ORIGINAL ARTICLE Lupus-prone strains vary in susceptibility to antibody-mediated end organ disease C Xie 1,2 , Y Du 1 , K Kumar 1 , L Li 1 , J Han 1 , K Liu 1 , XJ Zhou 3 and C Mohan 1 Renal involvement is the major cause of morbidity and mortality in lupus. Besides autoantibodies, intrinsic renal factors may contribute to the susceptibility to lupus nephritis. To determine how different mouse strains that develop spontaneous lupus fare in their susceptibility to immune mediated nephritis, mice from six lupus-prone strains and two non-lupus control strains (B6 and BALB/c) were challenged with rabbit anti-GBM sera. Among the strains tested, NZM2410 (or NZM) mice developed severe glomerulonephritis (GN), whereas BXSB and B6.lpr, NZB mice were relatively resistant to anti-GBM disease, as were the BALB/c controls. BWF1 and B6.Yaa mice exhibited intermediate degrees of GN that was comparable to the B6 controls. The severity of the renal disease in these strains did not appear to be related to the degree of the systemic immune response to the administered rabbit Ig. In addition, cytokine profiling demonstrated differential urinary excretion of several molecules in the NZM mice, compared with the controls. Together with our previous reports, our studies demonstrate that lupus-prone strains vary in their susceptibility to immune mediated nephritis, despite similar levels of circulating autoantibodies and comparable degrees of immune complex deposition in the kidneys. Genes and Immunity (2013) 14, 170–178; doi:10.1038/gene.2012.57; published online 7 February 2013 Keywords: systemic lupus erythematosus; lupus nephritis; genetics; anti-GBM INTRODUCTION Nephritis is a leading cause of morbidity and mortality in both human and murine systemic lupus erythematosus (SLE 1–6 ). To a certain extent this is likely to be due to the production of potentially nephrophilic autoantibodies, including anti-dsDNA and anti-glomerular autoantibodies. 7–9 On the other hand, it is also clear that antibody-independent mechanisms may also contribute to nephritis in SLE. It has long been observed that there is considerable discordance between anti-nuclear antibody (ANA) levels and severity of glomerulonephritis (GN) in SLE, as reviewed. 10,11 Studies in mouse strains that develop spontaneous lupus have indicated that GN and ANA production can be mediated by independent loci, and that nephritis can occur without the presence of ANAs. 12,13 It has become evident that signals from the innate immune system also has an important role in immune-mediated nephritis, as recently reviewed. 14 An elegant study that has illustrated the role of antibody-independent contributions to lupus nephritis is reported by Shlomchik et al. 12 in the MRL/lpr mouse model of lupus. MRL/lpr mice that have B-cells but cannot secrete immunoglobulin (Ig) exhibit substantial interstitial nephritis and vasculitis although less marked than that seen in the un-manipulated MRL/lpr controls. These studies indicate that antibody-independent mechanisms, including contributions from T-cells, myeloid cells and resident renal cells may also serve to potentiate lupus nephritis. Hence, it becomes important to study the genetic and molecular determinants of renal disease in lupus, independent of the determinants that dictate ANA (and anti-glomerular) antibody formation. In this respect, the anti-glomerular basement membrane (GBM)-induced nephritis model is emerging as an informative experimental tool. 15–20 This may relate to the fact that anti-GBM- induced nephritis and spontaneously arising lupus nephritis share similar downstream cellular and molecular events that lead to renal pathology and dysfunction despite differing in the nature of the initial antibody deposits. 14 This powerful tool has helped to identify certain strains such as 129/sv, BUB, DBA/1, C58 and NZW as being particularly susceptible to immune-mediated nephritis and others such as A/J, AKR, BALB/c, C3H, C57BL/6, DBA/2, DDY, FVB, MRL, NOD, P/J, SB, SJL and SWR as being less susceptible. 15–17 It is intriguing that some strains that possess genetic elements for the evolution of spontaneous lupus nephritis are also susceptible to anti-GBM nephritis (for example, NZW), while others are clearly not (for example, MRL). These observations raise an important question—to what extent are strains prone to spontaneous lupus also susceptible to anti-GBM induced nephritis? Can the NZB/NZW, NZM2410 and BXSB genomes and the lpr and Yaa lupus accelerating loci directly impact end-organ disease development, independent of their impacts on autoantibody generation? In this report, we assess the degree of nephritis in anti-GBM challenged C57BL/6.lpr (B6.lpr), C57BL/6.Yaa (B6. Yaa), BXSB, NZB, (NZB X NZW) F1 (BWF1), NZM2410 (NZM) lupus-prone mice as well as two control strains—BALB/c mice that are not susceptible to anti-GBM disease, and C57BL/6 (B6) mice that develop low-grade anti-GBM GN. RESULTS Proteinuria and azotemia in anti-GBM challenged mice In order to assess the sensitivity of different lupus-prone strains to anti-GBM nephritis, we challenged non-lupus prone B6 and 1 Department of Internal Medicine, Division of Rheumatology, The University of Texas, Southwestern Medical Center, Dallas, TX, USA; 2 Department of Internal Medicine, Division of Nephrology, The University of Texas, Southwestern Medical Center, Dallas, TX, USA and 3 Department of Pathology, The University of Texas, Southwestern Medical Center, Dallas, TX, USA. Correspondence: Dr C Mohan, Department of Internal Medicine/Rheumatology, UT Southwestern Medical Center, Mail Code 8884 Y8.212, 5323 Harry Hines Boulevard, Dallas, TX 75390-8884, USA. E-mail: Chandra.mohan@utsouthwestern.edu Received 5 July 2012; revised 15 November 2012; accepted 26 November 2012; published online 7 February 2013 Genes and Immunity (2013) 14, 170–178 & 2013 Macmillan Publishers Limited All rights reserved 1466-4879/13 www.nature.com/gene