Impaired clearance of dying cells in systemic lupus erythematosus

Gaipl, Udo S.; Voll, Reinhard; Sheriff, Ahmed; Franz, Sandra; Kalden, Joachim R.; Herrmann, Martin

doi:10.1016/j.autrev.2004.10.007

Cited by 187 publications

(146 citation statements)

References 32 publications

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“…Accordingly, the same molecules that are released at the time of cell death and constitute major autoantigens in SLE and several other systemic autoimmune diseases are also potent IFN␣ inducers and can act as endogenous adjuvants in the autoimmune process (see below). Because patients with SLE have reduced clearance and increased numbers of apoptotic cells (75), apoptotic cell material should be readily available in vivo to generate interferogenic immune complexes.…”

Section: Activation and Regulation Of Nipcs/pdcs In Slementioning

confidence: 99%

The type I interferon system in systemic lupus erythematosus

Rönnblom

Eloranta

Alm

2006

Arthritis & Rheumatism

304

246

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Section: Activation and Regulation Of Nipcs/pdcs In Slementioning

confidence: 99%

The type I interferon system in systemic lupus erythematosus

Rönnblom

Eloranta

Alm

2006

Arthritis & Rheumatism

304

246

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Section: Introductionmentioning

confidence: 99%

“…Dying cells are normally removed rapidly from tissues by phagocytes, without eliciting inflammatory or immune responses. Clearance of apoptotic cells is crucial for prevention of autoimmune diseases [11,12]. Mice with impaired macrophage phagocytosis exhibit splenomegaly due to accumulation of massive quantities of apoptotic cells and such defect in humans leads to retinitis pigmentosa [13].…”

Section: Introductionmentioning

confidence: 99%

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

et al. 2009

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Oncostatin M (OSM) has been implicated in immune regulation, though its precise role remains elusive. Here we show that OSM plays a crucial role in the prevention of autoimmune diseases. OSM-deficient mice showed normal development of T cells, B cells and DC; however, their thymus showed hypoplasia and altered medullary structure. Autoantibodies against dsDNA accumulated and glomerulonephritis developed in aged OSMdeficient mice. Apoptotic cells accumulated in the thymus of OSM-deficient mice, and the administration of dexamethasone in young OSM-deficient mice resulted in the massive accumulation of apoptotic thymocytes and production of autoantibodies. These results suggest that OSM plays a key role in the prevention of autoimmune disease by regulating the clearance of apoptotic thymocytes.Key words: Apoptosis . Autoimmunity . Phagocytosis Supporting Information available online IntroductionOncostatin M (OSM) is a member of the IL-6 family of cytokines, and the OSM receptor (OSMR) consists of gp130 and the OSMRb subunit [1]. OSM is produced by a variety of cells including hematopoietic cells and fibroblasts, and is involved in various biological systems [2]. We showed previously that the lack of OSM signaling causes altered bone marrow microenvironment [3,4]. As OSM is also produced by Th1 cells and DC [5][6][7][8], OSM is suggested to play a role in immune reactions. In fact, OSM from activated DC regulates CCL21 expression in microvascular endothelial cells and promotes the trafficking of DC to LN [8].Moreover, Tg mice that express OSM using the lck proximal promoter exhibit thymic hypertrophy [9,10], suggesting that OSM may play a role in T-cell development within the thymic environment.Apoptosis is an essential process for development and homeostasis and defective clearance of apoptotic cells can lead to production of autoantibody by releasing cell debris, breaking peripheral tolerance. Macrophages in various tissues play an essential role in the elimination of apoptotic cells by phagocytosis. A vast majority of thymocytes are depleted by apoptosis during T-cell selections; however, apoptotic cells are barely detected in the thymus, indicating the presence of a mechanism to eliminate apoptotic thymocytes. Dying cells are normally removed rapidly from tissues by phagocytes, without eliciting inflammatory or immune responses. Clearance of apoptotic cells is crucial for prevention of autoimmune diseases [11,12] 1664with impaired macrophage phagocytosis exhibit splenomegaly due to accumulation of massive quantities of apoptotic cells and such defect in humans leads to retinitis pigmentosa [13].Previously, we demonstrated that OSM induces the development of thymic macrophages with strong phagocytic activity from intrathymic progenitors via OSM-responsive thymic epithelial cells (TEC) [14,15]. In this report, we show that OSM deficiency resulted in thymic hypoplasia, defective clearance of apoptotic thymocytes, accumulation of autoantibody and glomerulonephritis. Administration of dexamethasone (Dex) in OSM-defi...

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“…Conceivably, surpassing the capacity for apoptotic cell clearance could trigger a local inflammatory reaction via the exposure of endogenous danger signals (12). Under such circumstances, apoptotic cell antigens are taken up by antigen-presenting cells (e.g., dendritic cells) that have been activated by proinflammatory signals.…”

mentioning

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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Impaired clearance of dying cells in systemic lupus erythematosus

Cited by 187 publications

References 32 publications

The type I interferon system in systemic lupus erythematosus

The type I interferon system in systemic lupus erythematosus

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

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

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