Disease Mechanisms in Rheumatology—Tools and Pathways: Plasmacytoid Dendritic Cells and Their Role in Autoimmune Rheumatic Diseases

Eloranta, Maija‐Leena; Alm, Gunnar V.; Rönnblom, Lars

doi:10.1002/art.37821

Cited by 68 publications

(58 citation statements)

References 93 publications

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“…Regarding the pathogenesis of SLE, selfdsDNA, together with autoantibodies, contributes to multiple clinical features of SLE, including immune complex (IC)-mediated tissue damage, inflammatory cytokine production and the interferon (IFN) signature. Of note, selfdsDNA is sensed mainly by plasmacytoid dendritic cells (pDC) through various DNA sensors, leading to robust type I interferon (IFN-I) production [7]. IFN-I has many immune functions, from stimulating differentiation and maturation of dendritic cells to activating T cells and promoting antibody production by B cells, which highlights the critical function of IFN-I in the pathogenesis of autoimmune diseases, especially SLE [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…Of note, selfdsDNA is sensed mainly by plasmacytoid dendritic cells (pDC) through various DNA sensors, leading to robust type I interferon (IFN-I) production [7]. IFN-I has many immune functions, from stimulating differentiation and maturation of dendritic cells to activating T cells and promoting antibody production by B cells, which highlights the critical function of IFN-I in the pathogenesis of autoimmune diseases, especially SLE [7,8]. In this review, we will summarize the knowledge concerning the mechanisms of self-dsDNA-mediated inflammation through DNA sensors and its functions in SLE pathogenesis, which may lead to the discovery of new therapeutic strategies of SLE.…”

Section: Introductionmentioning

confidence: 99%

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Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Bai

Tong

Liu

et al. 2017

Clinical and Experimental Immunology

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SummarySystemic lupus erythematosus (SLE) is a systemic and poly-aetiological autoimmune disease characterized by the production of antibodies to autologous double-stranded DNA (dsDNA) which serve as diagnostic and prognostic markers. The defective clearance of apoptotic material, together with neutrophil extracellular traps (NETs), provides abundant chromatin or self-dsDNA to trigger the production of anti-dsDNA antibodies, although the mechanisms remain to be elucidated. In SLE patients, the immune complex (IC) of dsDNA and its autoantibodies trigger the robust type I interferon (IFN-I) production through intracellular DNA sensors, which drives the adaptive immune system to break down self-tolerance. In this review, we will discuss the potential resources of self-dsDNA, the mechanisms of self-dsDNA-mediated inflammation through various DNA sensors and its functions in SLE pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Bai

Tong

Liu

et al. 2017

Clinical and Experimental Immunology

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“…Cell debris and ICs containing nucleic acids may therefore serve as endogenous IFNα inducers in SLE. The biological consequences of IFNα that have been implicated in the pathogenesis of lupus have recently been reviewed in detail [121] and include the facilitation of antigen presentation via increased upregulation of class I and II major histocompability complex (MHC), maturation of dendritic cells and stimulation of B cells to become antibody producing plasma cells [122,123]. Although far from all SLE patients have measurable IFNα in serum [124,125], the majority present with increased expression of type I IFN regulated genes, the "type I IFN signature" [126].…”

Section: Ifnαmentioning

confidence: 99%

Biomarkers and mediators in systemic lupus erythematosus : IFNα versus the CRP response, and evaluation of suPAR and anti-dsDNA antibody assays

Enocsson¹

2014

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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease which may affect multiple organ systems. Interferon alpha (IFNα) and autoantibodies that form immune complexes with nuclear antigens (ANA) are hallmarks believed to drive the disease into a vicious circle of inflammation, tissue damage, autoantigen exposure and autoantibody production.In SLE, the disease course is characterized by episodes of exacerbations alternating with remissions. In order to best treat the patient it is important to closely monitor symptoms and signs of disease activity. Because of the disease heterogeneity, no single biomarker has yet been found to reflect SLE disease activity in general, although anti-double stranded DNA (anti-dsDNA) antibodies sometimes indicate activity, primarily with renal involvement, and constitutes an item of the SLE disease activity score SLEDAI-2K. However, the method of anti-dsDNA measurement is not standardized and therefore varies between different laboratories. In many other inflammatory conditions, such as rheumatoid arthritis and during bacterial infections, the C-reactive protein (CRP) level is a good indicator of ongoing inflammation, but in SLE and during viral infections, CRP commonly fails to reflect the degree of inflammation. Both viral infections and SLE are characterized by IFNα, and we thus aimed to elucidate whether IFNα can inhibit CRP production. Further, four assays for anti-dsDNA antibody measurements were evaluated with regard to SLE disease specificity and activity, and a new potential biomarker of inflammation, the soluble urokinase plasminogen activator receptor (suPAR), was assessed in relation to disease activity and organ damage.An in vitro inhibitory effect of IFNα on CRP transcription and production was found in hepatocytes, and this was consolidated by in vivo studies of CRP and IFNα in sera from well-characterized SLE patients (KLURING; Kliniskt lupusregister i nordöstra Götaland). Here, CRP and disease activity were associated among patients without IFNα and without a CRP lowering gene variant (SNP rs1205). The poor disease activity compliance of CRP could therefore be explained, at least in part, by polymorphisms in the CRP gene and increased levels of IFNα. Critical differences between the methods measuring anti-dsDNA were found regarding disease specificity and ability to reflect disease activity and the results suggests the Crithidia luciliae immunofluorescence test (CLIFT) for diagnostic purposes and a bead-based multiplex assay (FIDIS) for monitoring of disease activity.

