Initiation Of Lupus Nephritis Research Articles

The effect of cell death in the initiation of lupus nephritis.

Cell death and the release of chromatin have been demonstrated to activate the immune system producing autoantibodies against nuclear antigens in patients with systemic lupus erythematosus (SLE). Apoptosis, necrosis, necroptosis, secondary necrosis, autophagy and the clearance of dying cells by phagocytosis are processes believed to have a role in tolerance avoidance, activation of autoimmune lymphocytes and tissue damage by effector cells. The released chromatin not only activates the immune system; it also acts as antigen for the autoantibodies produced, including anti-dsDNA antibodies. The subsequent immune complex formed is deposited within the basement membranes and the mesangial matrix of glomeruli. This may be considered as an initiating event in lupus nephritis. The origin of the released chromatin is still debated, and the possible mechanisms and cell sources are discussed in this study.

Combination of anti-C1q and anti-dsDNA antibodies is associated with higher renal disease activity and predicts renal prognosis of patients with lupus nephritis

Although nephritogenic autoantibodies are considered to play a central role in the initiation of lupus nephritis, whether these autoantibodies are associated with renal clinical and pathological activity or renal outcome is still controversial. Here, we investigated the associations of certain serum autoantibodies with renal disease activity and renal outcome in a large cohort of Chinese patients with lupus nephritis. One hundred and thirty-six Chinese patients with biopsy-proven lupus nephritis and with long-term follow up data were studied. Sera at renal biopsy were tested for a panel of autoantibodies, including anti-nuclear antibodies, anti-double-stranded DNA (anti-dsDNA) antibodies, anti-extractable nuclear antigen antibodies, anti-C-reactive protein antibodies, anti-C1q antibodies, anti-cardiolipin antibodies and anti-β2-glycoprotein I antibodies. Associations of these autoantibodies with clinical features, laboratory findings, histopathological data and renal outcomes were further investigated. Among the various autoantibodies, anti-dsDNA and anti-C1q antibodies were better than other antibodies to evaluate the renal disease activity. Anti-dsDNA antibodies were correlated with higher incidence of leukocyturia (P< 0.05), total pathological activity index (AI) score (P< 0.05), endocapillary hypercellularity (P< 0.05), subendothelial hyaline deposits (P< 0.05) and leukocyte infiltration (P< 0.05). Anti-C1q antibodies were correlated with leukocyturia (P< 0.01), hematuria (P< 0.003) and the majority of the histopathological AIs including total AI score (P< 0.003), endocapillary hypercellularity (P< 0.003), cellular crescents (P< 0.05), karyorrhexis/fibrinoid necrosis (P< 0.003), subendothelial hyaline deposits (P< 0.003) and leukocyte infiltration (P< 0.01). Patients with both anti-dsDNA and anti-C1q antibodies had higher renal disease activity and poorer renal outcome (log-rank test: P= 0.048) compared with those without the two antibodies. In univariate survival analysis of renal prognosis, neither the presence of anti-C1q nor the presence of anti-dsDNA antibodies was a risk factor of renal survival. However, the combination of the two antibodies predicted renal prognosis (hazard ratio 4.40, 95% confidence interval: 1.268-15.269, P= 0.02). Anti-C1q antibodies are more closely correlated with renal disease activity than the other autoantibodies. The combination of anti-C1q and anti-dsDNA autoantibodies indicates higher renal disease activity and predicts poor renal outcome.

The Proteasome Inhibitor Bortezomib Prevents Lupus Nephritis in the NZB/W F1 Mouse Model by Preservation of Glomerular and Tubulointerstitial Architecture

Background/Aims: Crucial steps in the initiation of lupus nephritis are the deposition of (auto-)antibodies and consequent complement activation. In spite of aggressive treatment patients may develop terminal renal failure. Therefore, new treatment strategies are needed. In extension to our previously published data we here analyzed the potential renoprotective mechanisms of bortezomib (BZ) in experimental lupus nephritis by focusing on morphological changes. Methods: Female NZB×NZW F1 mice develop lupus-like disease with extensive nephritis that finally leads to lethal renal failure. Treatment with 0.75 mg/kg BZ i.v. or placebo (PBS) twice per week started at 18 or 24 weeks of age. Antibody production was measured with ELISA and kidney damage was determined by quantitative morphological and immunohistochemical methods. Results: BZ treatment completely inhibited antibody production in both BZ-treated groups and prevented the development of nephritis in comparison to PBS-treated animals. Glomerular and tubulointerstitial damage scores, collagen IV expression, mean glomerular volume as well as tubulointerstitial proliferation and apoptosis were significantly lower after BZ treatment. Glomerular ultrastructure and in particular podocyte damage and loss were prevented by BZ treatment. Conclusions: BZ effectively prevents the development of nephritis in the NZB/W F1 mouse model. Specific protection of podocyte ultrastructure may critically contribute to renoprotection by BZ, which may also represent a potential new treatment option in human lupus nephritis.

Progression of Murine Lupus Nephritis Is Linked to Acquired Renal Dnase1 Deficiency and Not to Up-Regulated Apoptosis

The accumulation of apoptotic cells has been suggested as a possible mechanism of nucleosome conversion into self-antigens that may both initiate autoimmune responses and participate in immune complex deposition in lupus nephritis. In this study, we analyzed both the rate of transcription of apoptosis-related genes and the presence of activated apoptotic factors within kidneys of lupus-prone (NZBxNZW) F1 mice during disease progression. The results of this study demonstrated no activation of apoptotic pathways in kidneys of these lupus-prone mice at the time of appearance of anti-double standard DNA antibodies in serum, as well as the formation of mesangial immune deposits in glomeruli. In contrast, the transition of mesangial into membranoproliferative lupus nephritis coincided with an accumulation of activated caspase 3-positive cells in kidneys, in addition to a dramatic decrease in Dnase1 gene transcription. Highly reduced expression levels of the Dnase1 gene may be responsible for the accumulation of large chromatin-containing immune complexes in glomerular capillary membranes. Thus, the initiation of lupus nephritis is not linked to increased apoptotic activity in kidneys. The combined down-regulation of Dnase1 and the increased number of apoptotic cells, which is possibly due to their reduced clearance in affected kidneys, may together be responsible for the transformation of mild mesangial lupus nephritis into severe membranoproliferative, end-stage organ disease.

The role of antibodies directed against doublestranded DNA in the manifestations of systemic lupus erythematosus in childhood

The specificity of antibodies directed against dsDNA for SLE in a childhood population was tested by analyzing sera from 62 children with lupus and 283 children with other known or suspected autoimmune diseases. The role of these antibodies in the manifestations of SLE was then examined by correlating dsDNA Ab titer with clinical manifestations in 311 sera from 20 children followed for a mean of 51 months. Antibodies to dsDNA were found to be highly specific for SLE. The presence of antibodies in titers of 1:80 or greater correlated with the presence of active disease, arthritis, and rash, but not with azotemia, proteinuria, or increasing proteinuria; this indicated that their role in the induction of lupus nephritis was different from that in the induction of rash and arthritis. This may be due to a requirement for small immune complex formation during times of antigen excess in the initiation of lupus nephritis.