New Perspectives in Rheumatology: May You Live in Interesting Times: Challenges and Opportunities in Lupus Research

Sanz, Iñaki

doi:10.1002/art.40109

Cited by 8 publications

(6 citation statements)

References 90 publications

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“…Our data show strong associations between ARID3a expression and production of IFNα. IFNα is an inflammatory cytokine proposed to play a major role in SLE, and it is currently the target of several clinical trials that indicate that targeting IFNα responses may be beneficial [98,99,100,101]. Our data in B lymphocytes suggest that ARID3a may function upstream of IFNα [38].…”

Section: Discussionmentioning

confidence: 89%

New Frontiers: ARID3a in SLE

Garton

Barron

Ratliff

et al. 2019

Cells

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Systemic lupus erythematosus (SLE) is a devastating and heterogeneous autoimmune disease that affects multiple organs, and for which the underlying causes are unknown. The majority of SLE patients produce autoantibodies, have increased levels of type-I inflammatory cytokines, and can develop glomerulonephritis. Recent studies indicate an unexpected but strong association between increased disease activity in SLE patients and the expression of the DNA-binding protein ARID3a (A + T rich interaction domain protein 3a) in a number of peripheral blood cell types. ARID3a expression was first associated with autoantibody production in B cells; however, more recent findings also indicate associations with expression of the inflammatory cytokine interferon alpha in SLE plasmacytoid dendritic cells and low-density neutrophils. In addition, ARID3a is expressed in hematopoietic stem cells and some adult kidney progenitor cells. SLE cells expressing enhanced ARID3a levels show differential gene expression patterns compared with homologous healthy control cells, identifying new pathways potentially regulated by ARID3a. The associations of ARID3a expression with increased disease severity in SLE, suggest that it, or its downstream targets, may provide new therapeutic targets for SLE.

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Section: Discussionmentioning

confidence: 89%

New Frontiers: ARID3a in SLE

Garton

Barron

Ratliff

et al. 2019

Cells

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“…The diversity of the disease is a great obstacle and might reflect differences in pathogenesis between different subgroups. Several recent reviews highlight the importance of defining subgroups of SLE to better treat patients with tailored medicine, and in order to increase efficacy in clinical trials (2–5). Accordingly, there is a great need for exploring subgrouping and novel diagnostic biomarkers in SLE.…”

Section: Introductionmentioning

confidence: 99%

Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients

et al. 2019

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Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients ( n = 379) and matched population controls ( n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann–Whitney U -test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p -values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (p adjusted = 3 × 10 −9 , 3 × 10 −6 , and 5 × 10 −6 respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

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“…The role of the canonical receptor for extracellular DNA, TLR9, appears model-specific and its deletion often paradoxically exacerbates experimental SLE [64], suggesting a complex network of additional innate receptors involved. Finally, therapeutic approaches should be developed that target anti-DNA response specifically, as opposed to more general ways of immunosuppression [65]. Although an early attempt to treat SLE with DNASE1 was unsuccessful [66], this may have been due to suboptimal delivery of the drug.…”

Section: Discussionmentioning

confidence: 99%

DNA as a self-antigen: nature and regulation

Soni

Reizis

2018

Current Opinion in Immunology

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High-affinity antibodies to double-stranded DNA are a hallmark of systemic lupus erythematosus (SLE) and are thought to contribute to disease flares and tissue inflammation such as nephritis. Notwithstanding their clinical importance, major questions remain about the development and regulation of these pathogenic anti- NA responses. These include the mechanisms that prevent anti-DNA responses in healthy subjects, despite the constant generation of self-DNA and the abundance of DNA-reactive B cells; the nature and physical form of antigenic DNA in SLE; the regulation of DNA availability as an antigen; and potential therapeutic strategies targeting the pathogenic DNA in SLE. This review summarizes current progress in these directions, focusing on the role of secreted DNases in the regulation of antigenic extracellular DNA.

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New Perspectives in Rheumatology: May You Live in Interesting Times: Challenges and Opportunities in Lupus Research

Cited by 8 publications

References 90 publications

New Frontiers: ARID3a in SLE

New Frontiers: ARID3a in SLE

Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients

DNA as a self-antigen: nature and regulation

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