Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (ICs) and apoptotic cells and its role in inflammation. The classical pathway is thought to contribute to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. Mannose-binding lectin (MBL)-associated serine proteases (MASPs)-1 and -3 are responsible for activation of the alternative pathway by activation of complement factor D which is required to cleave C3b-bound factor B to Bb (the C3 convertase (C3bBb)) during the alternative pathway activation. The aim of this study was to investigate the role of essential components of the alternative pathway, MASP-1/3, on lupus-like renal disease in MRL/lpr mice.
Methods: MASP-1/3 gene-knockout MRL/lpr mice were generated by backcrossing MASP-1/3-/-C57BL/6 mice for seven generations to MRL/lpr mice, a mouse strain that spontaneously develops lupus-like disease. Alternative pathway activity in serum was measured by zymosan assay. Sera were analyzed every 2 weeks for total IgG, IgG anti-dsDNA autoantibodies, and C3 levels by ELISA. Urinary excretion of albumin was also determined. Kidneys were collected at 24 weeks for histologic evaluation.
Results: Sera from WT MRL/lpr mice showed significant C3 deposition on zymosan particles, whereas sera from MASP-1/3-/- MRL/lpr mice failed. Interestingly, compared to WT MRL/lpr mice, MASP-1/3-/- MRL/lpr mice had significantly increased levels of serum total IgG. However, there was no statistically significant difference of serum IgG anti-dsDNA antibody levels between the two groups. Serum C3 levels in WT MRL/lpr mice decreased as the mice aged. In contrast, serum C3 levels in MASP-1/3-/-mice were maintained, and were significantly higher than those in the WT group at and after week 16. There was no significant difference in glomerular IgG deposition levels between WT and MASP-1/3-/- groups. Importantly, minimal or no glomerular C3 deposition was observed in MASP-1/3-/- MRL/lpr mice, while it was ready evident in WT MRL/lpr mice. Unlike WT MRL/lpr mice, none of MASP-1/3-/- MRL/lpr mice developed albuminuria (no more than 100 micro-g/day/mouse) until 24 weeks of age. Pathological analysis revealed minimal or no glomerular disease in MASP-1/3-/- MRL/lpr mice; however, there was no significant reduction in interstitial nephritis compared to WT MRL/lpr mice.
Conclusion: Unlike WT MRL/lpr mice, MASP-1/3-/- MRL/lpr mice lacked activity of the alternative pathway, and had maintained serum C3 levels, no albuminuria, and minimal or no glomerular C3 deposition and glomerular pathologic changes. Thus, inhibition of the alternative pathway protects against the development of glomerular disease in lupus-prone MRL/lpr mice. MASP-1/3-/- MRL/lpr mice, however, had no significant reduction in interstitial nephritis, suggesting that the pathological mechanism of interstitial kidney disease was distinct from that of glomerular disease in MRL/lpr mice.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/masp-13-deficient-mrllpr-mice-lack-the-alternative-complement-pathway-activation-and-are-protected-from-development-of-lupus-like-glomerulonephritis/