Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Through the activation of Toll-like receptors (TLRs) or cytosolic RNA helicases, a large number of pathogenic or synthetic components can induce the transcription of genes coding for type I interferons (IFNs). This family of related cytokines includes notably, a single IFN-beta protein and 13 different IFN-alpha subtypes, whose biological activities are probably not the same. The aim of this study was to characterize the type I IFN subtypes produced in vitro by human peripheral blood mononuclear cells (PBMCs) in response to specific inducers. Thus, PBMCs obtained from a single donor, were exposed to various agents including Sendai virus, Herpes simplex virus-1 (HSV-1), poliovirus-IgG complexes and serum from a patient with systemic lupus erythematosus (SLE). Six hours later, mRNA was extracted and amplified by RT-PCR using primers which recognize IFN-B mRNA and the different IFN-A mRNA subtypes. IFN-A subtypes were identified by cloning and sequencing the amplification product. Antiviral activity was assayed in supernatant at 18 hours. Human PBMCs were found to express constitutively type I IFNs mRNA. Antiviral activity and expression of IFN-A and IFN-B mRNA increased with each inducing agent. Although almost all the IFN-A subtypes were detected, their relative abundance appeared to be dependent upon the inducing agent. Incubation of PBMCs with a neutralizing monoclonal antibody directed against the type I IFN receptor (IFNAR) did not affect the level of antiviral activity in the supernatant of induced PBMCs. Our results suggest that the level of IFN-alpha expressed by PBMCs cells is independent of IFNAR feedback signalling and that the nature of the inducing agent modifies the pattern of IFN-A subtypes preferentially expressed by these cells.
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PMID:Type I interferon subtypes produced by human peripheral mononuclear cells from one normal donor stimulated by viral and non-viral inducing factors. 1759 44

Neutralizing Abs to type I IFNs are of therapeutic significance, i.e., are currently evaluated for the treatment of autoimmune diseases with pathogenic IFN-alpha production such as for systemic lupus erythematosus. Unexpectedly, we observed that several neutralizing Abs reportedly known to counteract IFN-alpha or IFN-beta activity triggered an "IFN-like" response in quiescent primary human endothelial cells leading to activation of the transcription factor IFN-stimulated gene factor 3 and the expression of IFN-responsive genes. Furthermore, these Abs were found to enhance rather than inhibit type I IFN signals, and the effect was also detectable for distinct other cell types such as PBMCs. The stimulatory capacity of anti-IFN-alpha/beta Abs was mediated by the constitutive autocrine production of "subthreshold" IFN levels, involved the type I IFNR and was dependent on the Fc Ab domain, as Fab or F(ab')(2) fragments potently inhibited IFN activity. We thus propose that a combined effect of IFN recognition by the Ab paratope and the concomitant engagement of the Fc domain may trigger an IFN signal via the respective type I IFNR, which accounts for the observed IFN-like response to the neutralizing Abs. With respect to clinical applications, the finding may be of importance for the design of recombinant Abs vs Fab or F(ab')(2) fragments to efficiently counteract IFN activity without undesirable activating effects.
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PMID:Neutralizing type I IFN antibodies trigger an IFN-like response in endothelial cells. 1839 Jul 5

B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response.
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PMID:Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. 1847 19

Plasmacytoid dendritic cells (pDCs) can produce a large amount of interferon-alpha (IFN-alpha) upon exposure to TLR9 or TLR7 agonists. Human pDCs have been shown to play an important role in the pathogenesis of systemic lupus erythematosus (SLE) through increased production of IFN-alpha. So, how to negatively regulate activation of pDCs and how to evaluate the activation of pDC in SLE patients attract much attention. BDCA2 is selectively expressed on human pDCs, acting as a hallmark of human pDCs. In this study, we showed that BDCA2 expression on pDCs decreased along maturation of pDCs, and TLR7 or TLR9 agonists could further significantly downregulate pDCs to express BDCA2, suggesting that the activated pDCs exhibit decreased expression of BDCA2. Functionally, BDCA2 ligation significantly inhibited upregulation of CD40, CD86 and CCR7 expression, IFN-alpha, IFN-beta and IL-6 production by pDCs stimulated with CpG ODN. Moreover, BDCA2 ligation suppressed CpG ODN-activated pDCs to mediate Th1 response, including T cell proliferation, IFN-gamma production, and CD4(+)CCR5(+)Th1 development, confirming that BDCA2 is a negative regulator of TLR9-dependent activation of human pDCs. BDCA2 expression on pDCs from SLE patients decreased significantly but IFN-alpha production of these patients increased markedly as compared to that from healthy donors. Therefore, these results suggest that downregulation of BDCA2 expression on pDCs may reflect the activation of pDCs accumulated in SLE patients, and may be one marker for indication of the disease activity of SLE patients.
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PMID:TLR9/TLR7-triggered downregulation of BDCA2 expression on human plasmacytoid dendritic cells from healthy individuals and lupus patients. 1868 74

