Systemic Lupus Erythematosus Mice Research Articles

Hypertension in an experimental model of systemic lupus erythematosus occurs independently of the renal nerves

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder with prevalent hypertension and renal injury. In this study, we tested whether the renal nerves contribute to the development of hypertension in an established mouse model of SLE (NZBWF1). Female SLE and control (NZW/LacJ) mice were subjected to either bilateral renal denervation or a sham procedure at 32 wk of age. Two weeks later, blood pressure was assessed in conscious mice using carotid artery catheters. Blood pressure was higher in SLE mice compared with controls, as previously reported; however, blood pressure was not altered in the denervated SLE or control mice. The development of albuminuria was markedly blunted in denervated SLE mice; however, glomerulosclerosis was increased. Renal denervation reduced renal cortical expression of monocyte-chemoattractant protein in SLE mice but did not significantly alter renal monocyte/macrophage infiltration. Renal cortical TNF-α expression was also increased in sham SLE mice, but this was not impacted by denervation. This study suggests that the renal nerves do not have a significant role in the pathogenesis of hypertension, but have a complex effect on the associated renal inflammation and renal injury.

AB0206 Impaired expansion of myeloid derived supressor cells (MDSCS) in both murine and human lupus

BackgroundMDSCs (characterized in mice as CD11b+Gr1+ and in humans as CD14-HLA-DRlowCD15+CD33+) represent a phenotypically heterogeneous population of myeloid precursors of macrophages, dendritic cells and granulocytes. In EAE we have previously...

Concentrated fish oil (Lovaza®) extends lifespan and attenuates kidney disease in lupus-prone short-lived (NZBxNZW)F1 mice

A growing number of reports indicate that anti-inflammatory actions of fish oil (FO) are beneficial against systemic lupus erythematosus (SLE). However, the majority of pre-clinical studies were performed using 5-20% FO, which is higher than the clinically relevant dose for lupus patients. The present study was performed in order to determine the effective low dose of FDA-approved concentrated FO (Lovaza®) compared to the commonly used FO-18/12 (18-Eicosapentaenoic acid [EPA]/12-Docosahexaenoic acid [DHA]). We examined the dose-dependent response of Lovaza® (1% and 4%) on an SLE mouse strain (NZBxNZW)F1 and compared the same with 1% and 4% placebo, as well as 4% FO-18/12, maintaining standard chow as the control. Results show for the first time that 1% Lovaza® extends maximal lifespan (517 d) and 4% Lovaza® significantly extends both the median (502 d) and maximal (600 d) life span of (NZBxNZW)F1 mice. In contrast, FO-18/12 extends only median lifespan (410 d) compared to standard chow diet (301 d). Additionally, 4% Lovaza® significantly decreased anti-dsDNA antibodies, reduced glomerulonephritis and attenuated lipopolysaccharide-induced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in splenocytes compared to placebo. 4% Lovaza® was also shown to reduce the expression of inflammatory cytokines, including IL-1β, IL-6 and TNF-α, while increasing renal anti-oxidant enzymes in comparison to placebo. Notably, NFκB activation and p65 nuclear translocation were lowered by 4% Lovaza® compared to placebo. These data indicate that 1% Lovaza® is beneficial, but 4% Lovaza® is more effective in suppressing glomerulonephritis and extending life span of SLE-prone short-lived mice, possibly via reducing inflammation signaling and modulating oxidative stress.

A Novel Epitope from CD22 Regulates Th1 and Th17 Cell Function in Systemic Lupus Erythematosus

The published antibodies (Abs) against CD22 on B cells including Epratuzumab could inhibit B cell activation mainly through binding to C2-set Ig domain of CD22, but they are rarely reported to modulate the pathogenic CD4+ T cell function in systemic lupus erythematosus (SLE). Recently, it was proved that the extracellular amino-terminal V-set Ig domain of CD22 might mediate the interaction of B and T cells, but for now the exact effect of this domain on CD4+ T cell biology have not been identified. Thus, in this study, we screened out a peptide termed B2285 from this V-set Ig domain, developed the novel specific anti-B2285 Abs in rabbits, and investigated their effects in MRL/lpr mice with spontaneous SLE. The results showed that anti-B2285 Abs could ameliorate the disease severity obviously in spontaneous SLE mice with the decreased differentiations of Th1 and Th17 cells and no changes of Th2 and Treg cells. In co-cultured B cells and CD4+ T cells, this specific anti-CD22 Abs was observed to inhibit the anti-dsDNA Abs production, CD4+ T cells proliferation, the protein levels of T-bet and RORγt, and the mRNA levels of TNF-α, IFN-γ, IL-6 and IL-17 in CD4+ T cells. Moreover, the expression of CD45RO on CD4+ T cells could be also apparently diminished by this novel Abs. The data suggested that anti-B2285 Abs could slow SLE progression significantly by regulating Th1 and Th17 cells function via B-T cell interaction and the cytokine network regulation. The treatment against V-set Ig domain of CD22 would be a valuable therapeutic method for SLE and other autoimmune diseases.

