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T cells in systemic lupus erythematosus (SLE) exhibit multiple metabolic abnormalities. Excess iron can impair mitochondria and may contribute to SLE. To gain insights into this potential role of iron in SLE, we performed a CRISPR screen of iron handling genes on T cells. Transferrin receptor (CD71) was identified as differentially critical for T H 1 and inhibitory for induced regulatory T cells (iT regs ). Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Cell surface CD71 was enhanced in SLE-prone T cells by increased endosomal recycling. Blocking CD71 reduced intracellular iron and mTORC1 signaling, which inhibited T H 1 and T H 17 cells yet enhanced iT regs . In vivo treatment reduced kidney pathology and increased CD4 T cell production of IL-10 in SLE-prone mice. Disease severity correlated with CD71 expression on T H 17 cells from patients with SLE, and blocking CD71 in vitro enhanced IL-10 secretion. T cell iron uptake via CD71 thus contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology.

Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance. Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established. In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction. A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and restored tolerance induction to allografts in lupus-prone mice. The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance. These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies.

Purpose of Review: Accelerated atherosclerosis is a significant comorbidity and the leading cause of death for patients with systemic lupus erythematosus (SLE). It is now apparent that SLE-accelerated atherosclerosis is not driven solely by traditional cardiovascular risk factors, adding complexity to disease characterization and mechanistic understanding. In this review, we will summarize new insights into SLE-accelerated atherosclerosis evaluation, treatment, and mechanism., Recent Findings: Recent work highlights the need to incorporate inflammatory biomarkers into cardiovascular disease (CVD) risk assessments. This is especially true for SLE patients, in which mechanisms of immune dysfunction likely drive CVD progression. There is new evidence that commonly prescribed SLE therapeutics hinder atherosclerosis development. This effect is achieved both by reducing SLE-associated inflammation and by directly improving measures of atherosclerosis, emphasizing the interconnected mechanisms of the two conditions., Summary: SLE-accelerated atherosclerosis is most likely the consequence of chronic autoimmune inflammation. Therefore, diligent management of atherosclerosis requires assessment of SLE disease activity as well as traditional cardiovascular risk factors. This supports why many of the therapeutics classically used to control SLE also modulate atherosclerosis development. Greater understanding of the mechanisms underlying this condition will allow for the development of more targeted therapeutics and improved outcomes for SLE patients., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Accelerated atherosclerosis is a major source of morbidity in systemic lupus erythematosus (SLE). However, the cause of SLE-accelerated atherosclerosis remains unclear., Methods: CD4(+) T cells from C57/Bl/6 (B6) or SLE-susceptible B6.Sle1.2.3 (B6.SLE) mice were transferred into LDLr(-/-), Rag(-/-) mice. T cells were examined for cytokine production and expression of interleukin-10 receptor (IL-10R) and functional markers. T cells were isolated based on FoxP3(GFP) expression and transferred to LDLr(-/-), Rag(-/-) mice to establish a role for B6.SLE effector T cells (Teff) in atherosclerosis., Results: Mice receiving whole B6.SLE CD4(+) T cells displayed no other SLE phenotype; however, atherosclerosis was increased nearly 40%. We noted dysregulated IL-17 production and reduced frequency of IL-10R expression by B6.SLE regulatory T cells (Treg). Functional assays indicated resistance of B6.SLE Teff to suppression by both B6.SLE and B6 Treg. Transfer experiments with CD4(+)FoxP3(-) Teff and CD4(+)FoxP3(+) Treg from B6.SLE and B6 mice, respectively, resulted in increased atherosclerosis compared with B6 Teff and Treg recipients. Treg isolated from mice receiving B6.SLE Teff with B6 Treg had increased production of IL-17 and fewer expressed IL-10R compared with B6 Teff and Treg transfer., Conclusions: Transfer of B6.SLE Teff to LDLr(-/-), Rag(-/-) mice results in accelerated atherosclerosis independent of the source of Treg. In addition, the presence of B6.SLE Teff resulted in more IL-17-producing Treg and fewer expressing IL-10R, suggesting that B6.SLE Teff may mediate phenotypic changes in Treg. To our knowledge, this is the first study to provide direct evidence of the role of B6.SLE Teff in accelerating atherosclerosis through resistance to Treg suppression., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against self-antigens such as double-stranded DNA and phospholipids. Classical comorbidities of SLE include glomerulonephritis, infection, cardiovascular disease, arthritis, skin disorders, and neurological disease. In addition to these classical comorbidities, there is emerging evidence that SLE patients are at higher risk of developing insulin resistance and other components of the metabolic syndrome. Visceral adipose tissue inflammation is a central mediator of insulin resistance in the obese setting, but the mechanism behind the pathogenesis of metabolic disease in the SLE patient population is unclear. We hypothesize that lupus-associated changes in the adaptive immune system are associated with disruption in glucose homeostasis in the context of SLE. To test this hypothesis, we assessed the metabolic and immunological phenotype of SLE-prone B6.SLE mice. B6.SLE mice fed a low-fat diet had significantly worsened glucose tolerance, increased adipose tissue insulin resistance, increased β-cell insulin secretion, and increased adipocyte size compared with their respective B6 controls. Independently of diet, B cells isolated from the white adipose tissue of B6.SLE mice were skewed toward IgG production, and the level of IgG1 was elevated in the serum of SLE-prone mice. These data show that B6.SLE mice develop defects in glucose homeostasis even when fed a low-fat diet and suggest that B cells may play a role in this metabolic dysfunction.

