Lupus-prone strains vary in susceptibility to antibody-mediated end organ disease

Abstract

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.

Blockade of CD354 (TREM-1) Ameliorates Anti-GBM-Induced Nephritis

“…Anti-GBM serum was purchased from Lampire Laboratories [ 23 , 24 ]. Anti-GBM nephritis was induced in 8–12-week-old female mice [ 4 , 23 ]. Briefly, mice were pre-sensitized with rabbit IgG 250 μg/mouse, given intraperitoneally (i.p.)…”

“…Five days later, the mice received rabbit anti-GBM serum 200 μg IgG/25 g body weight, administered intravenously (i.v.) [ 4 , 23 ]. This dosing regimen was sufficient to induce proteinuria but not mortality.…”

“…injection initiated on day 7 (D7). Weekly serum samples and 24-h urine samples were collected as described [ 4 , 23 , 24 ].…”

“…Kidney specimens were prepared as 4-μm sections of formalin-fixed, dehydrated, and paraffin-embedded tissues [ 4 , 23 , 24 ]. Slides were stained with hematoxylin and eosin or periodic acid-Schiff (PAS).…”

“…Increased knowledge of pathogenic mechanisms could greatly enhance prognosis and treatment of kidney diseases. Murine models suggest that contributing factors to immune-mediated nephritis include autoantibodies such as anti-glomerular antibodies [ 3 , 4 ] and innate immune activation independent of autoantibody production [ 5 , 6 ]. Dendritic cells maintain renal self-tolerance mediated by T regulatory cells [ 7 ].…”