Session Type: Abstract Submissions (ACR)
Background/Purpose: Heterogeneity of clinical manifestations and pathogenic mechanisms has complicated treatment of SLE patients. The BOLD study allows evaluation of gene expression changes associated with disease flare without the impact of background immunosuppressants which have confounded previous studies.
Objectives: 1. Define immune functions or pathways impacted by disease activity. 2. Evaluate gene expression differences due to variations of cell subsets. 3. Uncover cell specific biological pathways that are associated with lupus disease activity.
Methods: The BOLD study enrolled patients with active disease at the baseline visit (BV) who were withdrawn from background immunosuppressive therapy and given intramuscular steroids to induce improvement (IV), and followed until flare (FV). An interim profiling of gene expression on 15 SLE patients was performed. Cell specific significance analysis of microarrays (csSAM) compares gene expression between two groups, each separately deconvolved to yield cell specific expression. The false discovery rate (FDR) for cell specific differentially expressed genes (DEG) between groups is assessed via permutations. csSAM analysis was performed comparing the BV to IV, IV to FV and BV to FV. Bioinformatics analysis of pathways and gene functions was performed using the sets of DEG.
Results: Correction for basophil frequencies yielded a FDR of 25% and identified 502 DEG comparing BV and IV. Genes overrepresented in signaling pathways associated with SLE included LCK, CD44, CD40LG, SOS1, TNFRSF13C (BLyS receptor), SLAMF1, IRF8, TNFAIP3, TNFRSF4, MIF, FCGR1A and FCGR1B. Comparing IV to FV, (representing a transition from low to high disease state without immune suppression on board), deconvolution on monocyte frequencies identified 68 DEG with an FDR of 25% at the FV. Genes in the p38 MAP Kinase, ERK/MAPK, IFN signaling, and IL-12 pathways were enriched. Comparing BV to FV, (same patients with active disease on and off immune suppressants), deconvolution on basophil frequencies using an FDR of 39% yielded 1421 DEG. Pathways overrepresented included antigen presentation and apoptosis. When assessing function enrichment, “antibody response” was overrepresented by 27 genes (p=2.27E-06) including BTK, CD86, TLR2, TNFRSF13B (TACI), and TNFSF13B (BLYS).
Conclusion: Basophil and monocyte adjusted DEG analysis suggests that pathways associated with SLE signaling, apoptosis, antigen presentation, and antibody response functions are associated with changes in gene expression at transitions between high and low disease activity. These biomarkers could identify therapeutic targets or identify patients who are or are not good candidates for different targeted therapies.
M. G. Dozmorov,
J. D. Wren,
S. T. Sridharan,
J. T. Merrill,
J. A. James,
J. M. Guthridge,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/correction-for-basophil-and-monocyte-frequencies-identifies-specific-gene-expression-differences-associated-with-sle-disease-flare-interim-report-from-the-bold-biomarkers-of-lupus-disease-study/