Caspase‐activated DNase is required for maintenance of tolerance to lupus nuclear autoantigens

Jog, Neelakshi R.; Frisoni, Lorenza; Shi, Qin; Monestier, Marc; Hernandez, Sairy; Craft, Joe; Prak, Eline T. Luning; Caricchio, Roberto

doi:10.1002/art.33448

Cited by 16 publications

(7 citation statements)

References 47 publications

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“…72 , 73 A cooperation of C1q and DNase I accelerates the degradation of necrotic cells-derived chromatin. 49 , 74 The combination of a failure in the effective and immunologically silent opsonization of dead cell remnants and the abnormal immunogenic opsonization by autoantibodies of secondary necrotic cell-derived materials substantially contributes to the development of autoimmune disease and fuels chronic inflammation. This highlights the important role of opsonization of dead and dying cells for the multifactorial and complex disorder SLE.…”

Section: Implications Of Impaired Phagocytosis On Autoimmunitymentioning

confidence: 99%

Inflammatory etiopathogenesis of systemic lupus erythematosus: an update

Podolska¹,

Biermann²,

Maueröder³

et al. 2015

JIR

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The immune system struggles every day between responding to foreign antigens and tolerating self-antigens to delicately maintain tissue homeostasis. If self-tolerance is broken, the development of autoimmunity can be the consequence, as it is in the case of the chronic inflammatory autoimmune disease systemic lupus erythematosus (SLE). SLE is considered to be a multifactorial disease comprising various processes and cell types that act abnormally and in a harmful way. Oxidative stress, infections, or, in general, tissue injury are accompanied by massive cellular demise. Several processes such as apoptosis, necrosis, or NETosis (formation of Neutrophil Extracellular Traps [NETs]) may occur alone or in combination. If clearance of dead cells is insufficient, cellular debris may accumulate and trigger inflammation and leakage of cytoplasmic and nuclear autoantigens like ribonucleoproteins, DNA, or histones. Inadequate removal of cellular remnants in the germinal centers of secondary lymphoid organs may result in the presentation of autoantigens by follicular dendritic cells to autoreactive B cells that had been generated by chance during the process of somatic hypermutation (loss of peripheral tolerance). The improper exposure of nuclear autoantigens in this delicate location is consequently prone to break self-tolerance to nuclear autoantigens. Indeed, the germline variants of autoantibodies often do not show autoreactivity. The subsequent production of autoantibodies plays a critical role in the development of the complex immunological disorder fostering SLE. Immune complexes composed of cell-derived autoantigens and autoantibodies are formed and get deposited in various tissues, such as the kidney, leading to severe organ damage. Alternatively, they may also be formed in situ by binding to planted antigens of circulating autoantibodies. Here, we review current knowledge about the etiopathogenesis of SLE including the involvement of different types of cell death, serving as the potential source of autoantigens, and impaired clearance of cell remnants, causing accumulation of cellular debris.

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Section: Implications Of Impaired Phagocytosis On Autoimmunitymentioning

confidence: 99%

Inflammatory etiopathogenesis of systemic lupus erythematosus: an update

Podolska¹,

Biermann²,

Maueröder³

et al. 2015

JIR

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“…Cleavage of DNA may also facilitate the phagocytic clearance of debris from apoptotic cells; any DNA that escapes phagocytic clearance may eliminated the blood nucleases and binding proteins. Interestingly, defects in intracellular and extracellular nucleases can predispose to autoimmunity, presumably by increasing the amount of immunoactive DNA in the system [15-17]. …”

Section: Immune Properties Of Extracellular Dnamentioning

confidence: 99%

The origin and properties of extracellular DNA: From PAMP to DAMP

Pisetsky

2012

Clinical Immunology

190

160

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DNA is a polymeric macromolecule whose biological activities depend on location as well as binding to associated molecules. Inside the cell, DNA is the source of genetic information and binds histones to form nucleosomes. DNA can exit the cell, however, to enter the extracellular space primarily during cell death, either apoptosis or necrosis, as well as NETosis. While bacterial DNA is a potent immune stimulant by virtue of its CpG motifs, mammalian DNA, which is ordinarily inactive, can acquire activity by associating with nuclear, cytoplasmic and serum proteins which promote its uptake into cells to stimulate internal DNA sensors, including toll-like receptor 9. Among these proteins, anti-DNA autoantibodies can form immune complexes with DNA to stimulate plasmacytoid dendritic cells to produce type 1 interferon. Together, these findings suggest that the immune properties of DNA are mutable and diverse, reflecting its context and the array of attached molecules.

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“…Interestingly, the study reveals that the majority of patients with SLE (61 %, n = 40) exhibit decreased ability to degrade chromatin from either NETs, primary or secondary necrotic cells by serum. As there are multiple nucleases expressed in different tissues and cellular locations [ 21 ], it is tempting to speculate that studies of other means of degradation such as endogenous degradation of apoptotic chromatin by caspase-activated DNase [ 22 ] as well as other intracellular DNases such as TREX1 [ 23 , 24 ] and DNase-gamma [ 25 ] may expand this group further and should be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

A subset of patients with systemic lupus erythematosus fails to degrade DNA from multiple clinically relevant sources

Leffler¹,

Ciacma²,

Gullstrand³

et al. 2015

Arthritis Res Ther

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IntroductionPatients with systemic lupus erythematosus (SLE) have a decreased ability to clear cell remnants and multiple deficiencies in the ability to degrade cellular chromatin have been linked to the disease. Since the discovery of neutrophil extracellular traps (NETs), a renewed interest has been sparked in this field of research with multiple studies reporting a decreased ability of patients with SLE to degrade NETs. In this study we extend these findings by investigating the ability of patients with SLE to degrade chromatin from multiple clinically relevant sources.MethodsWe use flow cytometry in combination with NET degradation and DNA zymogram assays to investigate the ability of sera from SLE patients to degrade chromatin from three different sources of DNA such as NETs, apoptotic and necrotic cells. This ability was further associated with clinical manifestations.ResultsWe found that 61 % of the patients had an affected degradation of at least one chromatin source. Further, degradation of NETs correlated with degradation of chromatin from secondary necrotic cells but not with degradation of chromatin from primary necrotic cells. Patients who fail to degrade several forms of DNA more often display anti-nuclear and nephritic involvement whereas this is not observed in patients with decreased ability to degrade chromatin from primary necrotic cells.ConclusionsThe majority of patients with SLE has a decreased ability to degrade chromatin from clinically relevant sources. This decreased ability is further reflected in their clinical presentation.

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Caspase‐activated DNase is required for maintenance of tolerance to lupus nuclear autoantigens

Cited by 16 publications

References 47 publications

Inflammatory etiopathogenesis of systemic lupus erythematosus: an update

Inflammatory etiopathogenesis of systemic lupus erythematosus: an update

The origin and properties of extracellular DNA: From PAMP to DAMP

A subset of patients with systemic lupus erythematosus fails to degrade DNA from multiple clinically relevant sources

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