Significance of anti‐nuclear and anti‐extracellular matrix autoantibodies for albuminuria in murine lupus nephritis; a longitudinal study on plasma and glomerular eluates in MRL/l mice
The relationship between autoantibody reactivities and nephritis in systemic lupus erythematosus (SLE) is unclear. We studied MRL/l mice which developed a considerable albuminuria (either mice with short (< 1 week) or heavy and prolonged (3 weeks) albuminuria) and compared them with non‐albuminuric age‐matched controls, with young (12 weeks old) non‐albuminuric mice and with mice which were followed for 36 weeks and did not develop albuminuria. In a longitudinal prospective study on plasma samples we correlated a variety of anti‐nuclear reactivities and reactivities against extracellular matrix (ECM) components, with the onset of albuminuria. We found that at the onset of albuminuria, anti‐DNA was higher while anti‐nucleosome and anti‐H2A/H2B‐DNA subnucleosome reactivities were lower compared with age‐matched non‐albuminuric mice. We also studied glomerular eluates of these mice in ELISA and in indirect immunofluorescence (IF). In the eluates we found with IF that anti‐glomerular basement membrane (GBM)‐tubular basement membrane (TBM) antibodies were already present in 12‐week‐old non‐albuminuric mice. These eluates showed no anti‐nuclear antibodies. In eluates of albuminuric mice more immunoglobulin was deposited, and anti‐ECM, anti‐DNA and anti‐nucleosome reactivities were higher than in eluates of age‐matched non‐albuminuric mice. The deposition of anti‐nucleosome antibodies preceded the deposition of anti‐DNA antibodies since they were deposited to a greater extent in mice with a short albuminuria. We conclude that anti‐GBM‐TBM antibodies are the first autoantibodies that deposit in glomeruli of MRL/l mice at an early age. The onset of albuminuria is associated with additional deposition of both anti‐ECM and anti‐nuclear (anti‐nucleosome and anti‐DNA) antibodies, but the difference with non‐albuminuric mice seems to be more quantitative than qualitative.