Rationale: Recent clinical and preclinical studies have demonstrated that systemic lupus erythematosus (SLE) is associated with an increased risk for cardiovascular disease (CVD). However, unlike in the general population, little is known regarding the efficacy of atheroprotective interventions in patients with SLE. The current study aims to determine the benefit of lymphocyte inhibition on reducing the atherosclerotic burden in SLE-susceptible LDLr-deficient mice., Methods: Female LDLr(-/-) mice were lethally irradiated and reconstituted with bone marrow from C57Bl/6 mice (LDLr.B6) or the SLE-susceptible B6.Sle1.2.3 mice (LDLr.Sle). At 16 weeks post transplant, mice were treated with atorvastatin (10 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or both (MMF-A) for 8 weeks, after which the extent of atherosclerosis and the presence of SLE were assessed., Results: Following 8 weeks of treatment, we observed that atorvastatin-mediated reduction in cholesterol levels attenuated atherogenesis in LDLr.B6 mice but failed to significantly reduce atherosclerotic lesion size in LDLr.Sle mice, in spite of a significant reduction in serum cholesterol levels. Treatment with MMF and MMF-A attenuated atherogenesis in LDLr.B6 and LDLr.Sle mice. In addition, MMF-containing regimens inhibited recruitment of CD4+ T cells to atherosclerotic lesions in LDLr.Sle mice. In these mice, MMF also reduced the proportion of activated splenic T cells, as well as interleukin 10 secretion by T cells. With regard to lupus activity, MMF had no overt effect on anti-double-stranded DNA (dsDNA) antibody titres or kidney function and pathology., Conclusions: The current study demonstrates that reduction of cholesterol levels alone is not atheroprotective in lupus-mediated atherogenesis. This is the first study to demonstrate that MMF reduces the atherosclerotic burden in a model of lupus-accelerated atherosclerosis. Our results suggest that MMF treatment may prove beneficial in preventing CVD in patients with SLE.

The atherosclerotic process is accelerated in patients with systemic lupus erythematosus (SLE). In addition to a robust lipid-lowering effect, various immunomodulatory functions have been ascribed to statins. By virtue of the latter they may be able to reduce atherosclerotic vascular disease in SLE by inhibiting immune activation within the arterial wall and by attenuating lupus activity. The effects of statins on SLE as well as on lupus-mediated atherogenesis in vivo are discussed in this viewpoint.

Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis. The underlying mechanisms are poorly understood, and investigations have been hampered by the absence of animal models that reflect the human condition of generalized atherosclerosis and lupus. We addressed this problem by transferring lupus susceptibility to low-density lipoprotein (LDL) receptor-deficient (LDLr-/-) mice, an established model of atherosclerosis, creating radiation chimeras with NZM2410-derived, lupus-susceptible, B6.Sle1.2.3 congenic or C57BL/6 control donors (LDLr.Sle and LDLr.B6, respectively). LDLr.Sle mice developed a lupus-like disease characterized by production of double-stranded DNA autoantibodies and renal disease. When fed a Western-type diet, LDLr.Sle chimeras had increased mortality and atherosclerotic lesions. The plaques of LDLr.Sle mice were highly inflammatory and contained more CD3+ T cells than controls. LDLr.Sle mice also had increased activation of CD4+ T and B cells and significantly higher antibody to oxidized LDL and cardiolipin. Collectively, these studies demonstrate that the lupus-susceptible immune system enhances atherogenesis and modulates plaque composition.

Systemic lupus erythematosus (SLE) is increasingly recognized as a risk factor for the development of premature atherosclerosis. The inflammatory process in both of these diseases is controlled by a variety of cell types of the innate and adaptive immune systems. Recent studies from several groups, including ours, have revealed a critical role of a unique subset of lymphocytes, termed invariant natural killer T (iNKT) cells, in the development of lupus-like autoimmunity and atherosclerosis in animal models. iNKT cells appear to play complex and divergent roles in the development of SLE and atherosclerosis. Our findings suggest that alterations in iNKT cell functions during the development of SLE may be related to the increased risk of SLE patients to develop atherosclerosis and coronary heart disease. We found that iNKT cell activation with the sponge-derived glycolipid alpha- galactosylceramide generally protects against the development of lupus-like autoimmunity in mice, whereas it exacerbates atherosclerosis. Therefore, while our studies have identified iNKT cells as potential therapeutic targets for SLE, further studies are necessary to design drugs that will avoid the underlying harmful effects of iNKT cell activation on the development of atherosclerosis.