Anti-dsDNA Antibodies Promote Initiation, and Acquired Loss of Renal Dnase1 Promotes Progression of Lupus Nephritis in Autoimmune (NZBxNZW)F1 Mice

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.

NETosis: how vital is it?

“…119 Nucleosome-induced injury was further compounded by the presence of underlying anti-DNA autoantibodies that promoted an acquired reduction in DNase1 expression within the kidney, ultimately resulting in accumulation of undigested extracellular chromatin. 119,120 Despite this evidence supporting a role of DNase in lupus pathogenesis, these investigations did not directly link DNase and NETosis to the development of SLE.…”

Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes

“…We have previously identified chromatin fragments as the glomerular target structure for nephritogenic autoantibodies in lupus nephritis (12,13,38) (for review, see refs. 8 and 9).…”

“…The reason for this is unclear but may relate to the possibility that, for example, T cell autoimmunity had been initiated before heparin treatment started in these mice. If so, full-blown humoral autoimmunity may appear with lupus nephritis as the inevitable consequence (38). Another explanation may be individual differences in the clearance capacity of heparin in vivo in mice (41,42), or that the dose of heparin needs to be increased.…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…MMP-9 involvement is further described for cardiovascular, respiratory and auto-immune diseases (e.g., Systemic Lupus Erythematosus, Sjögren's syndrome, Multiple Sclerosis, Rheumatoid Arthritis, polymyositis, asthma, chronic obstructive pulmonary disease, C protein-induced myocarditis, lupus nephritis, auto-immune inner ear disease and bullosus pemphigoid) Fenton et al, 2009;Hulkkonen et al, 2004;Ito et al, 2009;Ma et al, 2010;Matsumoto et al, 2009;Noseworthy et al, 2000;Pathak et al, 2011). In some cases, the molecular mechanisms underlying its pathogenic activity have been described in detail: therefore, the discussion of MMP-9 role in human pathologies will be limited to those more represented in literature (see Table 4).…”