Induction of cross-reactive anti-dsDNA antibodies in preautoimmune NZB/NZW mice by immunization with bacterial DNA.

Gilkeson, Gary S.; Pippen, Anne M.; Pisetsky, David S.

doi:10.1172/jci117793

Cited by 168 publications

(89 citation statements)

References 25 publications

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“…Under conditions in which normal mice produce antibodies that bind selectively to the immunizing bacterial antigen, autoimmune mice produce cross-reactive antibodies that bind both mammalian and bacterial DNA. These antibodies can also be distinguished by the pattern of reactivity with synthetic dsDNA antigens [10]. Studies on the sequences of induced antibodies suggest that abnormalities in the composition of the B cell repertoire (i.e.…”

Section: Discussionmentioning

confidence: 99%

Specificity and immunochemical properties of antibodies to bacterial DNA in sera of normal human subjects and patients with systemic lupus erythematosus (SLE)

Drayton

Pisetsky

1997

Clinical and Experimental Immunology

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SUMMARYTo elucidate the mechanisms of anti-DNA production, we assessed the binding of sera of normal human subjects (NHS) and patients with SLE to a panel of bacterial and mammalian DNA. Using singlestranded DNA as antigens in an ELISA, NHS showed significant binding to some but not all bacterial DNA, while lacking reactivity to calf thymus DNA. Among bacterial DNA, the highest levels of binding were observed with DNA from Micrococcus lysodeikticus and Staphylococcus aureus. In contrast, SLE sera showed high levels of binding to all DNA tested. To evaluate further immunochemical properties of the anti-DNA antibodies, the subclass distribution of these responses was evaluated by subclass-specific reagents. While NHS showed a predominance of IgG2 antibodies to bacterial DNA, SLE sera had a predominance of IgG1 antibodies to these antigens. Together, these results provide further evidence for the antigenicity of bacterial DNA and suggest that NHS and SLE anti-DNA differ in the patterns of epitope recognition as well as mechanisms of induction.

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Section: Discussionmentioning

confidence: 99%

Specificity and immunochemical properties of antibodies to bacterial DNA in sera of normal human subjects and patients with systemic lupus erythematosus (SLE)

Drayton

Pisetsky

1997

Clinical and Experimental Immunology

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“…Serum levels of antibodies to dsDNA were measured by ELISA as described in the literature. 48 Briefly, ELISA plates (Corning Life Sciences, Lowell, MA, USA) were coated with 100 ml of 5 mg/ml calf thymus DNA (Sigma) and incubated at 37 uC overnight. After washing, the plates were blocked with BSA, then incubated sequentially for 45 min at room temperature with 1 : 100 diluted serum followed by HRP-conjugated goat anti-mouse IgG gamma chain specific (1 : 4000; Southern Biotech, Birmingham, AL, USA), and finally 3,39,5,59-tetramethylbenzidine was added (Pierce).…”

Section: Measurement Of Proteinuriamentioning

confidence: 99%

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

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Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas lpr /Fas lpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8 1 T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

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“…Sera were tested for anti-dsDNA levels by ELISA as previously described [70]. Briefly, ELISA plates (DB Biosciences, Franklin Lakes, NJ) were coated with 100 lL of 100 lg/mL salmon sperm DNA made ds by passage through a 45-lm pore size filter (USA Scientific, Ocala, FL).…”

Section: Analysis Of Serum Anti-dsdna Levelsmentioning

confidence: 99%

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

et al. 2006

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To investigate the role of interferon regulatory factor-1 (IRF-1) in the development of lupus nephritis, IRF-1 -/-genotype mice were bred onto the MRL/lpJfas lpr (MRL/lpr) background. We examined kidney mesangial cell function and disease progression. Endpoints evaluated included inflammatory mediators, autoantibody production, immune complex deposition, renal pathology, T cell subset analysis, and duration of survival. Mesangial cells cultured from IRF-1 -/-mice produced significantly lower levels of nitric oxide and IL-12 but not TNF-a when stimulated with LPS + IFN-c. IRF-1 -/-mice showed less aggravated dermatitis compared to the wild-type mice. Anti-doublestranded DNA production and proteinuria were significantly decreased in IRF-1 -/-mice compared to IRF-1 +/+ mice. IgG and C3 deposition as well as glomerulonephritis were decreased in IRF-1 -/-mice at 26 wk of age compared to the IRF-1 +/+ mice. Splenic CD4 -CD8 -CD44 + T cells were decreased while CD4 + CD25 + T cells were increased in the IRF-1 -/-mice when compared to IRF-1 +/+ mice. Survival rates (ED 50 ) were 22 wk for IRF-1 +/+ mice and 45 wk for IRF-1 -/-mice. These findings suggest an important role of IRF-1 in mediating renal disease in MRL/lpr mice. IntroductionThe etiology of systemic lupus erythematosus remains an enigma although genetic factors influenced by environmental agents appear to trigger the disease. Clearly, B cells, T cells, and macrophages play important roles in the development of lupus pathology [1][2][3].Chronic expression of Th1 cytokines secreted by Th cells is particularly harmful due to their influence on the initiation and promotion of tissue destruction [4,5]. Cytokines, including IFN-c, promote inflammation and provide a positive amplification loop responsible for escalating autoimmune kidney damage [6].MRL/lpr mice develop glomerulonephritis and vasculitis at an early age (4-5 months) [7]. Renal disease is characterized by the early influx of activated T cells and macrophages into the kidney. Activated T cells secrete IFN-c, which induces macrophages to express CSF-1, IL-1b, and TNF-a. Macrophages accumulate in the kidney during inflammation and generate IFN-a, TNF-a, and reactive oxygen species. Locally produced chemokines, particularly monocyte chemoattractant protein (MCP)-1, are also instrumental in attracting and maintaining cellular influx [8] -12 [20]. In the IRF-1 -/-NOD mouse, insulitis and diabetes were decreased accompanied by an increased survival [21]. Additional studies have suggested a role of IRF-1 and IFN-regulated genes in mediating human lupus [22][23][24]. Based on the knowledge that IRF-1 modulates inflammatory mediator production, we sought to determine whether IRF-1 gene deletion alters the severity of lupus nephritis in MRL/lpr mice. Results IRF-1 MRL/lpr mouse phenotypeTo determine the role of IRF-1 in autoimmune disease, IRF-1-knockout mice were backcrossed for eight generations to the MRL/lpr mice. After eight backcrosses, the littermates were intercrossed to yield cohorts for these studies....

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Induction of cross-reactive anti-dsDNA antibodies in preautoimmune NZB/NZW mice by immunization with bacterial DNA.

Cited by 168 publications

References 25 publications

Specificity and immunochemical properties of antibodies to bacterial DNA in sera of normal human subjects and patients with systemic lupus erythematosus (SLE)

Specificity and immunochemical properties of antibodies to bacterial DNA in sera of normal human subjects and patients with systemic lupus erythematosus (SLE)

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

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