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NETs decorated with bioactive IL-33 infiltrate inflamed tissues and induce IFN-α production in patients with SLE.
Georgakis, S, Gkirtzimanaki, K, Papadaki, G, Gakiopoulou, H, Drakos, E, Eloranta, ML, Makridakis, M, Kontostathi, G, Zoidakis, J, Baira, E, et al
JCI insight. 2021;(21)
Abstract
IL-33, a nuclear alarmin released during cell death, exerts context-specific effects on adaptive and innate immune cells, eliciting potent inflammatory responses. We screened blood, skin, and kidney tissues from patients with systemic lupus erythematosus (SLE), a systemic autoimmune disease driven by unabated type I IFN production, and found increased amounts of extracellular IL-33 complexed with neutrophil extracellular traps (NETs), correlating with severe, active disease. Using a combination of molecular, imaging, and proteomic approaches, we show that SLE neutrophils, activated by disease immunocomplexes, release IL-33-decorated NETs that stimulate robust IFN-α synthesis by plasmacytoid DCs in a manner dependent on the IL-33 receptor ST2L. IL33-silenced neutrophil-like cells cultured under lupus-inducing conditions generated NETs with diminished interferogenic effect. Importantly, NETs derived from patients with SLE are enriched in mature bioactive isoforms of IL-33 processed by the neutrophil proteases elastase and cathepsin G. Pharmacological inhibition of these proteases neutralized IL-33-dependent IFN-α production elicited by NETs. We believe these data demonstrate a novel role for cleaved IL-33 alarmin decorating NETs in human SLE, linking neutrophil activation, type I IFN production, and end-organ inflammation, with skin pathology mirroring that observed in the kidneys.
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Trace Elements Associated with Systemic Lupus Erythematosus and Insulin Resistance.
Pedro, EM, da Rosa Franchi Santos, LF, Scavuzzi, BM, Iriyoda, TMV, Peixe, TS, Lozovoy, MAB, Reiche, EMV, Dichi, I, Simão, ANC, Santos, MJ
Biological trace element research. 2019;(1):34-44
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease of multifactorial origin. Studies have shown that trace elements such as zinc and copper may help maintain optimum function of the immune system and metabolism, while toxic metals such as lead may increase systemic autoimmunity. The current study aimed to assess the relationship between serum concentration of lithium (Li), vanadium (V), copper (Cu), zinc (Zn), molybdenum (Mo), cadmium (Cd), and lead (Pb) and SLE diagnosis, disease activity measured by SLE disease activity index (SLEDAI) and insulin resistance (IR). This case-control, cross-sectional study included 225 patients, 120 healthy controls, and 105 SLE patients. Serum concentration of Li, V, Cu, Zn, Mo, Cd, and Pb was measured. Serum concentrations of V (p < 0.001), Zn (p < 0.001), and Pb (p < 0.001) were lower and Mo (p < 0.001) and Li (p < 0.001) were higher in patients with SLE compared to healthy controls. SLE diagnosis was associated with higher serum Li (p < 0.001) concentration and lower V (p < 0.001), Zn (p = 0.003), and Pb (p = 0.020). Toxic metals and trace elements were not associated with disease activity. Levels of Cd were higher in patients with IR (p = 0.042). There was no significant association between IR and the other metals. The results indicate that SLE patients have different profiles of trace elements and toxic metals compared to healthy controls. While some toxic metals and trace elements were found to be associated with SLE diagnosis, they had no effect on disease activity and IR.
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Analysis of Sodium Chloride Intake and Treg/Th17 Lymphocytes in Healthy Individuals and Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus.
Vitales-Noyola, M, Layseca-Espinosa, E, Baranda, L, Abud-Mendoza, C, Niño-Moreno, P, Monsiváis-Urenda, A, Rosenstein, Y, González-Amaro, R
Journal of immunology research. 2018;:9627806
Abstract
We assessed different immune parameters in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) with low (LSI) and high (HSI) sodium intake. Thirty-eight patients with RA, thirty-seven with SLE, and twenty-eight healthy subjects were studied and classified as LSI or HSI. Levels and suppressive function of CD4+CD25+Foxp3+ and CD4+CD69+Foxp3- Treg cells were determined by flow cytometry in blood samples. Levels and in vitro differentiation of Th17 cells were also assessed. Similar levels of CD4+CD25+Foxp3+ and CD4+CD69+Foxp3- Treg cells were observed in LSI and HSI patients or controls. However, a positive correlation was detected between sodium intake and levels of CD4+CD25+Foxp3+ Treg cells in SLE and a negative association between CD4+CD69+Foxp3- Treg cells and sodium intake in RA. No other significant associations were detected, including disease activity and sodium intake. Moreover, the suppressor activity of CD4+CD25+Foxp3+ and CD4+CD69+Foxp3- Treg cells was similar in LSI and HSI patients or controls. The levels and in vitro differentiation of Th17 cells were also similar in LSI and HSI individuals. Our results suggest that, in the population studied (Mexican mestizo), the level of sodium intake is not apparently associated with different relevant immune parameters in healthy subjects or patients with SLE or RA.
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Topics on vitamin D in systemic lupus erythematosus: analysis of evidence and critical literature review.
