Targeting type I interferons in systemic lupus erythematous.
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ABSTRACT:
SUBMITTER: Bruera S
PROVIDER: S-EPMC9885195 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
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Targeting type I interferons in systemic lupus erythematous.
Bruera Sebastian S Chavula Thandiwe T Madan Riya R Agarwal Sandeep K SK
Frontiers in pharmacology 20230116
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with systemic clinical manifestations including, but not limited to, rash, inflammatory arthritis, serositis, glomerulonephritis, and cerebritis. Treatment options for SLE are expanding and the increase in our understanding of the immune pathogenesis is leading to the development of new therapeutics. Autoantibody formation and immune complex formation are important mediators in lupus pathogenesis, but an important role of the typ ...[more]
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Project description:Skewing of type I interferon (IFN) production and responses is a hallmark of systemic lupus erythematosus (SLE). Genetic and environmental contributions to IFN production lead to aberrant innate and adaptive immune activation even before clinical development of disease. Basic and translational research in this arena continues to identify contributions of IFNs to disease pathogenesis, and several promising therapeutic options for targeting of type I IFNs and their signaling pathways are in development for treatment of SLE patients.
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Project description:BackgroundPilot studies have estimated cancer incidence in patients with systemic lupus erythematous (SLE). However, the results have been inconclusive. To ascertain the correlation between SLE and malignancy more comprehensively and precisely, we conducted a meta-analysis.MethodsPubMed, the Cochrane Library and Embase databases through June 2014, were searched to identify observational studies evaluating the association between SLE and malignancy. The outcomes from these studies were measured as relative risks (RRs). A random or fixed effects model was chosen to calculate the pooled RR according to heterogeneity test. Between-study heterogeneity was assessed by estimating I2 index. Publication bias was assessed by Egger's test.ResultsA total of 16 papers, including 59,662 SLE patients, were suitable for the meta-analysis. Of these papers, 15 reported RRs for overall malignancy, 12 for non-Hodgkin lymphoma (NHL) and lung cancer, 7 for bladder cancer, 6 for Hodgkin lymphoma (HL) and leukemia, 5 for skin melanoma, and liver and thyroid cancers, 4 for multiple myeloma (MM), and esophageal and vaginal/vulvar cancers and 3 for laryngeal and non-melanoma skin cancers. The pooled RRs were 1.28 (95% CI, 1.17-1.41) for overall cancer, 5.40 (95% CI, 3.75-7.77) for NHL, 3.26(95% CI, 2.17-4.88) for HL, 2.01(95% CI, 1.61-2.52) for leukemia, 1.45(95% CI, 1.04-2.03) for MM, 4.19(95% CI, 1.98-8.87) for laryngeal cancer, 1.59 (95% CI, 1.44-1.76) for lung cancer, 1.86(95% CI, 1.21-2.88) for esophageal cancer, 3.21(95% CI, 1.70-6.05) for liver cancer, 3.67(95% CI, 2.80-4.81) for vaginal/vulvar cancer, 2.11(95% CI, 1.12-3.99) for bladder cancer, 1.51(95% CI, 1.12-2.03) for non-melanoma skin cancer, 1.78(95% CI, 1.35-2.33) for thyroid cancer, and 0.65(95% CI, 0.50-0.85) for skin melanoma. Only the meta-analyses of overall malignancy, NHL, and liver and bladder cancers produced substantial heterogeneity (I2, 57.6% vs 74.3% vs 67.7% vs 82.3%). No apparent publication bias was detected except for NHL studies.ConclusionsOur data support an association between SLE and malignancy, not only demonstrating an increased risk for NHL, HL, leukemia, and some non-hematologic malignancies, including laryngeal, lung, liver, vaginal/vulvar, and thyroid malignancies, but also a reduced risk for skin melanoma. Although an increased risk of MM, and esophageal, bladder and non-melanoma skin cancers was identified from the accumulated data in these studies, this observation requires confirmation.
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Project description:Multiple microRNAs (miRs) are associated with systemic autoimmune disease susceptibility/phenotype, including systemic lupus erythematosus (SLE). With this work, we aimed to unravel the association of the miR-27a gene (MIR27A) rs11671784G/A variant with SLE risk/severity. One-hundred sixty-three adult patients with SLE and matched controls were included. A TaqMan allelic discrimination assay was applied for MIR27A genotyping. Logistic regression models were run to test the association with SLE susceptibility/risk. Genotyping of 326 participants revealed that the heterozygote form was the most common genotype among the study cohort, accounting for 72% of the population (n = 234), while A/A and G/G represented 15% (n = 49) and 13% (n = 43), respectively. Similarly, the most prevalent genotype among cases was the A/G genotype, which was present in approximately 93.3% of cases (n = 152). In contrast, only eight and three patients had A/A and G/G genotypes, respectively. The MIR27A rs11671784 variant conferred protection against the development of SLE in several genetic models, including heterozygous (G/A vs. A/A; OR = 0.10, 95% CI = 0.05-0.23), dominant (G/A + G/G vs. AA; OR = 0.15, 95% CI = 0.07-0.34), and overdominant (G/A vs. A/A + G/G; OR = 0.07, 95% CI = 0.04-0.14) models. However, the G/G genotype was associated with increased SLE risk in the recessive model (G/G vs. A/A+ G/G; OR = 17.34, 95% CI = 5.24-57.38). Furthermore, the variant showed significant associations with musculoskeletal and mucocutaneous manifestations in the patient cohort (p = 0.035 and 0.009, respectively) and platelet and white blood cell counts (p = 0.034 and 0.049, respectively). In conclusion, the MIR27A rs11671784 variant showed a potentially significant association with SLE susceptibility/risk in the studied population. Larger-scale studies on multiethnic populations are recommended to verify the results.