The Impact of Genetic Susceptibility to Systemic Lupus Erythematosus on Placental Malaria in Mice

Severe malaria, including cerebral malaria (CM) and placental malaria (PM), have been recognized to have many of the features of uncontrolled inflammation. We recently showed that in mice genetic susceptibility to the lethal inflammatory autoimmune disease, systemic lupus erythematosus (SLE), conferred resistance to CM. Protection appeared to be mediated by immune mechanisms that allowed SLE-prone mice, prior to the onset of overt SLE symptoms, to better control their inflammatory response to Plasmodium infection. Here we extend these findings to ask does SLE susceptibility have 1) a cost to reproductive fitness and/or 2) an effect on PM in mice? The rates of conception for WT and SLE susceptible (SLEs) mice were similar as were the number and viability of fetuses in pregnant WT and SLEs mice indicating that SLE susceptibility does not have a reproductive cost. We found that Plasmodium chabaudi AS (Pc) infection disrupted early stages of pregnancy before the placenta was completely formed resulting in massive decidual necrosis 8 days after conception. Pc-infected pregnant SLEs mice had significantly more fetuses (∼1.8 fold) but SLE did not significantly affect fetal viability in infected animals. This was despite the fact that Pc-infected pregnant SLEs mice had more severe symptoms of malaria as compared to Pc-infected pregnant WT mice. Thus, although SLE susceptibility was not protective in PM in mice it also did not have a negative impact on reproductive fitness.

Metabolomics Study on the Effects of Jieduquyuziyin Prescription on Systemic Lupus Erythematosus Mice by LC-Q-TOF/MS

A metabolomics approach was applied to study the metabolites characters of systemic lupus erythematosus (SLE) and therapeutical effects of jieduquyuziyin prescription (JP). High performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF/MS) in positive mode was employed to analyze urine specimens of the SLE model mice (MRL/lpr) group, prednisone acetate (PA)-treated SLE mice group, JP-treated SLE mice group, and control group (C57BL/6 J). Software of Mass Hunter and Mass Profiler Professional (MPP) were used to process the data. Multivariate statistical analysis of principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were applied to recognize the data pattern. PCA result showed that there were obvious disorders of amino acid metabolism in SLE model. Ten compounds have significant contributions to classification were identified as differential metabolites, such as glycine, pantetheine, and phenylpyruvic acid. Metabolism of phenylalanine tended to recover to the normal state after treatment with PA. The changes of glycine, phenylalanine, and tryptophan in SLE mice showed some alleviation in JP-treated SLE group. Thus, the JP has a good therapeutic effect on the SLE model mice by regulating the dysfunctions of amino acid metabolism. These results may be helpful to further understand the pathological mechanisms of SLE from the whole metabolism.

Multispecificity of Immunoglobulin M Antibodies Raised against Advanced Glycation End Products: INVOLVEMENT OF ELECTRONEGATIVE POTENTIAL OF ANTIGENS

Advanced glycation end products (AGEs) can act as neoantigens to trigger immune responses. Natural IgM antibodies against AGEs recognize multiple molecules, including DNA and chemically modified proteins. There is a close relationship between the formation of AGEs and innate immune responses. Our findings highlight AGEs and related modified proteins as a source of multispecific natural antibodies Advanced glycation end products (AGEs) are a heterogeneous and complex group of compounds that are formed when reducing sugars, such as dehydroascorbic acid, react in a nonenzymatic way with amino acids in proteins and other macromolecules. AGEs are prevalent in the diabetic vasculature and contribute to the development of atherosclerosis. The presence and accumulation of AGEs in many different cell types affect the extracellular and intracellular structure and function. In the present study, we studied the immune response to the dehydroascorbic acid-derived AGEs and provide multiple lines of evidence suggesting that the AGEs could be an endogenous source of innate epitopes recognized by natural IgM antibodies. Prominent IgM titers to the AGEs were detected in the sera of normal mice and were significantly accelerated by the immunization with the AGEs. Patients with systemic lupus erythematosus (SLE), a potentially fatal systemic autoimmune disease characterized by the increased production of autoantibodies, showed significantly higher serum levels of the IgM titer against the AGEs than healthy individuals. A progressive increase in the IgM response against the AGEs was also observed in the SLE-prone mice. Strikingly, a subset of monoclonal antibodies, showing a specificity toward the AGEs, prepared from normal mice immunized with the AGEs and from the SLE mice cross-reacted with the double-stranded DNA. Moreover, they also cross-reacted with several other modified proteins, including the acetylated proteins, suggesting that the multiple specificity of the antibodies might be ascribed, at least in part, to the increased electronegative potential of the proteins. These findings suggest that the protein modification by the endogenous carbonyl compounds, generating electronegative proteins, could be a source of multispecific natural antibodies.

