The Renal Pathogenicity of Anti-DNA Antibodies

  • Putterman, Chaim (PI)

Project: Research project

Project Details

Description

Antibodies to double stranded (ds) DNA are not only highly specific for systemic lupus erythematosus
(SLE), but are also directly involved in the pathogenesis of lupus nephritis (LN), a major disease
manifestation. However, despite the clear association between anti-dsDNA antibodies and nephritis, the
mechanisms by which anti-DNA antibodies contribute to renal damage have yet to be conclusively
determined. LN may be initiated by formation of immune complexes in situ, via binding of anti-DNA
antibodies to nucleosomal antigens deposited on the glomerular basement membrane (GBM).
Alternatively, anti-DNA antibodies may be pathogenic not by virtue of binding to nuclear antigens, but
rather via binding to cross reactive renal targets. In the initial period of funding for this grant, we found that
pathogenic murine anti-DNA antibodies bind to mesangial cell (MC) a-actinin, and that high titers of anti-a-
actinin antibodies were present in the serum and kidney eluates of lupus mice. Furthermore, we reported
that in human SLE serum anti-a-actinin antibodies that bound to MC were present in high titers as well, and
were closely associated with the presence and activity of LN. Finally, pathogenic antibodies binding to MC
a-actinin directly modulated inflammatory gene expression including cytokines and neutrophil gelatinase
associated lipocalin (NGAL, lipocalin), via Fc-dependent and independent mechanisms. We hypothesize
that gene regulation induced by nephritogenic antibodies in kidney cells is an important contributor to the
pathogenesis of LN, mediated by binding to cell surface receptors and engagement of an additional
receptor from the Toll-like receptor (TLR) family, and that serum and/or urinary levels of NGAL may reflect
the degree of renal injury induced by nephritogenic antibodies. We propose to continue our studies to
understand the renal pathogenicity of anti-DNA antibodies. Specifically we will:
I) Study the importance of specificity for a-actinin in determining antibody nephritogenicity and the effects
of binding by pathogenic antibodies on a-actinin structure and function;
II) Investigate the mechanisms of direct gene modulation in kidney cells, including Fc receptor and TLR
signaling pathways; and
III) Determine if NGAL is a reliable marker for injury of kidney cells by nephritogenic antibodies, is NGAL
upregulation instrumental in the pathogenesis of SLE renal disease, and whether serum and/or urine levels
of NGAL may be useful as a biomarker for lupus nephritis.
StatusFinished
Effective start/end date7/10/086/30/09

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $365,200.00

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