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Project description:BACKGROUND/PURPOSE:Endothelium is a key element in the regulation of vascular homeostasis and its alteration can lead to the development of vascular diseases. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with potential extensive vascular lesions, involving skin vessels, renal glomeruli, cardiovascular system, brain, lung alveoli, gastrointestinal tract vessels and more. We aimed to assess endothelial dysregulation related biomarkers in pediatric-onset SLE (pSLE) patient serum and elucidate its correlation with their clinical features, laboratory parameters, and the overall disease activity. METHODS:Disease activities were evaluated by SLE disease activity index (SLEDAI). Patient characteristics were obtained by retrospective chart review. Six biomarkers associated with endothelial dysregulation, including Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Tie2, Vascular endothelial growth factor (VEGF), thrombomodulin, and a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS13) were tested through enzyme-linked immunosorbent assay (ELISA) measurement. RESULTS:This study comprised 118 pSLE patients. Data from 40 age-matched healthy controls were also obtained. The mean diagnostic age was 13 ± 4.12 years-old and 90.7% are females. Serum levels of VEGF, Tie2, thrombomodulin were significantly higher while serum ADAMTS13 was lower in active pSLE patients when compared to those with inactive diseases (all p < 0.05). In organ specific association, serum thrombomodulin level was higher in pSLE patient with renal involvement, and serum ADAMTS13 levels was negatively associated with neurological involvement (p < 0.05). A cutoff of thrombomodulin at 3333.6 pg/ml best correlated renal involvement. (AUC = 0.752, p < 0.01). CONCLUSION:Endothelial dysregulation associating proteins seems to be potent biomarkers for pSLE activity as well as organ involvement in pSLE patients. These biomarkers may be beneficial in understanding of the vascular pathogenesis and disease monitoring.
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Project description:Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type I IFN signature and SLE disease activity have yielded conflicting results. In addition to type I IFNs, type II and III IFNs may overlap and also contribute to the IFN signature. Different genetic backgrounds lead to overproduction of type I IFNs in SLE and contribute to the breakdown of peripheral tolerance by activation of antigen-presenting myeloid dendritic cells, thus triggering the expansion and differentiation of autoreactive lymphocytes. The consequence of the continuous stimulation of the immune system is manifested in different organ systems typical of SLE (e.g., mucocutaneous and cardiovascular involvement). After the discovery of the type I IFN signature, a number of different strategies have been developed to downregulate the IFN system in SLE patients, finally leading to the successful trial of anifrolumab, the second biologic to be approved for the treatment of SLE in 10 years. In this review, we will discuss the bench to bedside translation of the type I IFN pathway and put forward some issues that remain unresolved when selecting SLE patients for treatment with biologics targeting type I IFNs.
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Project description:ObjectiveAfrican Americans, East Asians, and Hispanics with systemic lupus erythematous (SLE) are more likely to develop lupus nephritis (LN) than are SLE patients of European descent. The etiology of this difference is not clear, and this study was undertaken to investigate how genetic variants might explain this effect.MethodsIn this cross-sectional study, 1244 SLE patients from multiethnic case collections were genotyped for 817,810 single-nucleotide polymorphisms (SNPs) across the genome. Continental genetic ancestry was estimated utilizing the program ADMIXTURE. Gene-based testing and pathway analysis was performed within each ethnic group and meta-analyzed across ethnicities. We also performed candidate SNP association tests with SNPs previously established as risk alleles for SLE, LN, and chronic kidney disease (CKD). Association testing and logistic regression models were performed with LN as the outcome, adjusted for continental ancestries, sex, disease duration, and age.ResultsWe studied 255 North European, 263 South European, 238 Hispanic, 224 African American and 264 East Asian SLE patients, of whom 606 had LN (48.7%). In genome-wide gene-based and candidate SNP analyses, we found distinct genes, pathways and established risk SNPs associated with LN for each ethnic group. Gene-based analyses showed significant associations between variation in ZNF546 (p = 1.0E-06), TRIM15 (p = 1.0E-06), and TRIMI0 (p = 1.0E-06) and LN among South Europeans, and TTC34 (p = 8.0E-06) was significantly associated with LN among Hispanics. The SNP rs8091180 in NFATC1 was associated with LN (OR 1.43, p = 3.3E-04) in the candidate SNP meta-analysis with the highest OR among African-Americans (OR 2.17, p = 0.0035).ConclusionDistinct genetic factors are associated with the risk of LN in SLE patients of different ethnicities. CKD risk alleles may play a role in the development of LN in addition to SLE-associated risk variants. These findings may further explain the clinical heterogeneity of LN risk and response to therapy observed between different ethnic groups.
