Abstract
'Omic'-driven research is exploratory in nature, and seeks to interrogate the entire molecular landscape, with the idea that key pathways or nodes that are aberrant in a disease could be uncovered through a brute-force scan. To date, comprehensive profiling using multiple omics platforms has yielded novel insights on a wide spectrum of diseases, as discussed elsewhere [1]. We recently applied a couple of proteomic and metabolomic approaches to study SLE. In particular, we used planar arrays to uncover novel autoantibodies in SLE, as well as novel serum or urine markers of disease. For the latter, we used planar arrays precoated with antibodies to 274 potential biomarker proteins to interrogate the blood and urine of SLE patients. Thirty of the molecules that were upregulated in SLE sera or urine on these arrays were subsequently validated using independent patient cohorts and orthogonal platforms. In addition to confirming several previously reported increases (including increased serum leptin, osteopontin, OPG, TGF, TNFR-II, and VCAM-1 in SLE), this new study also uncovered several additional proteins to be elevated in SLE. One example of the novel serum markers being pursued is sTREM-1. sTREM-1 is elevated in the serum of patients with lupus nephritis and within their kidneys. We have also verified that Trem-1 becomes upregulated in mice subjected to anti-GBM nephritis. This molecule may not only be a marker of disease, it may also constitute a novel therapeutic target because Trem-1 blockade curtails nephritis in the anti-GBM experimental nephritis model. Ongoing studies will test the therapeutic potential of this target in spontaneous lupus nephritis. Additional markers uncovered using the arrays will also be discussed. Omics-based exploratory scans empower us to discern molecules that are differentially expressed in SLE. The challenge ahead is to carefully validate new candidates in order to identify those with the best biomarker or therapeutic potential in SLE.
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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