Modulation of renal disease in autoimmune NZB/NZW mice by immunization with bacterial DNA.

Abstract

SummaryPreautoimmune New Zealand Black/White (NZB/NZW) mice immunized with Escherichia coli (EC) double stranded (ds) DNA produce antibodies that bind mammalian dsDNA and display specificities similar to spontaneous lupus anti-DNA. Since calf thymus (CT) dsDNA fails to induce these antibodies, these results suggest a special potency of foreign DNA in inducing serological manifestations of lupus in a susceptible host. To assess the effects of DNA immunization on clinical manifestations in NZB/NZW mice, we measured renal disease and survival of mice immunized with either (a) EC dsDNA as complexes with methylated bovine serum albumin (mBSA) in adjuvant; (b) CT dsDNA with mBSA in adjuvant; (c) mBSA alone in adjuvant; or (d) unimmunized. After immunization with EC dsDNA, NZB/NZW mice developed significant levels of anti-dsDNA antibodies. Nevertheless, these mice had less proteinuria, nitrate/nitrite excretion, and glomerular pathology than mice immunized with either mBSA alone, CT dsDNA/mBSA complexes, or unimmunized mice. Survival of the EC dsDNA immunized mice was significantly increased compared with the other mice. Furthermore, immunization of mice after the onset of anti-DNA production and proteinuria stabilized nephritis and prolonged survival. The improvement in renal disease occurred despite the expression of autoantibodies that bound mammalian dsDNA as well as glomerular antigens. These results suggest that bacterial DNA has immunological properties that attenuate murine lupus despite the induction of pathogenic antibodies.

A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells

“…The conclusion that TLR9 is involved in preventing the development of potentially damaging autoreactive responses fits with the observations from mouse disease models. Treatment of mice with CpG to stimulate TLR9 has alleviated disease severity in colitis, arthritis, and diabetes (50)(51)(52)(53). In addition, lupus-related renal disease is exacerbated in TLR9-deficient autoimmune prone mice (20)(21)(22)(23), and recent reports suggest that TLR9 is required to prevent pathological responses that result from TLR7-mediated signaling (24,25).…”

Vaccination with Empty Plasmid DNA or CpG Oligonucleotide Inhibits Diabetes in Nonobese Diabetic Mice: Modulation of Spontaneous 60-kDa Heat Shock Protein Autoimmunity

“…Gilkeson et al demonstrated that immunization with bacterial DNA can modulate renal disease in autoimmune NZB/NZW mice, while calf thymus DNA was not effective (26). Furthermore, improvement in renal disease was associated with the induction of Abs to glomerular Ags immediately after immunization (26). Boccacio and her colleagues have reported that noncoding plasmid DNA can inhibit experimental allergic encephalomyelitis while activating IFN-␥ in vitro (17).…”

“…However, modulation of autoimmune conditions by bacterial DNA has been already reported. Gilkeson et al demonstrated that immunization with bacterial DNA can modulate renal disease in autoimmune NZB/NZW mice, while calf thymus DNA was not effective (26). Furthermore, improvement in renal disease was associated with the induction of Abs to glomerular Ags immediately after immunization (26).…”

Effect of Late Modulation of Nitric Oxide Production on Murine Lupus

“…NZB/W mice develop a spontaneous autoimmune disease and produce elevated levels of NO as disease progresses (25). To determine the effect of blocking NO production on clinical disease, we treated NZB/W mice with NMMA and an arginine-free diet from 21 to 25 weeks of age.…”