Clearance deficiency and systemic lupus erythematosus (SLE)

Gaipl, Udo S.; Muñoz, Luis; Grossmayer, Gerhard E.; Lauber, Kirsten; Franz, Sandra; Sarter, Kerstin; Voll, Reinhard; Winkler, Thomas; Kuhn, Annegret; Kalden, Joachim R.; Kern, Peter; Herrmann, Martin

doi:10.1016/j.jaut.2007.02.005

Cited by 248 publications

(234 citation statements)

References 51 publications

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“…In fact, it has been demonstrated that monocyte secretion of IL-1β, IL-8, granulocyte macrophage colony-stimulating factor, and TNF-α is inhibited after phagocytosis of apoptotic cells whereas the secretion of antiinflammatory cytokines such as TGF-β1 and IL-10 is increased [7,42]; interestingly these data have been also confirmed in vivo [6]. However, it is well accepted that impaired clearance of apoptotic cells is related to the development of autoimmunity and promote the secretion of proinflammatory cytokines [43]. A recent study seems to clarify in part this paradox [17].…”

Section: Clearance Of Apoptotic Cells and Productsmentioning

confidence: 91%

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The consequences of apoptosis in autoimmunity

Lleo

Selmi

Invernizzi

et al. 2008

Journal of Autoimmunity

123

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The clearance of apoptotic cells is a highly regulated mechanism, normally associated with antiinflammatory response. During early stages of apoptosis the cell is promptly recognized and engulfed by professional phagocytes or tissue cells to avoid the outflow of intracellular content and limit the immunological reaction against released antigens. However, increasing evidences suggest that impairment in the uptake of apoptotic cell debris is linked to the development of autoimmunity. In fact, autoantigens have been demonstrated to be content within apoptotic bodies and apoptotic cells seems to be critical in the presentation of antigens, activation of innate immunity and regulation of macrophage cytokine secretion.We herein review the known mechanisms for regulating the uptake of the products of apoptosis in the development of autoimmunity.

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Section: Clearance Of Apoptotic Cells and Productsmentioning

confidence: 91%

“…[64] [43] Lupus nephritis (LN) LN is associated with high titers of circulating high-affinity, IgG anti-double-stranded DNA (anti-dsDNA) antibodies and glomerular immunoglobulin deposits. Large chromatin fragments, derived from apoptotic cells, are located in the membranes of nephritic kidneys from murine and human SLE.…”

Section: Mechanismmentioning

confidence: 99%

The consequences of apoptosis in autoimmunity

Lleo

Selmi

Invernizzi

et al. 2008

Journal of Autoimmunity

123

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“…Reduced apoptotic cell clearance has been suggested as a key element in the pathogenesis of SLE (10,28). Immune complexes containing chromatin particles have been shown to be deposited within both the glomerular basement membrane and the mesangial extracellular matrix and are thought to serve as a source of inflammatory signaling, but the origin of these chromatin deposits remains unknown.…”

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confidence: 99%

Alterations in Wnt pathway activity in mouse serum and kidneys during lupus development

Tveita

Rekvig

2011

Arthritis & Rheumatism

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Objective. The canonical Wnt/␤-catenin pathway was recently identified as a factor in the pathogenesis of several renal diseases. The aim of this study was to evaluate Wnt signaling activity during disease development in a murine model of lupus nephritis.Methods. Wnt activity and Dkk-1 expression were serially assayed in the serum and kidneys of (NZB ؋ NZW)F 1 mice during progression of lupus nephritis. The effects of serum obtained from mice with lupus and serum-equivalent concentrations of Dkk-1 on mesangial cells were assessed in vitro.Results. Gene expression analyses revealed increased canonical Wnt pathway activity in kidneys during development of lupus nephritis, paralleled by an increase in renal and serum levels of the Wnt inhibitor Dkk-1. Sera obtained from proteinuric-stage (NZB ؋ NZW)F 1 mice showed strong Wnt-inhibitory effects in vitro. Dkk-1 concentrations comparable to those observed in lupus-prone mice induced apoptosis in tubular and mesangial cells in vitro, whereas no such effect was seen for the range of concentrations observed in young prediseased mice and control BALB/c mice.Conclusion. These data demonstrate that renal Wnt signaling activity is increased in lupus and is accompanied by an increase in renal and serum levels of Dkk-1. The Wnt pathway is involved in the turnover of extracellular matrix constituents and represents a potential mediator of the morphologic changes that occur within the glomerulus during the development of nephritis. Furthermore, increased levels of Dkk-1 serve as a potential proapoptotic stimulus in vitro and possibly in vivo and could be an important element in the initiation and progression of systemic and end-organ disease manifestations in systemic lupus erythematosus.

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“…Then, 3 Hthymidine (1 μCi/well) (Amersham Biosciences) was added to the cultures for an additional 16 h. Cells were washed and harvested onto a glassfiber filter using an automated cell harvester (Perkin Elmer). T cell proliferation was determined by liquid scintillation counting.…”

Section: T Cell Suppression By Uvb-stromal Cellsmentioning

confidence: 99%

“…Evidence has shown that impaired function of phagocytosing apoptotic cells is associated with development of autoimmune diseases [1][2][3][4][5], suggesting that processing of apoptotic cells through phagocytosis plays an important role in the maintenance of self-tolerance. It has been documented that steady state apoptotic cells phagocytosed by dendritic cells can render dendritic cells to be tolerogenic and subsequently tolerize CD4+ T cells and CD8+ T cells through direct antigen presentation and antigen cross-presentation, respectively [6].…”

Section: Introductionmentioning

confidence: 99%

Infusion of UVB-treated splenic stromal cells induces suppression of β cell antigen-specific T cell responses in NOD mice

Xia

Qiu

Peng

et al. 2008

Journal of Autoimmunity

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Our previous study has demonstrated that transfusion of UVB-irradiation-induced apoptotic β cells effectively prevents type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. However, the limitation of β cell source would preclude the clinical application of this approach. Therefore, in the present study, we have attempted to establish a more practical approach by utilizing apoptotic non-β cells to prevent T1D. We find that apoptotic splenic stromal cells significantly suppress β cell antigen-reactive T cell proliferation in vitro and in vivo. Moreover, β cell antigen-specific T cells primed by β cell antigens in the presence of apoptotic stromal cells have markedly reduced responsiveness to the re-stimulation of the same β cell antigen. We also find that β cell antigenspecific IL-10-producing CD4+ T cells are induced in the presence of apoptotic splenic stromal cells. As expected, transfusion of apoptotic stromal cells effectively protected NOD mice from developing T1D. Furthermore, the proliferation of adoptively transferred β cell antigen-specific TCR-transgenic T cells in pancreatic draining lymph nodes is markedly suppressed in UVB-stroma-treated mice, indicating that UVB-stroma treatment induces immune tolerance to multiple β cell antigens. This study provides an effective and convenient approach for managing T1D by utilizing apoptotic non-β cells.

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Clearance deficiency and systemic lupus erythematosus (SLE)

Cited by 248 publications

References 51 publications

The consequences of apoptosis in autoimmunity

The consequences of apoptosis in autoimmunity

Alterations in Wnt pathway activity in mouse serum and kidneys during lupus development

Infusion of UVB-treated splenic stromal cells induces suppression of β cell antigen-specific T cell responses in NOD mice

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