Abstract
BackgroundLupus nephritis is characterized by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes (GBM). The latter defines end-stage disease.Methodology/PrincipalsIn the present study we determined the impact of antibodies to dsDNA, renal Dnase1 and matrix metalloprotease (MMP) mRNA levels and enzyme activities on early and late events in murine lupus nephritis. The major focus was to analyse if these factors were interrelated, and if changes in their expression explain basic processes accounting for lupus nephritis.FindingsEarly phases of nephritis were associated with chromatin-IgG complex deposition in the mesangial matrix. A striking observation was that this event correlated with appearance of anti-dsDNA antibodies and mild or clinically silent nephritis. These events preceded down-regulation of renal Dnase1. Later, renal Dnase1 mRNA level and enzyme activity were reduced, while MMP2 mRNA level and enzyme activity increased. Reduced levels of renal Dnase1 were associated in time with deficient fragmentation of chromatin from dead cells. Large fragments were retained and accumulated in GBM. Also, since chromatin fragments are prone to stimulate Toll-like receptors in e.g. dendritic cells, this may in fact explain increased expression of MMPs.SignificanceThese scenarios may explain the basis for deposition of chromatin-IgG complexes in glomeruli in early and late stages of nephritis, loss of glomerular integrity and finally renal failure.
Highlights
A wide spectrum of autoimmune responses and organ manifestations are characteristic of Systemic lupus erythematosus (SLE), and are used by the American College of Rheumatology (ACR) as criteria to classify SLE. [1] Of particular importance in context of the present study are criteria linked to development of kidney disease: Production of potentially pathogenic anti-dsDNA antibodies and deposition of chromatin-containing immune complexes in kidneys.Over time, different concepts have been discussed to describe possible basic processes linked to initiation of lupus nephritis, and to progression of mild into end-stage organ disease
This could be due to cross-reaction of anti-chromatin antibodies with inherent glomerular structures like laminin [2,3,4], a-actinin [5,6,7], or with membrane components of mesangial cells [8,9], or to binding of anti-chromatin antibodies to chromatin fragments exposed in affected glomeruli
We have recently demonstrated that reduced fragmentation of chromatin during evolution of nephritis concur with an acquired loss of renal Dnase1 mRNA at the time when nephritis transforms into end-stage organ disease [14,15]
Summary
A wide spectrum of autoimmune responses and organ manifestations are characteristic of Systemic lupus erythematosus (SLE), and are used by the American College of Rheumatology (ACR) as criteria to classify SLE. [1] Of particular importance in context of the present study are criteria linked to development of kidney disease: Production of potentially pathogenic anti-dsDNA antibodies (criterion # 10) and deposition of chromatin-containing immune complexes in kidneys (criterion # 7).Over time, different concepts have been discussed to describe possible basic processes linked to initiation of lupus nephritis, and to progression of mild into end-stage organ disease. There is a consensus stating that anti-dsDNA and anti-chromatin antibodies are central in initiation and maintenance of lupus nephritis, but there is no agreement as to how they interact with glomerular structures This could be due to cross-reaction of anti-chromatin antibodies with inherent glomerular structures like laminin [2,3,4], a-actinin [5,6,7], or with membrane components of mesangial cells [8,9], or to binding of anti-chromatin antibodies to chromatin fragments exposed in affected glomeruli. Lupus nephritis is characterized by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes (GBM)
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