Murine and Human Lupus Nephritis: Pathogenic Mechanisms and Theoretical Strategies for Therapy

The Role of Anti-DNA Antibodies in the Development of Lupus Nephritis: A Complementary, or Alternative, Viewpoint?

“…summarize an extensive series of elegant studies from their group exploring the pathogenesis of murine and human LN. 27 They report that intra-glomerular EDS containing extracellular chromatin fragments are in vivo targets of nephritogenic Ab and describe a two-step process in the pathogenesis of LN in lupus-prone NZB/W F1 mice, 28–33 beginning with mild mesangial proliferation and culminating in membranoproliferative nephritis with immune complex deposition. 34 The authors propose that human LN follows a parallel progressive pattern from WHO class II LN (deposition of immune complexes in the mesangium) to class IV (diffuse proliferative GN).…”

“…Furthermore, as noted by Pedersen et al , previous attempts to rescue murine models of LN by exogenous administration of DNase I yielded contradictory results, and has also not been a successful approach in LN patients. 45,46 Therefore, while Pedersen et al propose that basement-membrane bound chromatin in LN is not accessible to extracellular DNAse as an explanation for the lack of efficacy with exogenous administration, 27 one also needs to consider the possibility that the loss of DNase I observed in murine LN does not directly contribute to the pathogenicity of anti-dsDNA Ab (at least not initially) and it is perhaps rather a consequence of complex ongoing immune mechanisms as nephritis progresses. Interestingly, upregulation of MMPs is not limited to LN and can occur in several types of acute or chronic kidney injury, also in the absence of glomerular Ab deposition.…”

“…Pedersen et al further describe the role of heparin as a chaperone protein that enhances chromatin degradation and prevents large chromatin fragments from being presented to the immune system, 27 an effect mediated via its affinity for histone tails. 48,49 Indeed, treatment of NZB/W F1 mice with heparin delayed anti-dsDNA Ab production and reduced ab titers and the number of EDS.…”

Pathogenesis of proliferative lupus nephritis from a historical and personal perspective

“…The issue regarding the relative importance of DNA/anti-DNA and nucleosome/anti-nucleosome ICs in the pathogenesis of LN was once again raised by two recent review papers (12, 13). Pedersen et al (12) reviewed their studies that emphasized the importance of the nucleosome/anti-nucleosome IC in the pathogenesis of LN while Goilav and Putterman (13) were more conciliatory with the conclusion that both IC systems were complementary.…”

“…Pedersen et al (12) reviewed their studies that emphasized the importance of the nucleosome/anti-nucleosome IC in the pathogenesis of LN while Goilav and Putterman (13) were more conciliatory with the conclusion that both IC systems were complementary. Our 2004 publication in the Journal of Experimental Medicine (14) cited by Goilav and Puttermen (13) is relevant to this issue.…”