Background: Systemic Lupus Erythematosus (SLE) is a chronic, multisystem relapsing-remitting autoimmune disease with a prevalence of 1.4-15.13/100,000 adults globally. Drivers of pathogenesis are highly heterogenous, involving dysregulation of both the adaptive and innate arms of the immune system, which can lead to aberrant lymphocyte activation, autoantibody production, immune complex formation, complement activation, inflammation, and organ damage. The ability to accurately model the molecular pathways driving lupus pathogenesis is critical for the development and testing of effective therapeutics. Notably, clinical benefit has been demonstrated in subsets of lupus patients, highlighting the potential value of stratifying patients through identification of disease drivers in distinct patient subsets. Thus, it is critical to appropriately model disease and differentiate disease drivers in relevant preclinical models that can then serve as important tools for dissecting disease-relevant pathways, allowing better understanding of patient subsets and opening the door for new target discovery.

Objectives: 1. To evaluate the potential future translatability of mouse models of lupus to human SLE. 2. To dissect drivers of disease in distinct models that will allow for targeted therapeutics to be evaluated in the pre-clinical space.

Methods: Two mouse models of lupus-like disease were evaluated in these studies: the commonly used NZB/W lupus prone strain and C9orf72-deficient mice developed at Regeneron. C9orf72-deficient mice display a lupus-like phenotype previously described to include elevated autoantibodies and immune-mediated glomerulonephropathy, elevated levels of circulating cytokines, splenomegaly and lymphadenopathy, including expansion of myeloid and plasma cell populations. Profiling of immune populations and serological readouts was performed at regular time intervals using age matched female WT, NZB/W, and C9orf72 KO animals. Overexpression of IFN□via hydrodynamic DNA delivery (HDD) as used to evaluate the role of IFN□ in these strains, while B cell depletion was performed to determine the contribution of B cells to pathogenesis in each strain.

Results: In comparing these two mouse models, the respective contributions of IFN□ and BAFF, which represent pathways with currently approved targeted therapeutics in SLE, were evaluated and analyzed. Using HDD to deliver a low dose of IFN□ systemically, we have shown that disease progression in NZB/W animals is synchronized across animals and significantly accelerated, while disease progression in C9orf72 ^-/- mice is unaltered by overexpression of IFN□. These data suggest that NZB/W mice have disease that can be exacerbated by IFN□ and thus may represent a model for patients where Type I IFN is a key driver of disease. B cell/plasma cell depletion by overexpressing TACI-Ig by HDD to bind and sequester BAFF and APRIL in the C9orf72-deficient lupus model reversed lupus-associated phenotypes. Depletion of BAFF/APRIL in C9orf72 ^-/- resulted in a decrease in B cells and a rapid reduction in anti-dsDNA antibodies. These data indicate that the C9orf72 ^-/- model captures the dysregulated B cell tolerance pathways that can drive disease in some subsets of lupus patients.

Conclusion: Here we describe two models of SLE-like disease that respond differently to manipulation of two of the pathways targeted by existing approved therapeutics. Taken together, these data suggest that NZB/W and C9orf72 ^-/- mice can recapitulate distinct disease mechanisms relevant in human lupus patients and can be used in preclinical efforts to validate therapeutic strategies to target a heterogeneous SLE patient population.

REFERENCES: [1] Atanasio A, Decman V, White D, Ramos M, Ikiz B, Lee HC, Siao CJ, Brydges S, LaRosa E, Bai Y, Fury W, Burfeind P, Zamfirova R, Warshaw G, Orengo J, Oyejide A, Fralish M, Auerbach W, Poueymirou W, Freudenberg J, Gong G, Zambrowicz B, Valenzuela D, Yancopoulos G, Murphy A, Thurston G, Lai KM. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep. 2016 Mar 16;6:23204. doi: 10.1038/srep23204.

Acknowledgements: NIL.

Disclosure of Interests: Arielle Glatman Zaretsky May hold stock or stock options, Employee of Regeneron, Carley Tasker May own stock or stock options, Employee of Regeneron, Pablo Abreu May hold stock or stock options, Employee of Regeneron, Ciara Torres May own stock or stock options, Employee of Regeneron, Li-Hong Ben May own stock or stock options, Employee of Regeneron, Scott MacDonnell May own stocks or stock options, Employee of Regeneron, Andre Limnander May hold stock or stock options, Employee of Regeneron, Jamie Orengo May hold stock or stock options, Employee of Regeneron

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.