We present a 43-year-old woman with relapsing-remitting multiple sclerosis (MS) who developed lupus syndrome after 32 months of IFN-beta-1a therapy. She presented with malaise, myalgia, arthralgia and fever. Laboratory tests showed high erythrocyte sedimentation rate, anaemia and lymphopenia. Antibodies to double stranded DNA (dsDNA) of IgG, IgM and IgA classes were detected on Critidia luciliae. Additionally, high levels of anti-nucleosomal antibodies, low levels of anti-histone and anti-Ro/SSA antibodies were also found. Diagnosis of drug-induced SLE was established. Treatment with IFN-beta was discontinued and oral prednisone was started. Twelve weeks after cessation of IFN-beta therapy, the patient's symptoms completely resolved and autoantibodies disappeared. To the best of our knowledge, this is the first report of a patient with MS in whom treatment with IFN-beta induced lupus syndrome and antibodies to dsDNA and nucleosome.
Lupus 2009 Jan
PMID:Anti-double stranded DNA and lupus syndrome induced by interferon-beta therapy in a patient with multiple sclerosis. 1907 73

Exacerbation of disease in systemic lupus erythematosus (SLE) is associated with bacterial infection. In conventional dendritic cells (cDCs), the TLR4 ligand bacterial LPS induces IFN-beta gene expression but does not induce IFN-alpha. We hypothesized that when cDCs are primed by cytokines, as may frequently be the case in SLE, LPS would then induce the production of IFN-alpha, a cytokine believed to be important in lupus pathogenesis. In this study we show that mouse cDCs and human monocytes produce abundant IFN-alpha following TLR4 engagement whether the cells have been pretreated either with IFN-beta or with a supernatant from DCs activated by RNA-containing immune complexes from lupus patients. This TLR4-induced IFN-alpha induction is mediated by both an initial TRIF-dependent pathway and a subsequent MyD88-dependent pathway, in contrast to TLR3-induced IFN-alpha production, which is entirely TRIF-dependent. There is also a distinct requirement for IFN regulatory factors (IRFs), with LPS-induced IFN-alpha induction being entirely IRF7- and partially IRF5-dependent, in contrast to LPS-induced IFN-beta gene induction which is known to be IRF3-dependent but largely IRF7-independent. This data demonstrates a novel pathway for IFN-alpha production by cDCs and provides one possible explanation for how bacterial infection might precipitate disease flares in SLE.
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PMID:TLR4 ligands induce IFN-alpha production by mouse conventional dendritic cells and human monocytes after IFN-beta priming. 1912 25

