Molecular signatures in systemic lupus erythematosus: distinction between disease flare and infection

Mackay, Meggan; Oswald, Michaela; Sánchez‐Guerrero, Jorge; Lichauco, Juan Javier; Aranow, Cynthia; Kotkin, Sean; Korsunsky, Ilya; Gregersen, Peter K.; Diamond, Betty

doi:10.1136/lupus-2016-000159

Cited by 33 publications

(28 citation statements)

References 46 publications

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“…Of note, a strong IS can be found in many patients with SLE, supporting the idea that a dysregulated activation of the interferons also plays a crucial role in this multifactorial disorder [28].…”

mentioning

confidence: 67%

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

Piscianz

Cuzzoni

Sharma

et al. 2018

CMC

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The story of antimalarials as antinflammatory drugs dates back few centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, the molecular mechanisms of action have been partly clarified.The inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGAS-STING pathway deputed to the sensing of nucleic acid and to the production of type 1 interferons. This pathway is a fundamental mechanism for host defence, since it is able to detect microbial DNA and RNA and induce the immune response that will lead to the production of interferons. Of note, genetic defects in disposal of nucleic acids lead to inappropriate activation of the cGAS-STING pathway and inflammation. These disorders, named type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials.We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and, likely multifactorial disorders characterised by interferon inflammation, such as systemic lupus erythematosus.

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confidence: 67%

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

Piscianz

Cuzzoni

Sharma

et al. 2018

CMC

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“…The expression of CXorf21 transcript has previously been shown to be the most accurate delineator of disease flare from infection in SLE patients 18 . Interestingly, this previous study was conducted in largely non-European patients, suggesting the role of CXorf21 is not limited to individuals of European ancestry.…”

Section: Discussionmentioning

confidence: 99%

“…CXorf21 has been shown to escape XCI in lymphoblastoid cell lines (LCLs), and is one of only 14 X-linked genes that is differentially expressed between Klinefelter’s syndrome (47, XXY) and 46, XY males in LCLs 16,17 . A recent whole-blood gene expression study also identified CXorf21 as one of seven genes upregulated in female SLE patients displaying disease flare relative to those with infection 18 .…”

Section: Introductionmentioning

confidence: 97%

Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus

et al. 2019

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Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21 , a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21 . We propose that expression is amplified through modification of promoter and 3′-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.

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“…Likewise, kidneys from Fli-1 +/− lupus-prone NZM2410 mice displayed significantly fewer inflammatory infiltrates compared to the Fli-1 +/+ NZM2410 controls [8]. Interestingly, peripheral blood lymphocytes from patients with active SLE showed elevated expression of Fli-1 transcripts in parallel with disease activity [16]; elevated levels of Fli-1 were also associated with newly-developed or recurrent lupus nephritis in SLE patients [17]. The cytokine IL-17A plays an important role in the development of lupus nephritis; it is produced by T-helper 17 (Th17) cells and has powerful inflammatory properties [18,19].…”

Section: Introductionmentioning

confidence: 94%

Ets Family Transcription Factor Fli-1 Promotes Leukocyte Recruitment and Production of IL-17A in the MRL/Lpr Mouse Model of Lupus Nephritis

Sato

Zhang

Temmoku

et al. 2020

Cells

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The transcription factor Friend leukemia integration 1 (Fli-1) regulates the expression of numerous cytokines and chemokines and alters the progression of lupus nephritis in humans and in the MRL/MpJ-Fas lpr (MRL/lpr) mouse model. Th17-mediated immune responses are notably important as they promote ongoing inflammation. The purpose of this study is to determine the impact of Fli-1 on expression of interleukin-17A (IL-17A) and the infiltration of immune cells into the kidney. IL-17A concentrations were measured by ELISA in sera collected from MRL/lpr Fli-1-heterozygotes (Fli-1 +/− ) and MRL/lpr Fli-1 +/+ control littermates. Expression of IL-17A and related proinflammatory mediators was measured by real-time polymerase chain reaction (RT-PCR). Immunofluorescence staining was performed on renal tissue from MRL/lpr Fli-1 +/− and control littermates using anti-CD3, anti-CD4, and anti-IL-17A antibodies to detect Th17 cells and anti-CCL20 and anti-CD11b antibodies to identify CCL20 + monocytes. The expression of IL-17A in renal tissue was significantly reduced; this was accompanied by decreases in expression of IL-6, signal transducer and activator of transcription 3 (STAT3), and IL-1β. Likewise, we detected fewer CD3 + IL-17 + and CD4 + IL-17 + cells in renal tissue of MLR/lpr Fli-1 +/− mice and significantly fewer CCL20 + CD11b + monocytes. In conclusion, partial deletion of Fli-1 has a profound impact on IL-17A expression and on renal histopathology in the MRL/lpr mouse.

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Molecular signatures in systemic lupus erythematosus: distinction between disease flare and infection

Cited by 33 publications

References 46 publications

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus

Ets Family Transcription Factor Fli-1 Promotes Leukocyte Recruitment and Production of IL-17A in the MRL/Lpr Mouse Model of Lupus Nephritis

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