Local Renal Autoantibody Production in Lupus Nephritis

Cambridge Institute for Medical Research and the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2OY, United Kingdom.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 11/2010; 22(2):296-305. DOI: 10.1681/ASN.2010050515
Source: PubMed


Autoantibodies are central to the pathogenesis of several autoimmune diseases including systemic lupus erythematosus. Plasma cells secrete these autoantibodies, but the anatomical sites of these cells are not well defined. Here, we found that although dsDNA-specific plasma cells in NZB/W mice were present in spleen and bone marrow, a large number were in the kidneys and their number correlated with the serum dsDNA-IgG titer. We observed renal plasma cells only in mice with nephritis, where they located mainly to the tubulointerstitium of the cortex and outer medulla. These cells had the phenotypic characteristics of fully differentiated plasma cells and, similar to long-lived bone marrow plasma cells, they were not in cell cycle. In patients with lupus nephritis, plasma cells were often present in the medulla in those with the most severe disease, especially combined proliferative and membranous lupus nephritis. The identification of the kidney as a major site of autoreactive plasma cells has implications for our understanding of the pathogenesis of lupus nephritis and for strategies to deplete autoreactive plasma cells, a long-standing therapeutic aim.

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    • "[30] This phenotype is probably with clinical relevance, since B cell infiltration in situ is strongly correlated with severe nephritis and poor prognosis in lupus patients [30] Furthermore, elevated levels of the B cell chemoattractant CXCL13 in target tissue or in circulation is positively correlated with disease activation both in patients and mice. [29], [31] The function of the infiltrating B cells is not clear; however, several studies reporting antibody producing by local plasma cells in the kidney [32], [33] may shed some light on this issue. "
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    ABSTRACT: Objective This study was performed to investigate the therapeutic effects of iguratimod in a lupus mouse model. Methods Female MRL/lpr mice were treated with iguratimod, vehicle solution or cyclophosphamide. Proteinuria was monitored and kidney injury was blindly scored by a renal pathologist. Serum anti-double-stranded DNA antibodies were monitored by radioimmunoassay. Kidney IgG and CD20 were stained by immunohistochemistry. Splenic lymphocyte phenotypes were analyzed by flow cytometry. BAFF, IL-17A, IL-6, and IL-21 levels in serum and splenic lymphocytes were detected by ELISA or quantitative PCR. Results Compared with the vehicle-treated controls, MRL/lpr mice treated with iguratimod showed less protenuria, less acute pathological lesions and no chronic changes in the kidneys. There were significant differences in glomerular injury and vasculitis scores, as well as in the semi-quantitave analysis of immune complex deposition between the two groups. Disease activity markers in sera (anti-dsDNA antibodies and immunoglobulin levels) were reduced and hypocomplementemia was attenuated. Lymphocyte expression of BAFF, IL-6, IL-17A and IL-21 was decreased. The abnormal splenic B220+ T cell and plasma cell populations in MRL/lpr mice were reduced by iguratimod treatment, with recovery of the total B cell population and inhibition of B cell infiltration of the kidney tissue. The dosage of iguratimod used in this study showed no significant cytotoxic effects in vivo and no overt side-effects were observed. Conclusion Iguratimod ameliorates immune nephritis in MRL/lpr mice via a non-antiproliferative mechanism. Our data suggest a potential therapeutic role of iguratimod in lupus.
    PLoS ONE 10/2014; 9(10):e108273. DOI:10.1371/journal.pone.0108273 · 3.23 Impact Factor
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    • "Thus, we performed a double immune-staining of renal tissue with anti-collagen-IV (red in Fig. 8c) and anti-IgG (green in Fig. 8c). In untreated animals, plasma cells were mainly observed in the tubule-interstitium of the renal cortex where dendritic cells, macrophages, and other inflammatory cells are commonly found [28].A significant reduction in IgG immune-fluorescence was observed in all treatment groups, particularly in the CTLA4 and both CD40-siRNA groups (Fig. 8b). "
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    ABSTRACT: Lupus nephritis (LN) is an autoimmune disorder in which co-stimulatory signals have been involved. Here we tested a cholesterol-conjugated-anti-CD40-siRNA in dendritic cells (DC) in vitro and in a model of LPS to check its potency and tissue distribution. Then, we report the effects of Chol-siRNA in an experimental model of mice with established lupus nephritis. Our in vitro studies in DC show a 100%intracellular delivery of Chol-siRNA, with a significant reduction in CD40 after LPS stimuli. In vivo in ICR mice, the CD40-mRNA suppressive effects of our Chol-siRNA on renal tissue were remarkably sustained over a 5 days after a single preliminary dose of Chol-siRNA. The intra-peritoneal administration of Chol-siRNA to NZB/WF1 mice resulted in a reduction of anti-DNA antibody titers, and histopathological renal scores as compared to untreated animals. The higher dose of Chol-siRNA prevented the progression of proteinuria as effectively as cyclophosphamide, whereas the lower dose was as effective as CTLA4. Chol-siRNA markedly reduced insterstitialCD3+ and plasma cell infiltrates as well as glomerular deposits of IgG and C3. Circulating soluble CD40 and activated splenic lymphocyte subsets were also strikingly reduced by Chol-siRNA. Our data show the potency of our compound for the therapeutic use of anti-CD40-siRNA in human LN and other autoimmune disorders.
    PLoS ONE 08/2013; 8(6):e65068. DOI:10.1371/journal.pone.0065068 · 3.23 Impact Factor
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    • "This hypothesis is supported by the finding that glomerular deposition of anti-dsDNA antibodies in lupus nephritis is mediated by nucleosomes [66,67]. The kidneys are a major source of autoantibody-producing plasma cells in lupus nephritis and these differentiated plasma cells are frequently observed in patients with severe renal involvement (mainly classes III through V), potentially acting in amplifying the renal disease course [68]. Additional autoantibodies include anti-Smith (Sm) antibodies with a high specificity for SLE, while SSA and SSB are present in other CTDs as well [69]. "
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    ABSTRACT: Connective tissue diseases (CTDs) are a heterogeneous group of disorders that share certain clinical presentations and a disturbed immunoregulation, leading to autoantibody production. Subclinical or overt renal manifestations are frequently observed and complicate the clinical course of CTDs. Alterations of kidney function in Sjögren syndrome, systemic scleroderma (SSc), auto-immune myopathies (dermatomyositis and polymyositis), systemic lupus erythematosus (SLE), antiphospholipid syndrome nephropathy (APSN) as well as rheumatoid arthritis (RA) are frequently present and physicians should be aware of that. In SLE, renal prognosis significantly improved based on specific classification and treatment strategies adjusted to kidney biopsy findings. Patients with scleroderma renal crisis (SRC), which is usually characterized by severe hypertension, progressive decline of renal function and thrombotic microangiopathy, show a significant benefit of early angiotensin-converting-enzyme (ACE) inhibitor use in particular and strict blood pressure control in general. Treatment of the underlying autoimmune disorder or discontinuation of specific therapeutic agents improves kidney function in most patients with Sjögren syndrome, auto-immune myopathies, APSN and RA. In this review we focus on impairment of renal function in relation to underlying disease or adverse drug effects and implications on treatment decisions.
    BMC Medicine 04/2013; 11(1):95. DOI:10.1186/1741-7015-11-95 · 7.25 Impact Factor
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