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

Lupus nephritis is one of the most serious manifestations of systemic lupus erythematosus, and represents one of the criteria implemented to classify systemic lupus erythematosus. Although studied for decades, no consensus has been reached related to the basic cellular, molecular, and immunologic mechanism(s) responsible for lupus nephritis. No causal treatments have been developed; therapy is approached mainly with nonspecific immunosuppressive medications. More detailed insight into disease mechanisms therefore is indispensable to develop new therapeutic strategies. In this review, contemporary knowledge on the pathogenic mechanisms of lupus nephritis is discussed based on recent data in murine and human lupus nephritis. Specific focus is given to the effect of anti-double-stranded DNA/antinucleosome antibodies in the kidneys and whether they bind exposed chromatin fragments in glomeruli or whether they bind inherent glomerular structures by cross-recognition. Overall, the data presented here favor the exposed chromatin model because we did not find any indication to substantiate the anti-double-stranded DNA antibody cross-reacting model. At the end of this review we present data on why chromatin fragments are expressed in the glomeruli of patients with lupus nephritis, and discuss how this knowledge can be used to direct the development of future therapies.