Session Title: Systemic Lupus Erythematosus – Animal Models Poster
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Lupus nephritis (LN) affects ~70% of systemic lupus erythematosus (SLE) patients and is one of the main contributors to morbidity and mortality. While defective clearance of apoptotic cells (AC), autoantibodies, and type 1 interferons (IFN-I), are strongly implicated in lupus pathogenesis, the precise way that each impacts kidney protection and injury is unknown.
To investigate mechanisms of kidney injury in a lupus-like disease model, we created C57BL/6 mice with defective clearance of AC (Mfge8-/-) and anti-chromatin antibodies (sle1) that were also deficient in either C1q [C1q Triple mutant (C1qTM)] or C3 (C3TM). Kidney injury was evaluated by urine albumin/creatinine ratio (UACR), PAS staining, and immunofluorescence (IF) staining. The effect of IFN-I on disease was studied in C3TM mice by a single injection of an adenovirus expressing IFNα (AdV-IFNα).
Sle1 mice deficient in MFG-E8 developed significantly higher titers of autoantibodies directed at lupus antigens compared to sle1 mice alone. When Mfge8-/-Sle1 mice also had C1q or C3 deficiency, a further increase in anti-DNA and other autoantibodies was observed. Both TM strains showed AC accumulation in the kidneys and C1qTM mice had decreased survival. Remarkably, we detected glomerular deposition of C3/C3d in C1qTM and the membrane attack complex (MAC) in C3TM mice. To dissociate the effects of complement on B cells versus effects on the kidney, we studied the impact of defective AC clearance and complement deficiencies on kidney injury in double knockout (DKO) (Mfge8-/-C1q-/- or Mfge8-/-C3-/-) mice using Nephrotoxic Nephritis model (NTN). NTN in C1qDKO and C3DKO mice revealed a significantly elevated UACR compared to the single mutants, i.e. worse kidney disease. This effect was independent of antibody deposition in the kidney as similar IgG levels were detected in all NTS-treated strains. IF analyses revealed glomerular C3/C3d deposition in C1qDKO mice and MAC deposition in C3DKO mice. A single injection of AdV-IFNα accelerated kidney damage in C3TM mice, resulting in high anti-dsDNA IgG titers, UACR, renal IgG deposition, and PAS staining.
These findings demonstrate that, in the context of reduced clearance of AC, early complement components have two distinct functions: they prevent enhanced B cell autoreactivity and protect against kidney disease. Increased glomerular C3/C3d deposition in C1qTM and NTN C1qDKO mice suggest activation of the lectin or alternative complement pathways following AC accumulation. Increased MAC deposition in C3TM and NTN C3DKO mice indicates that, in the absence of C3 and presence of AC, a C3–independent mechanism leads to distal complement activation and MAC formation. This effect is further exacerbated by IFNα suggesting a mechanism of disease progression in human SLE in the context of C3 absence and/or consumption. These data prompt models of tissue injury in low complement states that will require assessment in human SLE and provide two distinct perspectives: i) a rationale for targeted therapeutics that are not currently used and ii) a cautionary note about the use of current complement inhibitor therapies.
To cite this abstract in AMA style:Skopelja-Gardner S, Peng Y, Hermanson P, Colonna L, Sun X, Tanaka L, Davidson A, Salant D, Elkon KB. Kidney Tissue Damage in Mice with Single and Combined Abnormalities in Complement, Interferon and Apoptotic Cell Clearance [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/kidney-tissue-damage-in-mice-with-single-and-combined-abnormalities-in-complement-interferon-and-apoptotic-cell-clearance/. Accessed July 3, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/kidney-tissue-damage-in-mice-with-single-and-combined-abnormalities-in-complement-interferon-and-apoptotic-cell-clearance/