Remnants of suicidal cells fostering systemic autoaggression: Apoptosis in the origin and maintenance of autoimmunity

Rovere, Patrizia; Sabbadini, Maria Grazia; Fazzini, Fausto; Bondanza, Attilio; Zimmermann, Valérie S.; Rugarli, C; Manfredi, Angelo A.

doi:10.1002/1529-0131(200008)43:8<1663::aid-anr1>3.0.co;2-1

Cited by 83 publications

(59 citation statements)

References 98 publications

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“…This phenomenon needs to be tightly regulated, as an unusual load of apoptotic bodies can induce systemic autoimmune disease [52]. Indeed, dead cells may also contribute to DC maturation, as it has been shown for necrotic or late apoptotic cells, but no early apoptotic cells.…”

Section: Dendritic Cells and Immune Tolerancementioning

confidence: 99%

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Blanco

Palucka

Pascual

et al. 2008

Cytokine & Growth Factor Reviews

455

362

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Dendritic cells (DCs) produce cytokines and are susceptible to cytokine-mediated activation. Thus, interaction of resting immature DCs with TLR ligands, for example nucleic acids, or with microbes leads to a cascade of pro-inflammatory cytokines and skewing of T cell responses. Conversely, several cytokines are able to trigger DC activation (maturation) via autocrine, for example TNF and plasmacytoid DCs, and paracrine, for example type I IFN and myeloid DCs, pathways. By controlling DC activation, cytokines regulate immune homeostasis and the balance between tolerance and immunity. The increased production and/or bioavailability of cytokines and associated alterations in DC homeostasis have been implicated in various human inflammatory and autoimmune diseases. Targeting these cytokines with biological agents as already is the case with TNF and IL-1 represents a success of immunology and the coming years will expand the range of cytokines as therapeutic targets in autoinflammatory and autoimmune pathology.

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Section: Dendritic Cells and Immune Tolerancementioning

confidence: 99%

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Blanco

Palucka

Pascual

et al. 2008

Cytokine & Growth Factor Reviews

455

362

View full text Add to dashboard Cite

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“…However, the lpr and gld mice suffer from a severe lymphoproliferative disorder, which is not characteristic of patients with SLE who are often Finally, a few individuals with an lpr-type genetic abnormality have been identified as having a lymphoproliferative disease like the MRL/lpr mouse but which is not much like SLE 16,17 . The evidence has been increasing that SLE is associated with too much apoptosis rather than too little 10,13,18 . Normally, apoptotic cells and their contents are cleared effectively by phagocytes 14 .…”

Section: Systemic Lupus Erythematosus: a Disease Of Too Little Or Toomentioning

confidence: 99%

“…Apoptotic blebs occur in the skin after UV exposure and contain proteins normally found in the nucleus, including Ro, La and nucleosomes, all classical autoantigens of SLE. The formation of some of these autoantigens may depend on the activities of certain proteases that are active during apoptosis such as granzyme B 13,18 .…”

Section: Systemic Lupus Erythematosus: a Disease Of Too Little Or Toomentioning

confidence: 99%

“…Intracellular proteins do not usually encounter the immune system because phagocytes remove them intact, but deficient phagocyte-mediated clearance of intact apoptotic cells occurs in SLE. This results in fragmentation and the release of intracellular antigens that can trigger an immune response 13,18 . However, there is a conundrum: T cells can recognise only peptides, but the most characteristic antibodies in SLE are to DNA and phospholipids.…”

Section: Deficient Clearance Of Apoptotic Cells and The Generation Ofmentioning

confidence: 99%

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Update on systemic lupus erythematosus: autoantibodies and apoptosis

Gordon

Salmon

2001

Clinical Medicine

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“…Previous studies on Ptx3 Ϫ/Ϫ mice suggested that PTX3 acts as a central "node" in cumulus matrix organization by establishing multivalent contacts to the HA-binding protein tumor necrosis factor-stimulated gene-6 protein (TSG-6) (9,14,15) and the serum protein inter-␣-inhibitor (16). PTX3 also plays a role in regulating the scavenger activity of macrophages and dendritic cells by direct binding to apoptotic cells (17)(18)(19)(20).…”

mentioning

confidence: 99%

Structural Characterization of PTX3 Disulfide Bond Network and Its Multimeric Status in Cumulus Matrix Organization

Inforzato

Rivieccio²,

Morreale

et al. 2008

Journal of Biological Chemistry

123

129

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PTX3 is an acute phase glycoprotein that plays key roles in resistance to certain pathogens and in female fertility. PTX3 exerts its functions by interacting with a number of structurally unrelated molecules, a capacity that is likely to rely on its complex multimeric structure stabilized by interchain disulfide bonds. In this study, PAGE analyses performed under both native and denaturing conditions indicated that human recombinant PTX3 is mainly composed of covalently linked octamers. The network of disulfide bonds supporting this octameric assembly was resolved by mass spectrometry and Cys to Ser site-directed mutagenesis. Here we report that cysteine residues at positions 47, 49, and 103 in the N-terminal domain form three symmetric interchain disulfide bonds stabilizing four protein subunits in a tetrameric arrangement. Additional interchain disulfide bonds formed by the C-terminal domain cysteines Cys 317 and Cys 318 are responsible for linking the PTX3 tetramers into octamers. We also identified three intrachain disulfide bonds within the C-terminal domain that we used as structural constraints to build a new three-dimensional model for this domain. Previously it has been shown that PTX3 is a key component of the cumulus oophorus extracellular matrix, which forms around the oocyte prior to ovulation, because cumuli from PTX3 ؊/؊ mice show defective matrix organization. Recombinant PTX3 is able to restore the normal phenotype ex vivo in cumuli from PTX3 ؊/؊ mice. Here we demonstrate that PTX3 Cys to Ser mutants, mainly assembled into tetramers, exhibited wild type rescue activity, whereas a mutant, predominantly composed of dimers, had impaired functionality. These findings indicate that protein oligomerization is essential for PTX3 activity within the cumulus matrix and implicate PTX3 tetramers as the functional molecular units required for cumulus matrix organization and stabilization.

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Remnants of suicidal cells fostering systemic autoaggression: Apoptosis in the origin and maintenance of autoimmunity

Cited by 83 publications

References 98 publications

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Update on systemic lupus erythematosus: autoantibodies and apoptosis

Structural Characterization of PTX3 Disulfide Bond Network and Its Multimeric Status in Cumulus Matrix Organization

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