Background/Purpose: Lupus nephritis (LN) is a major contributor to morbidity and mortality in systemic lupus erythematosus (SLE). Defective clearance of apoptotic cells (AC), autoantibodies, and low complement levels are three hallmarks of SLE pathogenesis that have not yet been captured in a single disease model.  We posit that such a model will allow us to elucidate the clinically relevant mechanisms of kidney injury in SLE and shed light on the multifaceted role of complement in this disease.  

Methods: To investigate mechanisms of kidney injury in a disease model that mimics the polygenic nature of human SLE, we generated C57BL/6 mice that produced anti-chromatin antibodies (Sle1), had defective clearance of AC (Mfge8-/-) and were deficient in either C1q [C1q Triple mutant (C1qTM)] or C3 (C3TM). Kidney injury was evaluated by urine albumin/creatinine ratio (UACR), PAS staining, immunofluorescence (IF) staining and electron microscopy (EM). The effect of thrombin inhibition with argatroban on kidney injury in Mfge8-/-C3-/- (C3 double mutant, DM) mice was studied in the nephrotoxic-nephritis (NTN) model of kidney injury.

Results: C1qTM and C3TM mice, but not any double mutant controls, developed spontaneous membranoproliferative glomerulonephritis (MPGN) with PAS positive deposits, glomerular hypercellularity and variable mesangial and endocapillary proliferation at ~10 months of age. EM revealed features reminiscent of human LN: “wire loop” and glomerular mesangial immune deposits in fibrillary organized structures. MPGN in C1qTM and C3TM mice was accompanied by increased glomerular deposition of IgG and AC. At 5 months of age, C1qTM and C3TM mice spontaneously developed high anti-dsDNA and anti-chromatin IgG titers as well as marked antigen spreading, including antigens previously implicated in LN pathogenesis.    

                  Remarkably, IF staining revealed membrane attack complex (MAC) deposition in both TM strains. In C1qTM mice MAC deposition was associated with glomerular deposition of C3/C3d. Terminal complement activation in C3TM kidneys was accompanied by increased glomerular deposition of the thrombin substrate, fibrin. We also observed increased thrombin enzymatic activity in the plasma of C3TM mice, relative to C1qTM controls. Using the NTN model of kidney injury in Mfge8-/-C3-/- mice, the thrombin inhibitor, argatroban, significantly reduced glomerular MAC deposition and UACR, compared to vehicle treated controls.

Conclusion: In the context of reduced clearance of AC (Mfge8-/-) and non-pathogenic autoantibodies (Sle1), early complement component deficiencies (C1q or C3) have two distinct effects: i) their absence leads to B cell activation and epitope spreading and ii) surrogate pathways allow terminal complement MAC activation. In C1qTM mice, increased glomerular C3/C3d deposition suggests activation of the lectin or alternative complement pathways, in the absence of C1q. Increased fibrin deposition in C3TM and rescue of proteinuria in NTN C3DM mice by a thrombin inhibitor, suggest that thrombin acts as a C5 convertase in low C3 states. These data encourage surrogate pathway evaluation in SLE patients with low complement states and offer new potential targets for therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/surrogate-pathways-of-complement-activation-in-novel-polygenic-sle-like-models-of-kidney-injury/