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OP0186 Immune Complex Bound U1 and Y1 RNA Correlates with Interferon-Stimulated Gene Expression and Disease Activity: An Observational Study of Sysytemic Lupus Erythematosus Patients
  1. J. Doedens1,
  2. W. Jones2,
  3. K. Hill3,
  4. M. Mason4,
  5. P. Linsley5,
  6. P. Mease6,
  7. M. Dall'Era7,
  8. C. Aranow8,
  9. R. Martin9,
  10. S. Cohen10,
  11. R. Fleischmann10,
  12. A. Kivitz11,
  13. D. Burge1,
  14. D. Chaussabel12,
  15. K. Elkon13,
  16. J. Posada1,14,
  17. C. Gabel1
  1. 1Resolve Therapeutics, Seattle
  2. 2EA Genomics/Q2 Solutions, Durham
  3. 3PlasmaLab International
  4. 4Sage Bionetworks
  5. 5Benaroya Research
  6. 6Swedish Medical Center, Seattle
  7. 7University of California San Francisco, San Francisco
  8. 8Feinstein Institute for Medical Research, Manhasset
  9. 9Michigan State University, East Lansing
  10. 10Metroplex Clinic al Research Center, Dallas
  11. 11Altoona Center for Clnical Research, Duncansville, United States
  12. 12Sidra Medical and Research Center, Doha, Qatar
  13. 13Rheumatology, University of Washington
  14. 14Rheumatology, Resolve Therapeutics, Seattle, United States

Abstract

Background Immune complexes (ICs) containing RNA are thought to play a central role in driving interferon (IFN) production and systemic inflammation in systemic lupus erythematosus (SLE) via activation of intracellular Toll-Like Receptors (TLRs). However, quantitation of IC-bound RNAs in SLE patient plasma has not previously been performed.

Objectives To quantify IC-associated U1 and Y1 RNA and relate the findings to the interferon (IFN) signature and SLE clinical activity.

Methods Medications and SLEDAI measurements were completed on 228 SLE patients. Autoantibodies were quantified by a Bioplex assay. Peripheral blood transcript profiles for 186 selected genes were quantified by a dynamic array QPCR analysis. ICs were isolated from plasma by protein A bead capture and associated RNA quantified by QPCR using primer/probes designed to detect small, noncoding U1 and Y1 RNA transcripts.

Results The autoantibodies anti-SmRNP and anti-Ro60 displayed the strongest associations with IC-bound U1 and Y1 RNA levels, respectively. When patients were grouped into 4 categories based on the presence of ICs containing U1 and/or Y1 RNA, blood gene expression changes in the U1-/ Y1- group were significantly lower than observed in the three groups possessing U1 alone, Y1 alone, or both RNA molecules. Within the U1 RNA-positive groups, the top 10 up-regulated genes were increased 10–48 fold compared to healthy volunteers (associated p values exceeding 10–15) and corresponded to known IFN-inducible transcripts. IC-bound U1 and Y1 RNA levels showed significant correlations with each other and also with disease activity (SLEDAI) (p<0.0003).

Conclusions The enhanced expression of IFN-inducible transcripts in blood from patients possessing IC-bound U1 and/or Y1 RNA lends further support to the hypothesis that these RNA molecules are involved in triggering TLR7 and stimulating interferon production in SLE patients. Therapeutic strategies that seek to reduce the quantities of RNA associated with ICs may be an attractive approach to blocking downstream IFN production and immune system activation.

Disclosure of Interest None declared

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