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“…SLE is a systemic rheumatic disease characterized by antinuclear antibody (ANA) production, increased expression of interferon alpha (IFNα) regulated genes, decrease in complement protein levels and deficient handling of dying cells which results in tissue deposition of immune complexes and subsequent inflammation and damage to organs [16,17]. The disease can affect almost any organ and has an extreme heterogeneity which constitutes a challenge in the diagnosis and treatment of the patients.…”

Section: Introductionmentioning

confidence: 99%

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

Enocsson¹,

Sjöwall²,

Wetterö³

2015

Clinica Chimica Acta

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The expression of uPAR is mainly regulated by growth factors and pro-inflammatory cytokines like basic fibroblast growth factor, epidermal growth factor, tumor necrosis factor, interleukin ( suPAR as a clinical marker of inflammation and organ damagePlasma membrane expression of uPAR as well as the levels of circulating suPAR have been investigated in relation to a broad range of conditions and suPAR has been referred to as a "molecular crystal ball" due to its prognostic value in diseases like tuberculosis, HIV, sepsis and cancer [2,6,13,26,58,59]. Further, it has been reported that it reflects overall immune activation and systemic inflammation [2]. suPAR has also emerged as a potential biomarker of fibrosis in chronic liver diseases of diverse etiology [10,11,[60][61][62].Recently, suPAR attracted significant attention in primary focal segmental glomerulosclerosis (FSGS). data from this pilot study revealed significantly higher suPAR levels among patients with moderately or highly elevated SDI after study inclusion, compared to patients without SDI increase (Figure 2).Furthermore, there were higher death rates among patients in the two groups with SDI increase (Figure 2). However, it is well known that present organ damage predicts further organ damage [17,100], and thus, adjustment for SDI at baseline should be performed to reduce the risk of bias. A stepwise linear multiple regression analysis was therefore performed to evaluate the impact of suPAR on future SDI increase. After adjusting for age, sex and SDI at study inclusion, we found suPAR levels to have a significant impact on future SDI increase (p = 0.005, standardized β = 0.20) whereas SDI at study inclusion was excluded from the model. Since recent studies have revealed an inverse correlation between serum suPAR and glomerular filtration [67,68,96], we also included estimated glomerular filtration (eGFR) (calculated by the 4-variable Modification of Diet in Renal Disease StudyGroup formula [101]) in the analysis, but eGFR was not retained in the model. From these results, we suggest that suPAR can actually predict organ damage independent of present SDI score or eGFR, but that a prospective study examining the association between suPAR levels at the time of diagnosis with future SDI would be preferable.In line with these findings, elevated suPAR levels have previously been demonstrated to associate with the risk of developing cancer, cardiovascular disease and type 2 diabetes later in life in the general population [7]. Importantly, these associations were independent of CRP, which is known for its predictive value in cardiovascular disease [7,102].7 Potential roles of suPAR in SLE pathogenesisAssessment of circulating suPAR levels at the clinical laboratory could possibly become a future way to estimate organ damage in SLE, and suPAR would be an even more appealing biomarker candidate if the levels could be mechanistically linked to the disease. The pathogenesis of SLE is notoriously complex and not fully understood, but includes disturbances in t...

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Disease Mechanisms in Rheumatology—Tools and Pathways: Plasmacytoid Dendritic Cells and Their Role in Autoimmune Rheumatic Diseases

Cited by 68 publications

References 93 publications

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Biomarkers and mediators in systemic lupus erythematosus : IFNα versus the CRP response, and evaluation of suPAR and anti-dsDNA antibody assays

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

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