Abstract
Systemic lupus erythematosus is a systemic inflammatory disease characterized by anti-DNA production in association with immune complex deposition. These complexes can deposit in the tissue to incite inflammation as well as stimulate cytokine production by plasmacytoid dendritic cells. While the properties of anti-DNA antibodies have been extensively characterized, little is known about the nature of the DNA in the immune complexes although its origin is generally considered to be cell death. Among sources of extracellular DNA, microparticles (MPs) are small membrane-bound vesicles released from activated and dying cells by a blebbing process. As shown by flow cytometry, these particles display DNA as well as other nuclear molecules in an antigenically accessible form as indicated by the binding of monoclonal anti-DNA antibodies as well as plasma from patients with lupus. Furthermore, plasma from patients with lupus contains increased number of particles with bound IgG, suggesting that MPs can form immune complexes found in lupus. To assess whether MPs play a similar role in murine lupus, we used flow cytometry to measure the presence of MPs with bound IgG in the blood of MRL-lpr/lpr and NZB/W mice; in addition, we tested the binding of plasma of these mice to MPs from apoptotic cells. The results of these studies showed important differences in the serological findings of the two strains as reflected by the much higher numbers of MPs with bound IgG in the blood of MRL-lpr/lpr compared with NZB/W mice. These studies also showed that antibodies from MRL-lpr/lpr mice bound much better to MPs from apoptotic cells than those from NZB/W mice. Since particles in NZB/W blood bound to monoclonal anti-nuclear antibodies as well as MRL-lpr/lpr plasma, these findings indicate antigenic activity despite the lack of particle IgG complexes in NZB/W blood. Together, these studies indicate important differences in the serological features of the two strains as reflected by the capacity of antibodies to bind to MPs. These differences may impact on the process of immune complex formation and its consequences as well as the respective role of anti-DNA and other autoantibodies in nephritis in NZB/W mice.
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
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