Inappropriate activation of TLR9 has been found to be involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. TLR9 antagonists have been proposed to be therapeutic for some kinds of autoimmune diseases. In contrast, new negative regulators of TLR9 signal pathway need to be identified, and the mechanisms for the control of TLR9 response need to be fully investigated. It is well known that TLR9 will be finally transported to late endosome/lysosome once activated; however, the exact mechanism and the biological significance of the redistribution have not been fully elucidated. Ras related in brain (Rab)7b is a small guanosine triphosphatase, identified by us before, which is mainly localized in late endosome/lysosome. Our previous study shows that Rab7b can negatively regulate TLR4 signaling by promoting lysosomal degradation of TLR4. In this study, we show that TLR9 ligation can inhibit Rab7b expression in macrophages via ERK and p38 activation. In turn, the late endosome/lysosome-localized Rab7b can colocalize with TLR9 in lysosomal-associated membrane protein 1-positive compartment and down-regulate the expression of the TLR9 in macrophages by promoting TLR9 degradation once TLR9 is activated. Accordingly, Rab7b can negatively regulate TLR9-triggered production of TNF-alpha, IL-6, and IFN-beta in macrophages by impairing activation of MAPKs and NF-kappaB pathways. Our results suggest that the late endosome/lysosome-localized Rab7b can down-regulate TLR9-triggered proinflammatory cytokine and type I IFN production by impairing TLR9 signaling via promotion of TLR9 degradation.
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PMID:Late endosome/lysosome-localized Rab7b suppresses TLR9-initiated proinflammatory cytokine and type I IFN production in macrophages. 1958 7

Type I IFNs play an important, yet poorly characterized, role in systemic lupus erythematosus. To better understand the interplay between type I IFNs and the activation of autoreactive B cells, we evaluated the effect of type I IFN receptor (IFNAR) deficiency in murine B cell responses to common TLR ligands. In comparison to wild-type B cells, TLR7-stimulated IFNAR(-/-) B cells proliferated significantly less well and did not up-regulate costimulatory molecules. By contrast, IFNAR1(-/-) B cells did not produce cytokines, but did proliferate and up-regulate activation markers in response to other TLR ligands. These defects were not due to a difference in the distribution of B cell populations or a failure to produce a soluble factor other than a type I IFN. Instead, the compromised response pattern reflected the disruption of an IFN-beta feedback loop and constitutively low expression of TLR7 in the IFNAR1(-/-) B cells. These results highlight subtle differences in the IFN dependence of TLR7 responses compared with other TLR-mediated B cell responses.
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PMID:Murine B cell response to TLR7 ligands depends on an IFN-beta feedback loop. 1958 8

Autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, result from a loss of tolerance to self-antigens and immune-mediated injury precipitated by the overproduction of type I IFN and inflammatory cytokines. We have identified the inositol 5' phosphatase SHIP-1 as a negative regulator of TLR3-induced type I IFN production. SHIP-1-deficient macrophages display enhanced TLR-induced IFN-beta production, and overexpression of SHIP-1 negatively regulates the ability of TLR3 and its adaptor, Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta, to induce IFN-beta promoter activity, indicating that SHIP-1 negatively regulates TLR-induced IFN-beta production. Further dissection of the IFN-beta pathway implicates TANK-binding kinase 1 (TBK1) as the target for SHIP-1. Critically, in the absence of SHIP-1, TBK1 appears to be hyperphosphorylated both in unstimulated cells and following TLR3 stimulation. In addition, TBK1 appears to be constitutively associated with Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta and TNFR-associated factor 3 in SHIP-1 deficient cells, whereas in wild-type cells this association is inducible following TLR3 stimulation. In support of a role for SHIP-1 in regulating complex formation, confocal microscopy demonstrates that TBK1 distribution in the cell is significantly altered in SHIP-1-deficient cells, with more prominent endosomal staining observed, compared with wild-type controls. Taken together, our results point to SHIP-1 as a critical negative regulator of IFN-beta production downstream of TLR3 through the regulation of TBK1 localization and activity.
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PMID:Absence of SHIP-1 results in constitutive phosphorylation of tank-binding kinase 1 and enhanced TLR3-dependent IFN-beta production. 2010 Sep 29

TNF and type I interferons (IFNs) are induced by microbial stimuli and mediate innate immune responses. They are also involved in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Activated macrophages are an important driving force of inflammatory reactions and one of the major producers of TNF in innate immunity and chronic inflammation. Despite the fact that cells at sites of damage are continuously exposed to both cytokines, little is known about mechanisms regulating TNF and type I IFN interactions during inflammation. In this review, we discuss the role of an IFN-beta-mediated autocrine loop in the regulation of gene expression program induced by TNF in myeloid cells.
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PMID:Type I interferon: a new player in TNF signaling. 2017 89


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