Systemic Lupus Erythematosus: Presence in Human Serum of an Unusual Acid-Labile Leukocyte Interferon

Preble, Olivia T.; Black, Roberta J.; Friedman, Robert M.; Klippel, John H.; Vilček, Ján

doi:10.1126/science.6176024

Cited by 429 publications

(201 citation statements)

References 17 publications

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“…Antibodies to nucleic antigens, for example, nucleosomes, histones, and DNA, are common, but antibodies of many other specificities can be found (1). The type I interferon (IFN) system has been proposed to have a pivotal etiopathogenic role in SLE (2,3) because the production of IFN␣ is activated in SLE patients, and this activation correlates with disease activity and severity (4)(5)(6)(7)(8). Moreover, IFN␣ therapy of certain malignancies and persistent viral infections is often associated with autoimmune side effects that usually disappear when the IFN␣ treatment is terminated (for review, see refs.…”

mentioning

confidence: 99%

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Lövgren

Eloranta

Båve

et al. 2004

Arthritis & Rheumatism

503

411

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Objective. To investigate the release of interferon-␣ (IFN␣)-inducing material by necrotic or apoptotic cells, its properties, and the necessity of autoantibodies from systemic lupus erythematosus (SLE) patients for the interferogenic activity.Methods. U937 monocytic leukemia cells or peripheral blood mononuclear cells (PBMCs) were rendered necrotic by freeze-thawing or apoptotic by treatment with ultraviolet light. Cell culture supernatants from these cells and IgG from SLE patients (SLE IgG) were added to cultures of normal PBMCs or purified plasmacytoid dendritic cells (PDCs). The importance of nucleic acids for IFN␣ induction was investigated by RNase and DNase treatment. The IFN␣ levels were measured by immunoassay.Results. Both necrotic and apoptotic U937 cells released material that, combined with SLE IgG, induced IFN␣ production in PDCs. The release from apoptotic cells occurred with a 16-hour delay, in late apoptosis. Also, normal PBMCs released IFN␣-inducing material, but only during necrosis. The interferogenic activity of the necrotic material required the presence of RNA, while both RNA and DNA were important in the apoptotic material. In both cases, the presence of SLE IgG was necessary, and its activity correlated with the presence of antibodies to RNA-binding proteins, but not anti-DNA antibodies.Conclusion. Necrotic and late apoptotic cells release material that, combined with SLE IgG, induces production of IFN␣ in PDCs. The IFN␣ inducers probably consist of immune complexes (ICs) containing RNA and possibly DNA as essential interferogenic components. The presence of such interferogenic ICs could explain the ongoing production of IFN␣ in SLE and could be of etiopathogenic importance.

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confidence: 99%

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Lövgren

Eloranta

Båve

et al. 2004

Arthritis & Rheumatism

503

411

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“…Serum interferon (IFN)-α concentrations are elevated in patients with systemic lupus erythematosus (SLE) [1] and contribute to the break of peripheral tolerance by sustaining the differentiation of myeloid dendritic cells [2]. IFN-α actually increases the differentiation of monocytes into dendritic cells that present antigens from dying cells to CD4 + lymphocytes, resulting in their proliferation.…”

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confidence: 99%

Neutrophils and interferon-α-producing cells: who produces interferon in lupus?

Decker

2011

Arthritis Res Ther

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Interferon-α plays a crucial role in the pathogenesis of systemic lupus erythematosus. Nevertheless, the different human cell types producing this cytokine as well as the stimuli inducing its production have not been completely characterized. So far, a subpopulation of dendritic cells activated by immune complexes has been identified as major producers of interferon-α in patients with lupus. However, those cells represent a minor population and some studies have reported the secretion of interferon-α by other cells. On the other hand, more than 50% of blood leukocytes are neutrophils and their functions are still not fully understood. Recent data suggest that neutrophils, though usually not considered interferon-α-producing cells, may represent an unexpected source of this cytokine in response to some lupus stimuli.

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“…IFN-a is another important factor in the development of SLE, and elevated levels of this antiviral cytokine or IFN-a-induced genes are frequently observed in patients with SLE [12][13][14][15]. Activation of the class I IFN system has been confirmed by recent studies using microarray approaches [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…Current explanations for the loss of tolerance in states of complement deficiency include impaired elimination of apoptotic bodies [4,5] or dying cells [6] as a source of autoantigens [7,8], and inadequate regulation of follicular B cells via the complement receptor CD21/35 [3], although the absence of CD21, or its most important ligand (C3d), does not seem to be associated with SLE [9,10]. As such, neither model alone can adequately account for the association of complement deficiency and SLE [11].IFN-a is another important factor in the development of SLE, and elevated levels of this antiviral cytokine or IFN-a-induced genes are frequently observed in patients with SLE [12][13][14][15]. Activation of the class I IFN system has been confirmed by recent studies using microarray approaches [16][17][18][19].…”

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confidence: 99%

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

et al. 2007

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Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis and dermatitis, and the presence of antinuclear autoantibodies, is associated with complement factor deficiencies in the classical activation pathway. In addition, IFN-a seems to be a key cytokine in SLE as an activated IFN-a system is regularly observed in patients with SLE. Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA. The apoptotic DNA is targeted to the splenic marginal zone where it accumulates and induces IFN-a. As such, we present here a unifying hypothesis for the induction of SLE that incorporates the role of complement deficiency and elevated levels of IFN-a. IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibodies against various nuclear antigens, as well as the generation of immune complexes (IC) leading to inflammatory responses in skin, kidneys, joints, the vasculature and the heart [1]. Susceptibility genes for SLE include those involved in the deficiency of early complement factors of the classical pathway (C1, C4, C2) [2], which has been confirmed in animal models for complement deficiency [3,4]. Current explanations for the loss of tolerance in states of complement deficiency include impaired elimination of apoptotic bodies [4,5] or dying cells [6] as a source of autoantigens [7,8], and inadequate regulation of follicular B cells via the complement receptor CD21/35 [3], although the absence of CD21, or its most important ligand (C3d), does not seem to be associated with SLE [9,10]. As such, neither model alone can adequately account for the association of complement deficiency and SLE [11].IFN-a is another important factor in the development of SLE, and elevated levels of this antiviral cytokine or IFN-a-induced genes are frequently observed in patients with SLE [12][13][14][15]. Activation of the class I IFN system has been confirmed by recent studies using microarray approaches [16][17][18][19]. Moreover, the administration of IFN-a for therapeutic purposes induces typical SLE autoantibodies as a side effect [20,21]. Both these phenomena are poorly understood and no unifying hypothesis, incorporating the role of complement deficiency and elevated IFN-a levels in the induction of SLE, exists. Recently, we described an unusual deposition of IgMcontaining immune complexes (IgM-IC) in the splenic marginal zone (MZ) of complement C4-deficient (C4 null ) mice. This IgM-IC deposition led to restoration of a humoral immune response against foreign antigens within those IC, when compared to mice receiving antigen only [22]. Murine MZ macrophages are known to produce IFN-a [23] and we hypothesized that intravascular nuclear antigen levels would be elevated as a result of complement deficiency and that natural IgM anti-DNA antibodies would mediate the IC deposition in the splenic MZ. Here, the nuclear antigens would induce IFN-a, which i...

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Systemic Lupus Erythematosus: Presence in Human Serum of an Unusual Acid-Labile Leukocyte Interferon

Cited by 429 publications

References 17 publications

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Neutrophils and interferon-α-producing cells: who produces interferon in lupus?

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

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