Mutation of DNASE1 in people with systemic lupus erythematosus

Yasutomo, Koji; Horiuchi, Takahiko; Kubo, Shoji; Tsukamoto, Hiroshi; Hashimura, Chinami; Urushihara, Maki; Kuroda, Yasuhiro

doi:10.1038/91070

Cited by 537 publications

(352 citation statements)

References 9 publications

Supporting

Mentioning

333

Contrasting

Unclassified

Order By: Relevance

“…Moreover, it appeared that nucleosome integrity was essential for DC maturation because heat-treated nucleosomes as well as DNase I-treated nucleosomes were poor activators of DC. It is important to recall in this study that SLE patients have an impaired DNase I activity (28). Now, it is known that DNase I is a major serum DNase and impaired DNase I activity has been suggested to be responsible for higher nucleosome concentrations in sera from SLE patients.…”

Section: Discussionmentioning

confidence: 83%

Nucleosome, the Main Autoantigen in Systemic Lupus Erythematosus, Induces Direct Dendritic Cell Activation via a MyD88-Independent Pathway: Consequences on Inflammation

Decker

Singh‐Jasuja

Haager

et al. 2005

The Journal of Immunology

106

View full text Add to dashboard Cite

Nucleosome is the major autoantigen in systemic lupus erythematosus. It is found as a circulating complex in the sera of patients and seems to play a key role in disease development. In this study, we show for the first time that physiologic concentrations of purified nucleosomes directly induce in vitro dendritic cell (DC) maturation of mouse bone marrow-derived DC, human monocyte-derived DC (MDDC), and purified human myeloid DC as observed by stimulation of allogenic cells in MLR, cytokine secretion, and CD86 up-regulation. Importantly, nucleosomes act as free complexes without the need for immune complex formation or for the presence of unmethylated CpG DNA motifs, and we thus identified a new mechanism of DC activation by nucleosomes. We have clearly demonstrated that this activation is nucleosome-specific and endotoxin-independent. Particularly, nucleosomes induce MDDC to secrete cytokines known to be detected in high concentrations in the sera of patients. Moreover, activated MDDC secrete IL-8, a neutrophil chemoattractant also detected in patient sera, and thus might favor the inflammation observed in patients. Both normal and lupus MDDC are sensitive to nucleosome-induced activation. Finally, injection of purified nucleosomes to normal mice induces in vivo DC maturation. Altogether, these results strengthen the key role of nucleosomes in systemic lupus erythematosus and might explain how peripheral tolerance is broken in patients.

show abstract

Section: Discussionmentioning

confidence: 83%

Nucleosome, the Main Autoantigen in Systemic Lupus Erythematosus, Induces Direct Dendritic Cell Activation via a MyD88-Independent Pathway: Consequences on Inflammation

Decker

Singh‐Jasuja

Haager

et al. 2005

The Journal of Immunology

106

View full text Add to dashboard Cite

show abstract

“…Indeed, high levels of circulating nucleosomes have been found in some patients with SLE (41). High titers of IgG against nucleosomal antigens were also found in 2 patients with a heterozygous nonsense mutation in exon 2 of DNase I (42). However, it is obvious that additional genes are involved in the DNA clearance process (43,44).…”

Section: Discussionmentioning

confidence: 99%

Cooperation between C1q and DNase I in the clearance of necrotic cell–derived chromatin

Gaipl¹,

Beyer²,

Heyder³

et al. 2004

Arthritis & Rheumatism

105

View full text Add to dashboard Cite

Objective. The efficient uptake of dying cells by phagocytes is essential to the avoidance of chronic inflammation. Some human autoimmune responses are thought to be driven by autoantigens from apoptotic or necrotic cells. We analyzed the role of C1q and DNase I in the disposal of necrotic cell-derived chromatin because deficiencies in these serum factors predispose to the development of systemic autoimmune disorders, such as systemic lupus erythematosus.Methods. Human necrotic peripheral blood lymphocytes were incubated in cell culture medium supplemented with various sera or serum components. Chromatin degradation was monitored by measuring the residual DNA content by flow cytometry. The uptake of necrotic cell-derived nuclei was analyzed by in vitro phagocytosis assays.Results. Reconstitution of C1q-depleted serum with C1q strongly increased its ability to degrade necrotic cell-derived chromatin. Although C1q itself displayed no DNase activity, it strongly augmented the activity of serum DNase I. Whereas an excess of recombinant DNase I degraded chromatin in the absence of C1q, efficient uptake of the predigested material by monocyte-derived phagocytes required the presence of C1q. These data show that C1q and DNase I cooperate in the degradation of chromatin from necrotic cells. Furthermore, C1q was found to be necessary for effective uptake of degraded chromatin by monocyte-derived phagocytes.Conclusion. C1q or DNase I deficiencies may precipitate autoimmunity in humans by a mechanism similar to that of other molecules that are involved in the safe, efficient, and rapid disposal of dying cells.

show abstract

“…In fact, deoxyribonuclease 2 (DNase 2) is one of the potential candidate genes located at 19p13.2 partly because mutations in DNase1 have been implicated in lupus by others. 20 Indeed, lowactivity (DNase2 L) and high-activity (DNase2 H) polymorphisms are known. 21 DNase 2 has been implicated in diverse functions including the degradation of foreign DNA, genomic instability, and the mediation of DNA digestion associated with apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Genome scan stratified by the presence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2)

et al. 2002

View full text Add to dashboard Cite

show abstract

Mutation of DNASE1 in people with systemic lupus erythematosus

Cited by 537 publications

References 9 publications

Nucleosome, the Main Autoantigen in Systemic Lupus Erythematosus, Induces Direct Dendritic Cell Activation via a MyD88-Independent Pathway: Consequences on Inflammation

Nucleosome, the Main Autoantigen in Systemic Lupus Erythematosus, Induces Direct Dendritic Cell Activation via a MyD88-Independent Pathway: Consequences on Inflammation

Cooperation between C1q and DNase I in the clearance of necrotic cell–derived chromatin

Genome scan stratified by the presence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2)

Contact Info

Product

Resources

About