BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

Abstract

Objective. To determine whether overexpression of BAFF can accelerate the development of systemic lupus erythematosus-associated end-organ disease in hosts with an underlying autoimmune diathesis.Methods. We introduced a BAFF transgene (Tg) into autoimmune-prone B6.Sle1 and B6.Nba2 mice and evaluated these mice for serologic autoimmunity and renal pathology.Results Conclusion. BAFF-driven effects on glomerular pathology may be mediated, at least in part, by autoantibodies with specificities other than chromatin and/or by autoantibody-independent means. There is an uncoupling of BAFF-driven precocious glomerular pathology from concomitant development of clinically apparent renal disease, strongly suggesting that BAFF overexpression works in concert with other factors to promote overt renal disease.Renal involvement in patients with systemic lupus erythematosus (SLE) is clinically apparent in ϳ50% of cases and leads to considerable morbidity. The vast majority of SLE patients with renal involvement develop increased proteinuria, sometimes to degrees great enough to adversely affect systemic fluid balance and hemodynamics (nephrotic syndrome). Glomerular disease is widely believed to be the major contributor to this increased proteinuria. Indeed, the World Health Organization (WHO) classification of lupus nephritis focuses almost entirely on glomerular lesions, with little attention to tubular, interstitial, or vascular lesions. Accordingly, factors which promote glomerular disease in SLE may be vital to the pathogenesis of lupus nephritis.

Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 × NZW)F1 mice

“…8,10,13 We analyzed the serum levels of total IgM and IgG in 3-month-old IFNAR þ / þ , IFNAR þ /À and IFNAR À/À B6.Nba2 mice to address whether IFNab signaling plays a role in early antibody production. There was a trend toward reduced levels of both total serum IgM and total serum IgG in IFNAR þ /À and IFNAR À/À B6.Nba2 mice, as compared with IFNAR þ / þ B6.Nab2 mice.…”

Genetic susceptibility to PolyI:C-induced IFNα/β-dependent accelerated disease in lupus-prone mice

“…Some of these genes (such as BAFF, MCP-1 and IRF-1) have been assigned a functional role in mouse lupus development. 4,53,54 Future studies combining polyI:C treatment with systemic blockade of BAFF, MCP-1, IRF-1 or other IFNa/b induced factors might help define the pathway(s) by which increased endogenous IFNa/b can result in accelerated lupus-like disease.…”

“…6 B6.Nba2 mice, in which the Nba2 (New Zealand Black autoimmunity 2) locus on distal chromosome 1 is derived from the New Zealand Black (NZB) strain, 7 develop elevated levels of circulating IgG ANA and IC deposition in the kidney glomeruli by the time they are 2-3 months old. 4,7 However, these mice fail to develop proteinuria and show no evidence of accelerated mortality when compared to normal B6 mice. In contrast, 490% of (B6.Nba2 Â NZW)F1 female mice develop signs of lupus-like nephritis starting around 6 months of age, 7 supporting the idea that NZW animals encode gene(s) that increase their susceptibility to kidney damage.…”

“…2,3 Still, some mouse models of SLE show deposition of immunoglobulin G (IgG) immune complexes (IC) in the kidney glomeruli without this leading to kidney disease, suggesting that elevated ANA production and IC deposition in themselves are insufficient for full disease development. 4,5 Studies have suggested that susceptibility to renal failure is genetically defined.…”

BAFF Expression is Increased in Patients with Lupus Nephritis and Associated with Antinucleosome Antibodies, C1 Inhibitor, Α-1-Acid-Glycoprotein and Endothelial Activation Markers

“…Binding of BAFF to one of three receptors on mature B cells (BAFF-R, TACI and BCMA), induces either Ig class switching, cell proliferation or increased survival of B cells including autoreactive B cells [9]. Transgenic (Tg) mice that overexpress BAFF develop an autoimmune disorder, that resembles SLE including immunecomplex mediated glomerulonephritis [10][11][12]. In general, experimental studies suggest that overexpression of BAFF promotes LN, but evidence from human studies is lacking.…”