Extranuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis

Gabler, Christoph; Blank, Norbert; Hieronymus, Thomas; Schiller, Martin; Berden, Jo H. M.; Kalden, Joachim R.; Lorenz, Hanns‐Martin

doi:10.1136/ard.2003.011452

Cited by 48 publications

(37 citation statements)

References 31 publications

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“…Furthermore, it was recently shown that an extranuclear accumulation of histones and nucleosomes is an early event of apoptosis in human lymphoblasts. Dysregulation of early apoptosis might lead to an overload of autoantigens (and in particular of nucleosomes) in circulation or in target tissues [78] and support the induction of autoimmunity against nuclear components [79]. We showed that in a subgroup of patients with SLE apoptotic cells accumulated in the germinal centers of the lymph nodes.…”

Section: Intrinsic Clearance Defects In Some Systemic Lupus Erythematmentioning

confidence: 91%

Defects in the disposal of dying cells lead to autoimmunity

Gaipl¹,

Franz²,

Voll³

et al. 2004

Curr Rheumatol Rep

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The fast and efficient uptake of dying cells is of main importance to prevent contact of the immune system with intracellular autoantigens. Insufficient clearance of the latter is discussed to drive the humoral autoimmune response in systemic lupus erythematosus. Many adaptor molecules and receptors are involved in the recognition of dying cells. In this paper we focus on the involvement of phosphatidylserine, glycoproteins, and complement and DNaseI in the clearance of apoptotic and necrotic cells, respectively. Furthermore, extracellular danger signals released from necrotic cells are discussed and the uptake process of primary necrotic cells is investigated in detail. Last but not least, the character and origin of clearance defects observed in some systemic lupus erythematosus patients is presented.

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Section: Intrinsic Clearance Defects In Some Systemic Lupus Erythematmentioning

confidence: 91%

Defects in the disposal of dying cells lead to autoimmunity

Gaipl¹,

Franz²,

Voll³

et al. 2004

Curr Rheumatol Rep

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“…4C). In mature cells, H3 and H4 are nuclear proteins (19), and the observation that NK3R immunoprecipitated both histones in 2 M NaCl-treated rats could only occur after NK3R was translocated into the nucleus. To check for nondiscriminant protein-protein interactions, the membranes were checked for the presence of Lamin B2, a nuclear membrane protein.…”

Section: Co-ip: Nk3r and Acetylated H4 And Acetylated H3mentioning

confidence: 93%

Neurokinin 3 receptor forms a complex with acetylated histone H3 and H4 in hypothalamic neurons following hyperosmotic challenge

Flynn

Jensen

Thakar³

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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The neurokinin 3 receptor (NK3R) is a G protein-coupled receptor that is expressed in brain and is highly expressed by magnocellular vasopressinergic neurons in both the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus. Hyperosmolarity causes a ligand-mediated internalization of NK3Rs to the cytoplasm and to the nuclei of vasopressinergic PVN neurons. This receptor activation-dependent pathway is presumed to be a means to directly transmit synaptic signals from the cell membrane to the nucleus. The present study evaluated in vivo the subnuclear domains that associate with NK3R. Rats were administered 2 M NaCl (intragastric) or no intragastric load, and 40 min later, the PVN was dissected and nuclei were isolated. Using double-immuno-transmission electron microscopy (TEM), we show that, compared with controls, hyperosmolarity causes a significant increase in NK3R Immunogold beads in the nucleus of PVN neurons. Furthermore, NK3R spatially colocalized with histone H4 and with highly acetylated H4 in nuclei isolated from the PVN of rats administered 2 M NaCl, but not in nuclei from control rats. Next, coimmunoprecipitation experiments showed that acetylated H4, as well as acetylated H3, were pulled down with NK3R in the PVN nuclear enriched fraction from rats treated with 2 M NaCl, but not from control rats. In response to hyperosmolarity, NK3R is transported to the nucleus of PVN neurons and associates with transcriptionally active chromatin, where it may influence the transcription of genes.

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“…Previously, we have already shown an accumulation of nuclear antigens in the cytoplasm of apoptotic lymphocytes. 9 It has been described that nucleosomes are exposed on the cellular surface during apoptosis. 10 This autoantigen translocation can enhance phagocytosis of apoptotic material and presentation of autoantigens.…”

mentioning

confidence: 99%

Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis

et al. 2007

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A dysregulation of apoptosis or an ineffective clearance of apoptotic material is suspected to be involved in the pathogenesis of systemic lupus erythematodes. Subcellular fragments such as apoptotic bodies (ABs) have been recognized as modulators of intercellular communication and immune function. In this context, we have been interested whether nuclear and cytoplasmic antigens are relocated into ABs. In the present study, we characterized ABs isolated from apoptozing lymphoblasts. We found an accumulation of the linker-histone (histone 1) as well as the core-histones (histone 2A, histone 2B, histone 3, histone 4) in ABs. Further, they contained DNA, RNA and the ribonuclear protein La/SSB. Proteins such as cytochrome c, HSP 70, prohibitin, p53, nuclear matrix antigen or lamin B were excluded from ABs. The content of ABs differed from that observed in membrane microparticles isolated from viable cells. Formation of ABs occurred early during apoptosis. It was observed before DNAdegradation or phosphatidylserine exposure was detected. ABs were engulfed by monocyte-derived phagocytes. These findings suggest that immunogenic molecules are actively translocated into ABs followed by a rapid engulfment of the latter by environmental phagocytes. In autoimmune diseases, a defect in the clearance of ABs or AB formation may contribute to the development of autoimmunity.

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Extranuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis

Cited by 48 publications

References 31 publications

Defects in the disposal of dying cells lead to autoimmunity

Defects in the disposal of dying cells lead to autoimmunity

Neurokinin 3 receptor forms a complex with acetylated histone H3 and H4 in hypothalamic neurons following hyperosmotic challenge

Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis

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