Peptide inhibition of glomerular deposition of an anti-DNA antibody

Abstract

Antibodies to double-stranded DNA are pathognomonic of systemic lupus erythematosus and deposit in the kidneys of lupus patients to cause glomerulonephritis. Recent data suggest that a significant proportion of anti-DNA antibodies may cross-react with renal antigens and be sequestered in the kidney by virtue of this cross-reactivity. If this is true, antigenic competition for pathogenic antibodies might prevent their deposition in kidneys and the ensuing tissue damage. To generate surrogate antigens that could be used for this purpose, we have used peptide display phage libraries to identify peptides that react with R4A, a pathogenic mouse monoclonal anti-DNA antibody that deposits in glomeruli. We have demonstrated that the peptides bind in or near the double-stranded DNA binding site. Furthermore, the peptides are bound preferentially by the R4A antibody as compared with two closely related antibodies derived from it, one of which deposits in renal tubules and one of which displays no renal pathogenicity. Administration of one of these peptides in a soluble form protects mice from renal deposition of the R4A anti-DNA antibody in vivo. This represents a new therapeutic approach in systemic lupus erythematosus that focuses on protecting target organs from antibody mediated injury.

Antibody repertoire analysis in polygenic autoimmune diseases

“…Autoantibodies can be present years before the onset of clinical symptoms 17. Transfer of human autoantibodies from patients with SLE can cause glomerulonephritis and proteinuria in murine experimental systems,18, 19 emphasizing that they can be pathogenic. Genome‐wide association studies (GWAS) have shown that over 80 loci can contribute to the risk of developing SLE 20.…”

Association of IgG anti‐NR2 glutamate receptor antibodies in cerebrospinal fluid with neuropsychiatric systemic lupus erythematosus

“…Several different antigenic cross-reactivities for anti-DNA antibodies have been identified (3). Recently, a pentapeptide with the sequence DWEYS (a molecular mimic of double-stranded DNA) was demonstrated to be present in the extracellular domain of murine and human N-methyl-D-asparate (NMDA) receptor subunits NR2a and NR2b (4). Furthermore, in patients with SLE, anti-DNA antibodies that cross-react with NR2 glutamate receptors have been shown to mediate apoptotic death of neurons in vivo and in vitro (5).…”

Immunity and behavior: Antibodies alter emotion

“…These Abs are known to deposit in renal glomeruli, thereby contributing to lupus nephritis, as well as in skin and serosal membranes (13)(14)(15). We have previously demonstrated that a subset of these Abs cross-reacts with a 5-aa consensus sequence (D͞E W D͞E Y S͞G, or DWEYS for short) present in the NR2A and NR2B subunits of the NMDA receptor (NMDAR) (16,17).…”