Complement Deficiencies Result in Surrogate Pathways of Complement Activation in Novel Polygenic Lupus-like Models of Kidney Injury

Abstract

Lupus nephritis (LN) is a major contributor to morbidity and mortality in lupus patients, but the mechanisms of kidney damage remain unclear. In this study, we introduce, to our knowledge, novel models of LN designed to resemble the polygenic nature of human lupus by embodying three key genetic alterations: the Sle1 interval leading to anti-chromatin autoantibodies; Mfge8 2/2 , leading to defective clearance of apoptotic cells; and either C1q 2/2 or C3 2/2 , leading to low complement levels. We report that proliferative glomerulonephritis arose only in the presence of all three abnormalities (i.e., in Sle1.Mfge8 2/2 C1q 2/2 and Sle1.Mfge8 2/2 C3 2/2 triple-mutant [TM] strains [C1q 2/2 TM and C3 2/2 TM, respectively]), with structural kidney changes resembling those in LN patients. Unexpectedly, both TM strains had significant increases in autoantibody titers, Ag spread, and IgG deposition in the kidneys. Despite the early complement component deficiencies, we observed assembly of the pathogenic terminal complement membrane attack complex in both TM strains. In C1q 2/2 TM mice, colocalization of MASP-2 and C3 in both the glomeruli and tubules indicated that the lectin pathway likely contributed to complement activation and tissue injury in this strain. Interestingly, enhanced thrombin activation in C3 2/2 TM mice and reduction of kidney injury following attenuation of thrombin generation by argatroban in a serum-transfer nephrotoxic model identified thrombin as a surrogate pathway for complement activation in C3-deficient mice. These novel mouse models of human lupus inform the requirements for nephritis and provide targets for intervention.

C1q as a target molecule to treat human disease: What do mouse studies teach us?

“…In summary, while in lupus prone strains C1q deficiency readily accelerates lupus nephritis ( 9 , 80 , 81 ), other forms of immune complex glomerulonephritis are not necessarily affected by C1q deficiency ( 86 ). Similarly, immune mediated nephritis induced by injection of anti-glomerular antibodies is deteriorated in certain mice strains but not on a non-permissive C57BL/6 background suggesting that the sole absence of C1q is not sufficient to cause disease but requires additional genetic and/or environmental factors ( 83 – 85 ).…”

“…While C1q deficiency was associated with an increase of apoptotic cells in kidneys, clearance did not require C3 activation ( 80 ). C1q deficiency also acted as disease accelerator in a polygenetic model of LN in which low complement was mimicked by C1q deficiency, autoantibody formation was induced by Sle1 knockout ( Sle1 -KO) and defective clearance of apoptotic cells by Mfge8 knockout ( Mfge8- KO ) ( 81 ). There was, however, no significant effect when comparing C1q sufficient Sle1 -KO with C1q deficient Sle1 -KO mice.…”

Group 3 Innate Lymphoid Cells Exacerbate Lupus Nephritis by Promoting B Cell Activation in Kidney Ectopic Lymphoid Structures

“…In addition to the spontaneous LN model, accumulation of renal ILC3s was also verified in nephrotoxic serum nephritis (NTN) (Figure S5 , Supporting Information), an induced LN model characterized by crescent formation, leukocyte infiltration and renal functional impairment. [ 15 ]…”

Role of intracellular complement activation in kidney fibrosis

“…Using polygenic murine model of systemic lupus erythematosus, the authors suggest that the deposition of damage-associated molecular pattern molecules, such as mannose binding lectin (MBL) collectins and ficolins, may induce tissue factor expression and activate downstream complement pathways such as lectin and thrombin. Assembly of the MAC can lead to necrosis and increased kidney tissue inflammation (Skopelja-Gardner et al, 2020).…”