Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the formation of autoantibodies, immune complex deposition, elevated production of type I interferons (IFNs), and inflammatory-mediated multi-organ damage. Lupus nephritis (LN) flares contribute to high mortality and morbidity among patients. Activation of endosomal toll-like receptor (TLR) 7 is an important trigger of LN activity. Stimulation of TLR7 leads to type I interferon (IFN) production and nuclear factor kappaB (NFkB) activation. Type I IFNs are important for TLR7-mediated immunoproliferation, but their role in TLR7-mediated nephritis has not been examined. This study explores the novel hypothesis that TLR7 promotion of lupus nephritis is independent of type I IFNs.
Methods: To address this hypothesis, we use the lupus prone NZM 2328 and iNZM (NZM2328 lacking a functional type I IFN receptor) murine models. In order to induce LN flares, we administered 100μg of R848 (TLR 7 agonist) epicutaneously to the right ear or intraperitoneally (IP) to 10-week old female NZM2328 and iNZM mice thrice weekly. Serum was collected from mice every 2 weeks and urine collected every week. Mice were harvested at 14 days or at LN onset. Double stranded DNA antibodies were quantified via ELISA. Immunofluorescence for C3 and IgG was performed on kidney tissue to examine the extent of immune complex deposition. Flow cytometry was used to characterize the immune cell populations in the kidney for both strains. Real-time qPCR was performed to examine gene expression in the kidney following R848 treatment.
Results: Lymphoproliferative response to R848 was absent in iNZM mice, consistent with previous reports. Notably, both NZM2328 and iNZM mice exhibit a decline in survival after 3 to 4 weeks of R848 treatment. This decline was significantly more robust with epicutaneous vs. IP injection of R848. Both NZM and iNZM mice demonstrated equivalent acceleration of lupus characteristics including: rise in dsDNA antibodies, increased kidney immune complex deposition, and development of proteinuria. They also demonstrated infiltration of the kidney by macrophages and dendritic cells 2 weeks into treatment. Transcriptional changes within the kidney identified upregulation of inflammasome-associated genes as a shared response in both NZM2328 and iNZM mice after R848 treatment.
Conclusion: The development of TLR7-mediated lupus nephritis flares occurs independent of type I IFN signaling. Further investigation into the role of the inflammasome in mediating TLR7-driven lupus is key to development of novel therapies which may prevent lupus nephritis flare induction.
To cite this abstract in AMA style:Wolf S, Reed TJ, Jacob CO, Kahlenberg JM. TLR-7-Mediated Lupus Nephritis Flares Are Independent of Type I Interferon Signaling [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/tlr-7-mediated-lupus-nephritis-flares-are-independent-of-type-i-interferon-signaling/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tlr-7-mediated-lupus-nephritis-flares-are-independent-of-type-i-interferon-signaling/