Humoral immune system activation promotes the development of hypertension

Circulating autoantibodies are elevated in patients with essential hypertension suggesting the possibility of humoral immune system activation. Whether humoral immunity underlies the pathogenesis of hypertension is unclear. We hypothesized that humoral immune suppression (B cell depletion) would prevent the development of hypertension in a mouse model of the autoimmune disease systemic lupus erythematosus (SLE). Female SLE (NZBWF1) and control mice (NZW) were treated weekly with anti‐CD20 (10 mg/kg, Genentech) or vehicle (anti‐IgG) starting at 20, 26, and 30 weeks of age and ending at 34 weeks. Anti‐CD20 treatment reduced spleen weight in all groups regardless of treatment duration. Mean arterial pressure (MAP; mmHg) was higher in SLE mice compared to controls in all groups [(20 weeks; 134±1 vs 115±3, p<0.01); (26 weeks; 139±5 vs 116±2, p<0.001); (30 weeks; 138±2 vs 117±6, p<0.001)]. Anti‐CD20 did not alter MAP in SLE mice treated from 26 (131±3) or 30 (135±4) weeks of age. However, MAP was lower in SLE mice treated with anti‐CD20 starting at 20 weeks of age (120±3; p=0.01). Anti‐CD20 did not affect MAP in any control group. These data suggest that suppression of humoral immunity early in disease progression, but not later, can prevent the development of hypertension and supports the idea of autoimmunity as an underlying mechanism.AHA4350019/5T32HL105324, HL085907/HL092284/HL085907S1/UMMC‐IRSP, HL051971

17β‐estradiol attenuates renal TNFα and the progression of hypertension in mice with systemic lupus erythematosus

The autoimmune disorder systemic lupus erythematosus (SLE) primarily affects young women suggesting a pathogenic role for estrogen. Cardiovascular and renal disease are the major causes of mortality in women with SLE, and hypertension, a major cardio‐renal risk factor, is prevalent in these women. This led to the hypothesis that estrogen promotes hypertension and renal injury during SLE. To test this, 30 week old female SLE (NZBWF1) and control (NZW/LacJ) mice underwent either an ovariectomy (OVX) or sham operation. A subset of OVX mice were supplemented with 17β‐estradiol (E2). At 34 weeks of age, mean arterial pressure (MAP in mmHg) was higher in SLE sham mice (133±3) than controls (120±3, p<0.05) as was the prevalence of albuminuria (33% vs 0%). OVX did not alter MAP (115±3) or albuminuria in controls; however, contrary to our hypothesis, OVX in SLE mice exacerbated the hypertension (154±3, p<0.05 vs SLE sham) and prevalence of albuminuria (75% vs 33%). This was associated with increased renal TNFα protein expression (3.2±0.8 SLE OVX vs 1.8±0.5 SLE sham), an inflammatory cytokine that contributes to SLE hypertension. E2 repletion prevented the increase in pressure caused by OVX in SLE mice (132±2) and reduced albuminuria and renal TNFα (2.3±0.3). These data suggest that estrogen protects against SLE hypertension via reduction of renal inflammatory cytokines. (HL085907, HL051971, AHA12050150, UMC‐IRSP).

Nicotine reduces blood pressure in mouse model of systemic lupus erythematosus

Stimulation of the cholinergic anti‐inflammatory pathway through nicotinic acetylcholine receptors (α7nAchR) can suppress systemic inflammation by a mechanism involving vagus nerve activation. Evidence supports an important role for immune system activation and inflammation in the pathogenesis of hypertension. Hypertension and renal injury are prevalent in human patients with the chronic autoimmune inflammatory disorder, systemic lupus erythematosus (SLE), and some evidence suggests that these patients have impaired vagal function. Based on this, we hypothesized that the cholinergic anti‐inflammatory pathway is impaired in SLE and that activation of the pathway via nicotine would reduce blood pressure in mice with SLE. Female SLE (NZBWF1) and control (NZW) mice were infused with nicotine or vehicle for 7 days (2 mg/kg subcutaneous) after which time blood pressure was assessed. Blood pressure (mmHg) was higher in vehicle‐treated SLE mice compared to controls (135±7 vs. 114±4). Blood pressure in nicotine‐treated SLE (119±9) and control (114±1) mice was similar to vehicle‐treated controls. These data implicate impairment of the cholinergic anti‐inflammatory pathway in the development of SLE‐associated hypertension and suggest that it may be an important pathway to target clinically in patients with chronic inflammatory diseases associated with hypertension. AHA4350019, 5T32HL10532, HL051971

Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice

The ability to selectively inactivate immune cells with immunosuppressants is a much sought-after modality for the treatment of systemic lupus erythematosus and autoimmunity in general. Here, we designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). Treatment with MPA-loaded nanogels increased the median survival time (MST) of lupus-prone NZB/W F1 mice by 3 months with prophylactic use (MST was 50 weeks versus 38 weeks without treatment), and by 2 months when administered after the development of severe renal damage (MST after proteinuria onset was 12.5 weeks versus 4 weeks without treatment). Equivalent and greater doses of MPA administered in buffer were not efficacious. Nanogels had enhanced biodistribution to organs and association with immune cells. CD4-targeted nanogels yielded similar therapeutic results compared with nontargeted formulations, with protection from glomerulonephritis and decreases in IFN-γ-positive CD4 T cells. DCs that internalized nanogels helped mediate immunosuppression, as they had reduced production of inflammatory cytokines such as IFN-γ and IL-12. Our results demonstrate efficacy of nanogel-based lupus therapy and implicate a mechanism by which immunosuppression is enhanced, in part, by the targeting of antigen-presenting cells.

Calcium/Calmodulin-Dependent Protein Kinase IV Suppresses IL-2 Production and Regulatory T Cell Activity in Lupus

The activity of calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased in T cells from patients with systemic lupus erythematosus (SLE) and has been shown to reduce IL-2 production by promoting the effect of the transcriptional repressor cAMP responsive element modulator-α on the IL2 promoter. In this article, we demonstrate that T cells from MRL/lpr mice display increased levels of CaMK4 in the nucleus, and that genetic deletion of Camk4 results in improved survival. We demonstrate that absence of CaMK4 restores IL-2 production, curbs increased T cell activation, and augments the number and activity of regulatory T cells. Analogously, silencing of CaMK4 in T cells from patients with SLE increases the expression of FoxP3 on stimulation in the presence of TGF-β. Our results demonstrate the importance of the serine/threonine kinase CaMK4 in the generation and function of regulatory T cells in patients with SLE and lupus-prone mice, and its potential to serve as a therapeutic target.

Abstract 174: T Cells Promote the Progression of Hypertension and Renal Injury during Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder with prevalent hypertension and is a novel disease model to study the link between immune system activation and the development of hypertension. T cells have a central role in the pathogenesis of autoimmune disorders and were recently reported to promote angiotensin II and salt-sensitive hypertension. Despite their well known role in the pathogenesis of autoimmune disease and recent data suggesting an important role in the pathogenesis of hypertension, whether T cells mechanistically contribute to the prevalent hypertension during SLE remains unclear. In order to test this, experiments were designed to determine whether inhibition of T cell proliferation attenuates the progression of hypertension and renal injury in female SLE mice with established renal injury (albuminuria ≥ 100 mg/dL). SLE and control mice were administered either antibody to CD3, a component of the T cell receptor expressed on all T cells, or an anti-IgG isotype control for up to 4 weeks (intranasally; 25 μg/week). Splenic CD3 + CD4 + T cells were increased in SLE mice compared to controls (7.0 ± 4.2% vs. 3.1 ± 1.5% gated) and were reduced after the anti-CD3 treatment (2.4 ± 1.1% gated), likely reflecting a reduction in spleen weight. Anti-dsDNA autoantibodies characteristic to SLE were increased in vehicle-treated SLE mice compared to controls (19.8 ± 7.3 vs. 0.74 ± 0.07, n=10) and were blunted in the anti-CD3 treated SLE mice (9.7± 3.8, n=10). Blood pressure (mmHg) was increased in SLE mice compared to controls (156 ± 3 vs. 112 ± 4, p=0.001), and was lower in anti-CD3 treated SLE mice (137 ± 4; p=0.01) but not controls (117 ± 2). In anti-IgG treated SLE mice, albuminuria increased (+38.9 ± 36.8%) over the course of the study, whereas albuminuria in anti-CD3 treated SLE mice was unchanged (-2.53 ± 17.3%). Preliminary renal histology suggests that the anti-CD3 treatment attenuated the progression of glomerulosclerosis and preserved renal vascular structure (i.e., interlobular arteries, vasa recta). No renal injury was observed in the control mice. These data suggest that T cells have an important mechanistic role in the progression of autoimmune-associated hypertension, perhaps by promoting renal vascular structural changes and injury.

