Disposal of dying cells: A balancing act between infection and autoimmunity

Gaipl, Udo S.; Brunner, Jürgen; Beyer, Thomas; Voll, Reinhard; Kalden, Joachim R.; Herrmann, Martin

doi:10.1002/art.10744

Cited by 33 publications

(23 citation statements)

References 65 publications

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“…Changes on the surfaces of apoptotic and necrotic cells are extremely important for their recognition and disposal. Some SLE patients appear to have an impaired ability to clear apoptotic and necrotic cells from tissues; this could predispose to disruption of mechanisms of peripheral tolerance against self antigens (39,41,42).…”

Section: Discussionmentioning

confidence: 99%

“…In late stages of apoptosis, dead cells can be cleared via backup mechanisms such as complementmediated uptake (12,14,41,43). Recently, it has been shown that the high mobility group box chromosomal protein 1 (HMGB-1), which is "frozen" on the chromatin of apoptotic cells and remains immobilized even under conditions of secondary necrosis, is released by primary necrotic cells and contributes to the inflammatory response (44).…”

Section: Discussionmentioning

confidence: 99%

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Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

Böttcher

Gaipl

Fürnrohr³

et al. 2006

Arthritis & Rheumatism

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Objective. Uningested dead cells may be an important source of autoantigens and may trigger autoimmune diseases such as systemic lupus erythematosus (SLE). Multiple receptors involved in the clearance of apoptotic cells have been described; however, little is known about the receptors and ligands involved in uptake of necrotic cells that release autoantigens as well.Methods. The uptake of autologous necrotic peripheral blood lymphocytes into human monocyte-derived macrophages was qualitatively and quantitatively monitored by confocal microscopy and 2-color flow cytometry, respectively. Blocking experiments were performed to examine the receptors and molecules involved in the phagocytosis of necrotic cells. Cytokine secretion by lipopolysaccharide-activated monocytes and macrophages was determined by enzyme-linked immunosorbent assay.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

Böttcher

Gaipl

Fürnrohr³

et al. 2006

Arthritis & Rheumatism

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“…Self-sustaining, clinically evident autoimmunity has been proposed to depend on the failure of the balance between cytokines that drive the differentiation of the major subsets of DC, like TNF-a and IFN-a [6]. The latter factor in particular plays a leading role in the pathogenesis of the prototypic systemic autoimmune disease, systemic lupus erythematosus, a disease in which the deregulated clearance of dying cells is crucial [65]. Further investigation is warranted to determine the potential of the regulated release of HMGB1 in human disease.…”

Section: Discussionmentioning

confidence: 99%

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

et al. 2005

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Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the bestcharacterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. IntroductionDendritic cells (DC) are potent antigen-presenting cells bridging the innate and adaptive immune responses. To date, two subsets of DC have been identified in humans: myeloid DC and plasmacytoid DC (PDC), the latter also referred to as type I interferon (IFN-a)-producing cells [1][2][3][4][5][6]. PDC recognize viral or bacterial DNA patterns, consisting of unmethylated CpG motifs in the context of species-dependent surrounding sequences (CpG) [7]. As a consequence they produce, within a few hours, large amounts of . Based on their ability to induce IFN-a secretion by PDC, two types of CpG have been described: CpG 2216 (CpG-A), which induces high amounts of IFN-a, and CpG 2006 (CpG-B), which promotes survival, maturation and migration of PDC to the lymph nodes, but induces lower amounts of . PDC sustain the priming of naive T cells and their differentiation into Th1/Th2 effectors [15][16][17] or into regulatory T cells [16,[18][19][20][21][22].Recent studies shed light on the events involved in the recognition of microbial DNA by human PDC, the only subset of human DC that expresses the Toll-like receptor 9 (TLR9) [12]. Both CpG-A and CpG-B have been shown to activate PDC via TLR9 [23]. Upon phagocytosis PDC lyse microorganisms in phagolysosomes, where microbial DNA interacts with and activates TLR9 derived from the endoplasmic reticulum [24]. TLR9 activation leads to recruitment of the MyD88 adaptor protein and phosphorylation of the IL-1R-associated kinase (IRAK). Phosphorylated IRAK associates with the adaptor molecule TNF-associated factor 6 (TRAF6) [25]. Two separate signaling pathways, JNK and NF-jB, are then activated, promoting PDC maturation and survival. IFN-a induction, an event exclusively occurring in PDC, depends on the formation of a complex consisting of MyD88, TRAF6 and the IRF7 transcription factor, as well as on TRAF6-dependent ubiquitination [26].The events that determine the outcome of the interaction of PDC with T cells, and in particular the induction of effector or regulatory immune responses, are poorly characterized. Environmental signals that Here we report that HMGB1 is exported from the nucleus of PDC upon selective engagement of TLR9 an...

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“…Apoptotic cell death has been associated with the progression of numerous autoimmune diseases [1][2][3]. Sjögren's syndrome (SS), also known as dry eye-dry mouth syndrome, is an autoimmune disease manifested by lymphocyte infiltration, loss of secretion from secretory gland cells, and apoptosis [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Interferon-gamma sensitizes the human salivary gland cell line, HSG, to tumor necrosis factor-alpha induced activation of dual apoptotic pathways

2006

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Activated immune cells secrete proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma) and Fas ligand (FasL) and these cytokines have been reported to induce apoptosis in numerous cell types. Apoptotic cell death has been associated with the progression of numerous autoimmune diseases. Proinflammatory cytokines are reportedly involved in apoptosis in the salivary glands of patients with Sjögren's syndrome (SS); an autoimmune disorder characterized by the destruction of salivary and lachrymal glands. In this study, we used the HSG cell line to determine if exposure to proinflammatory cytokines induces apoptosis in human salivary gland cells. In addition, we identified the mediators controlling the apoptotic process in response to TNF alpha and IFN gamma. TNF-alpha and IFN-gamma induced apoptosis in HSG cells and resulted in the activation of caspase 8 and the "death receptor" pathway. We further determined that caspase 9 and the "mitochondrial" pathway was also activated. Induction of the intrinsic and extrinsic pathways in HSG cells resulted in substrate cleavage by effector caspases, in particular the cleavage of alpha II spectrin, an autoantigen in Sjögren's syndrome. Our results suggest that HSG cells provide a model system to study processes regulating proinflammatory cytokine-induced apoptotic cell death.

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Disposal of dying cells: A balancing act between infection and autoimmunity

Cited by 33 publications

References 65 publications

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

Interferon-gamma sensitizes the human salivary gland cell line, HSG, to tumor necrosis factor-alpha induced activation of dual apoptotic pathways

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