Marinho, A, Taveira, M, Vasconcelos, C
Immunologic research. 2017;(2):495-511
Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiorgan inflammation, linked to the loss of immune tolerance to self-antigens and the production of a diversity of autoantibodies. The phenotype and progression of SLE have been linked to a combination of environmental, genetic, and hormonal factors. One such environmental factor is vitamin D, a vital hormone with well-established effects on mineral metabolism, skeletal health, and effects on cardiovascular system. The purpose of this article is to make the analysis of evidence and literature review of the pleomorphic effects of Vitamin D in SLE. The article is structured in topics of interest based in the authors' opinion and summarizes the evidence of studies and trials of vitamin D in SLE.
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Oxidative stress in the pathogenesis of atherothrombosis associated with anti-phospholipid syndrome and systemic lupus erythematosus: new therapeutic approaches.
López-Pedrera, C, Barbarroja, N, Jimenez-Gomez, Y, Collantes-Estevez, E, Aguirre, MA, Cuadrado, MJ
Rheumatology (Oxford, England). 2016;(12):2096-2108
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Abstract
Atherothrombosis is a recurrent complication in APS and SLE patients. Oxidative stress has been suggested as a key player underlying this process. Autoantibodies have been pointed to as the main contributors to abnormality in the oxidative status observed in APS and SLE patients, promoting the increased production of oxidant species and the reduction of antioxidant molecules. This imbalance causes vascular damage through the activation of immune cells, including monocytes, lymphocytes and neutrophils, causing the expression of pro-inflammatory and procoagulant molecules, the formation of neutrophil extracellular traps and the adhesion of these cells to the endothelium; the induction of cellular apoptosis and impaired cell clearance, which in turn enhances autoantibody neogeneration; and cytotoxicity of endothelial cells. This review describes the mechanisms underlying the role of oxidative stress in the pathogenesis of atherothrombosis associated with APS and SLE, focused on the effect of autoantibodies, the different cell types involved and the diverse effectors, including cytokines, procoagulant proteins and their main modulators, such as oxidant/antioxidant species and intracellular pathways in each pathology. We further discuss new therapies aimed at restoring the oxidative stress balance and subsequently to tackle atherothrombosis in APS and SLE.
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Randomized, Double-Blind, Placebo-Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients With Systemic Lupus Erythematosus.
Aranow, C, Kamen, DL, Dall'Era, M, Massarotti, EM, Mackay, MC, Koumpouras, F, Coca, A, Chatham, WW, Clowse, ME, Criscione-Schreiber, LG, et al
Arthritis & rheumatology (Hoboken, N.J.). 2015;(7):1848-57
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Abstract
OBJECTIVE Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE. METHODS SLE patients (n = 57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level ≤20 ng/ml, an elevated anti-double-stranded DNA antibody level, and an IFN signature (as determined by measuring the expression levels of 3 IFN response genes) were randomized into a 12-week double-blind, placebo-controlled trial of vitamin D3 at doses of 2,000 IU or 4,000 IU. An IFN signature response was defined as a 50% reduction in the expression of 1 of the 3 genes or a 25% reduction in the expression of 2 of the 3 genes. Disease activity, adverse events, and endocrine effects were assessed. RESULTS Baseline characteristics of the patients in the 3 treatment groups (placebo, low-dose vitamin D3 , or high-dose vitamin D3 ) were similar. Repletion of 25(OH)D (i.e., levels ≥30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D3 . The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, there was no difference in the percentage of patients with an IFN signature response between those who remained vitamin D deficient and those who demonstrated repletion of vitamin D. Modular microarray analysis of a subset of patients (n = 40) did not reveal changes from baseline in any modules (including the IFN-inducible module) in any of the treatment groups, and no differences in expression were found between patients who demonstrated vitamin D repletion and patients who were persistently vitamin D deficient. Vitamin D3 was well tolerated, and there were no safety concerns. CONCLUSION Vitamin D3 supplementation up to 4,000 IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D-deficient SLE patients. Higher 25(OH)D levels sustained for a longer duration may be required to affect immunologic outcomes.
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Role of peroxynitrite-modified biomolecules in the etiopathogenesis of systemic lupus erythematosus.
Ahmad, R, Ahsan, H
Clinical and experimental medicine. 2014;(1):1-11
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by autoantibodies directed against various biomolecules. The initial immunogens that drive the development of SLE are unknown, but characteristics of the immune response in SLE suggest that it is an antigen-driven response, and a chromatin antigen could be one of the immunogens for the production of antinuclear antibodies (ANA) in SLE. Other factors implicated in the pathogenesis of SLE include nitrogen-free radicals such as nitric oxide and peroxynitrite. The free radical-mediated damage to proteins results in the modification of amino acid residues, cross-linking of side chains and fragmentation. The tyrosine residues in proteins are susceptible to attack by various reactive nitrogen intermediates, including peroxynitrite to form 3-nitrotyrosine (3-NT). The presence of nitrated proteins in vivo indicates that peptides derived from the proteolytic degradation of modified proteins could serve as neoantigens. Histones are highly conserved proteins that are rich in basic amino acids lysine and arginine. Autoantibodies against histones and anti-DNA antibodies are present in SLE. The anti-DNA autoantibodies coexist with anti-histone autoantibodies and may react with chromatin-associated histones and histone complexes. Elevated levels of reactive nitrogen species (RNS) in SLE patients suggest a possible role in the pathogenesis of the disease. The alteration of proteins resulting from photomodification or peroxynitrite could lead to the development of antibodies. Therefore, the modified proteins or photoadducts could have important implications in autoimmunity, and understanding the pathophysiology of peroxynitrite-modified biomolecules could lead to a better understanding of autoimmune phenomenon in SLE.