adopted.
Why Was This Study Done?
A gluten-free diet keeps celiac disease in check but does not cure it and is very difficult to follow. Even the minute amounts of gluten found in medicines, for example, can trigger the production of autoantibodies and active disease. But developing a cure is impossible without a better understanding of how celiac disease develops. Why, for example, do celiac disease patients make anti-transglutaminase antibodies? Were they made initially to ward off an infectious agent but unfortunately also recognized transglutaminase? In this study, the researchers asked whether “molecular mimicry”—cross-reactivity between self-molecules and foreign molecules on bacteria or viruses (pathogens)—might initiate celiac disease. They also asked whether innate immunity (the part of the immune system that responds quickly to general features on pathogens) as well as adaptive immunity (the production of antibodies and immune cells that recognize specific features on pathogens) is involved in the development of celiac disease.
What Did the Researchers Do and Find?
The researchers purified antibodies from blood provided by patients with celiac disease when they were eating food containing gluten and when they were on a gluten-free diet. They used these to identify celiac peptide, a synthetic protein fragment that was recognized only by the antibodies made by patients with active disease. By searching a database of pathogen proteins, the researchers discovered that rotavirus protein VP-7 contains a very similar peptide; a search of a database of human proteins indicated that celiac peptide also resembles peptides found in tissue transglutaminase, Toll-like receptor 4 (TLR4; a protein involved in the innate immune response), and several other self-antigens. Patient antibodies purified through their ability to bind to celiac peptide also bound to VP-7 and to these self-antigens, and only patients with active disease made these antibodies. The researchers also investigated whether these anti-celiac peptide antibodies might affect the gut or the innate immune system. The antibodies increased the permeability of a layer of gut cells growing in a laboratory dish by interacting with the self-antigen desmoglein 1. This protein helps to make impermeable seals between the cells that line the gut so that food antigens in the gut cannot seep out into the tissues where the immune system might detect them. In addition, by binding to TLR4, the anti-celiac peptide antibodies activated monocytes—cells that function in both the innate and adaptive immune response.
What Do These Findings Mean?
The finding that some anti-transglutaminase antibodies recognize the viral protein VP-7 could mean that rotavirus infection, which causes gastroenteritis, helps to initiate celiac disease in susceptible individuals through molecular mimicry. Furthermore, the identification of other self-antigens that contain peptides recognized by the antibodies made during active disease starts to explain why damage occurs outside the gut in people with celiac disease. The ability of these antibodies to recognize all these peptides could be coincidental, but the observation that the antibodies have relevant functional effects—the ability to increase intestinal permeability and to activate monocytes—makes this less likely. More research is needed to reveal exactly how infections and the innate immune response affect the development of celiac disease, but every piece of new information brings the possibility of a cure a little closer.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030358.
US National Institute of Diabetes and Digestive and Kidney Diseases, information for patients on celiac disease
MedlinePlus encyclopedia entries on celiac disease and on autoimmunity
Wikipedia pages on celiac disease and on autoimmunity (note that Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030358
PMCID: PMC1569884  PMID: 16984219
13.  Antibodies against Human Cytomegalovirus in the Pathogenesis of Systemic Sclerosis: A Gene Array Approach 
PLoS Medicine  2005;3(1):e2.
Background
Systemic sclerosis is an autoimmune disease characterized by immunological abnormalities, vascular damage, and fibroblast proliferation. We have previously shown that a molecular mimicry mechanism links antibodies against the human-cytomegalovirus-derived protein UL94 to the pathogenesis of systemic sclerosis. The UL94 epitope shows homology with NAG-2, a surface molecule highly expressed on endothelial cells. Anti-UL94 peptide antibodies purified from patients' sera induce apoptosis of endothelial cells upon engagement of the NAG-2–integrin complex.
Methods and Findings
We show here that NAG-2 is expressed on dermal fibroblasts and that anti-UL94 antibodies bind to fibroblasts. We have used the gene array strategy (Affimetrix oligonucleotide microarrays) to analyze the transcriptional profile in response to a 4-h and an 8-h treatment with antibodies against the UL94 peptide in endothelial cells and dermal fibroblasts. Exposure of endothelial cells to anti-UL94 antibodies had a profound impact on gene expression, resulting in the upregulation of 1,645 transcripts. Several gene clusters were upregulated including genes encoding adhesion molecules, chemokines, colony-stimulating factors (CSFs), growth factors, and molecules involved in apoptosis. Following antibody stimulation, dermal fibroblasts showed an upregulation of 989 transcripts and acquired a “scleroderma-like” phenotype. Indeed, genes involved in extracellular matrix deposition, growth factors, chemokines, and cytokines were upregulated. We confirmed the microarray results by real-time quantitative polymerase chain reaction and by measuring some of the corresponding proteins with ELISA and Western blotting.
Conclusion
Our results show that anti-human-cytomegalovirus antibodies may be linked to the pathogenesis of systemic sclerosis not only by inducing endothelial cell activation and apoptosis but also by causing activation of fibroblasts, one of the hallmarks of the disease.
Anti-human-cytomegalovirus antibodies may be linked to the pathogenesis of systemic sclerosis by inducing endothelial cell activation and apoptosis, and fibroblast activation and proliferation.
doi:10.1371/journal.pmed.0030002
PMCID: PMC1298939  PMID: 16318412

Results 1-13 (13)