Year-end Sale % OFF 
Abstract
Systemic lupus erythematosus is a genetically complex autoimmune disease. A large body of evidence suggests an important role for epigenetic variation, particularly DNA methylation changes, in the pathogenesis of lupus. We recently performed a comprehensive evaluation of the DNA methylome in lupus T cells and identified a number of differentially methylated loci that can contribute to the pathogenesis of the disease. By analyzing the interaction between genetic risk, T-cell DNA demethylation, and the SLEDAI scores, we demonstrated that the (genetic risk)/(T-cell DNA methylation) ratio increased directly with disease activity in lupus patients. Furthermore, men with lupus require a higher genetic risk and/or lower T-cell DNA methylation levels to achieve a lupus flare of equal severity to women, suggesting genetic-epigenetic interaction in explaining the sex bias in lupus. We have also established the genetic region containing methyl-CpG-binding protein 2 (MECP2) as a lupus susceptibility locus. MeCp-2 is a key transcription factor critically involved in regulating the expression of methylation-sensitive genes, and directly recruits DNA methyltransferase 1 (DNMT1). Indeed, recent data from our group demonstrate that the lupus-associated variants in MECP2 induce DNA methylation changes in key inflammatory genes. Our data suggest that efforts to study genetic-epigenetic interactions in lupus will further our understanding of the disease pathogenesis and might help to explain, at least in part, the missing heritability in lupus.
Highlights
Antinuclear antibodies can be detected in up to 25% of the population; only 5 to 7% are afflicted with an autoimmune disease
We have previously shown that B6 mice with an introgressed homozygous NZB chromosome 1 (c1) interval (70 to 100 cM) develop high titers of antinuclear antibodies and severe glomerulonephritis
Using subcongenic mice with shorter c1 intervals, we found that expansion of TH1, TH17, and TFH cells was closely associated with the severity of glomerulonephritis
Summary
Hyperactivity of the type I interferon (IFN) pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE). ILT3 expression levels on PDCs and MDCs from 18 patients and 10 controls were studied by flow cytometry. Results: The rs11540761 SNP in the extracellular region was associated with decreased cell surface expression of ILT3 on circulating MDCs and to a lesser extent PDCs in SLE patients. The cytoplasmically located rs1048801 SNP was not associated with a change in DC expression of ILT3. Both SNPs were significantly and independently associated with increased levels of serum type I IFN activity in SLE patients. A64 Nonlymphoma hematological malignancies in systemic lupus erythematosus M Lu1*, R Ramsey-Goldman, S Bernatsky, M Petri, S Manzi, MB Urowitz, D Gladman, PR Fortin, E Ginzler, E Yelin, S-C Bae, DJ Wallace, S Jacobsen, MA Dooley, CA Peschken, GS Alarcón, O Nived, L Gottesman, L Criswell, G Sturfelt, L Dreyer, JL Lee, AE Clarke1 1Division of Clinical Epidemiology, McGill University Health Centre, Montreal, QC, Canada; 2Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3Johns Hopkins University School of Medicine, Baltimore, MD, USA; 4West Penn Allegheny Health System, Pittsburgh, PA, USA; 5Toronto Western Hospital, Toronto, ON, Canada; 6Division of Rheumatology, Université de Laval, QC, Canada; 7State University of New York - Downstate Medical Center, Brooklyn, NY, USA; 8Division of Rheumatology, University of California San Francisco, San Francisco, CA, USA; 9The Hospital for Rheumatic Diseases, Hanyang University, Seoul, Korea; 10Cedars-Sinai Medical Center/David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 11Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 12University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 13University of Manitoba, Winnipeg, MB, Canada; 14The University of Alabama, Birmingham, AL, USA; 15Lund University Hospital, Lund, Sweden; 16Rigshospitalet and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark Arthritis Research & Therapy 2012, 14(Suppl 3):A64
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