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Project description:Type I and type III interferons (IFNs) share several properties in common, including the induction of signaling pathways, the activation of gene transcripts, and immune responses, against viral infection. Recent advances in the understanding of the molecular basis of innate and adaptive immunity have led to the re-examination of the role of these IFNs in autoimmune diseases. To date, a variety of IFN-regulated genes, termed IFN signature genes, have been identified. The expressions of these genes significantly increase in systemic lupus erythematosus (SLE), highlighting the role of type I and type III IFNs in the pathogenesis of SLE. In this review, we first discussed the signaling pathways and the immunoregulatory roles of type I and type III IFNs. Next, we discussed the roles of these IFNs in the pathogenesis of autoimmune diseases, including SLE. In SLE, IFN-stimulated genes induced by IFN signaling contribute to a positive feedback loop of autoimmunity, resulting in perpetual autoimmune inflammation. Based on this, we discussed the use of several specific IFN blocking strategies using anti-IFN-α antibodies, anti-IFN-α receptor antibodies, and IFN-α-kinoid or downstream small molecules, which intervene in Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, in clinical trials for SLE patients. Hopefully, the development of novel regimens targeting IFN signaling pathways will shed light on promising future therapeutic applications for SLE patients.
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Project description:Endothelial cell (EC) dysfunction is a hallmark of Systemic Lupus Erythematosus (SLE) and Tie2 is a receptor essential for vascular stability. Inflammatory processes promote inhibition of Tie2 homeostatic activation, driving vascular dysfunction. In this work we determined whether type I Interferons (IFN) induce Tie2 signalling-mediated endothelial dysfunction in patients with SLE. Serum levels of Angiopoietin (Ang)-1, Ang-2 and soluble (s)Tie1 in patients with SLE and healthy controls were measured by ELISA. Monocytes from patients with SLE and Human Umbilical Vein EC (HUVEC) were stimulated with IFN-α, IFN-β (1000 I.U.) or SLE serum (20%). mRNA and protein expression, phosphorylation and translocation were determined by quantitative PCR, ELISA, Western Blot, flow cytometry and confocal microscopy. Viability and angiogenic capacity were determined by calcein and tube formation assays. We found that sTie1 and Ang-2 serum levels were increased and Ang-1 decreased in patients with SLE and were associated with clinical characteristics. Type I IFN significantly decreased Ang-1 and increased Ang-2 in monocytes from patients with SLE. Type I IFN increased sTie1 and Ang-2 secretion and reduced Tie2 activation in HUVEC. Functionally, type I IFN significantly reduced EC viability and impaired angiogenesis in a Tie2 signalling-dependent manner. Finally, SLE serum increased Ang-2 and sTie1 secretion and significantly decreased tube formation. Importantly, Tie1 and IFNAR1 knockdown reversed these effects in tube formation. Overall, type I IFN play an important role in the stability of EC by inhibiting Tie2 signalling, suggesting that these processes may be implicated in the cardiovascular events observed in patients with SLE.
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Project description:IntroductionMyositis in systemic lupus erythematous may present in a wide range of clinical spectrum. It can be part of an overlap syndrome, or mixed connective tissue disease or a musculoskeletal manifestation of systemic lupus erythematous itself.Case presentationHere, we present a young girl with an underlying systemic lupus erythematous presented with the typical manifestation of severe proximal myopathy in the background of normal creatine kinase values. The diagnosis of systemic lupus erythematous myopathy was made after excluding other more common causes of myopathies which in itself is a very rare occurrence.DiscussionsA normal creatine kinase values does not exclude systemic lupus erythematous myositis, but make the diagnosis more challenging. However, there are other parameters or diagnostic tools which can be used to exclude a myositis.ConclusionThis case elucidates the importance of history and physical examination in the face of some conflicting laboratory data.
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Project description:Given the importance of monocytes in pathogenesis of infectious and other inflammatory disorders, delineating functional and phenotypic characterization of monocyte subsets has emerged as a critical requirement. Although human monocytes have been subdivided into three different populations based on surface expression of CD14 and CD16, published reports suffer from contradictions with respect to subset phenotypes and function. This has been attributed to discrepancies in reliable gating strategies for flow cytometric characterization and purification protocols contributing to significant changes in receptor expression. By using a combination of multicolour flow cytometry and a high-dimensional automated clustering algorithm to confirm robustness of gating strategy and analysis of ex-vivo activation of whole blood with LPS we demonstrate the following: a. 'Classical' monocytes are phagocytic with no inflammatory attributes, b. 'Non-classical' subtype display 'inflammatory' characteristics on activation and display properties for antigen presentation and c. 'Intermediate' subtype that constitutes a very small percentage in circulation (under physiological conditions) appear to be transitional monocytes that display both phagocytic and inflammatory function. Analysis of blood from patients with Sepsis, a pathogen driven acute inflammatory disease and Systemic Lupus Erythmatosus (SLE), a chronic inflammatory disorder validated the broad conclusions drawn in the study.
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