Abstract 10: Disparate Temporal Regulation of Blood Pressure by Estrogens During Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominantly affects young women. Due to this partiality towards women, estrogen is commonly implicated in disease development. The potential for estrogens to promote SLE disease progression stems from data showing that removal of estrogens in young female mice with SLE (6-8 week old NZBWF1 mice) delays the development of renal injury and mortality. The primary cause of mortality in women with SLE is cardiovascular disease, and hypertension, a major cardiovascular risk factor, is highly prevalent in this patient population. Based on the presumed role of estrogen to promote SLE, we hypothesized that estrogen promotes hypertension during SLE. To test this, 30 week old SLE mice (NZBWF1) and control mice (NZW/LacJ) were subjected to either ovariectomy (OVX) or a sham operation and a subset of these mice were replete with 17β-estradiol (E2, 5μg/mouse, s.c., 2x/week). At 34 weeks of age, mean arterial pressure (MAP in mmHg) was measured by carotid catheter in conscious freely moving mice. MAP was higher in SLE sham mice compared to control shams (133±3, n=17 vs. 120±3, n=13, p<0.05). Contrary to our hypothesis, OVX at 30 weeks exacerbated the hypertension (154±3, n=9, p<0.05 vs. SLE sham) and prevalence of albuminuria in mice with SLE (83%, 10 of 12 vs 36%, 5 of 14 measured by dipstick > 100 mg/dL). OVX did not alter MAP (115±3, n=9) or albuminuria in control mice. The hypertensive response to OVX was prevented in OVX SLE mice replete with E2 (133±4, n=3) suggesting a protective role for E2 against SLE-associated hypertension. Because previous studies showed that estrogen removal in young mice delayed SLE disease progression, we tested whether OVX starting at 8 weeks of age delayed the development of hypertension. OVX in young SLE mice did not significantly alter the progression of SLE-associated hypertension (141±4, n=4 measured at 34 weeks of age). Consistent with previous work of others, OVX in young SLE mice reduced the prevalence of albuminuria (20%, 1 of 5 vs 33%, 1 of 3). These data suggest that estrogen has a complex temporal role in the pathogenesis of SLE with the potential to promote disease early in life, but protect against the progression of SLE associated hypertension later in the course of the disease.

Murine BAFF expression is up-regulated by estrogen and interferons: Implications for sex bias in the development of autoimmunity

Systemic lupus erythematosus (SLE) in patients and certain mouse models exhibits a strong sex bias. Additionally, in most patients, increased serum levels of type I interferon (IFN-α) are associated with severity of the disease. Because increased levels of B cell activating factor (BAFF) in SLE patients and mouse models are associated with the development of SLE, we investigated whether the female sex hormone estrogen (E2) and/or IFNs (IFN-α or γ) could regulate the expression of murine BAFF. We found that steady-state levels of BAFF mRNA and protein were measurably higher in immune cells (CD11b+, CD11c+, and CD19+) isolated from C57BL/6 females than the age-matched male mice. Treatment of immune cells with IFN or E2 significantly increased levels of BAFF mRNA and protein and a deficiency of estrogen receptor-α, IRF5, or STAT1 expression in splenic cells decreased expression of BAFF. Moreover, treatment of RAW264.7 macrophage cells with IFN-α, IFN-γ, or E2 induced expression of BAFF. Interestingly, increased expression of p202, an IFN and estrogen-inducible protein, in RAW264.7 cells significantly increased the expression levels of BAFF and also stimulated the activity of the BAFF-luc-reporter. Accordingly, the increased expression of the p202 protein in lupus-prone B6.Nba2-ABC than non lupus-prone C57BL/6 and B6.Nba2-C female mice was associated with increased expression levels of BAFF. Together, our observations demonstrated that estrogen and IFN-induced increased levels of the p202 protein in immune cells contribute to sex bias in part through up-regulation of BAFF expression.

Recent therapeutic advances in the treatment of systemic lupus erythematosus

William Stohl received a BS from the Massachusetts Institute of Technology in 1973, a MD from the University of Pennsylvania in 1977 and a PhD from the University of Pennsylvania in 1979. After completing his internship and residency in internal medicine, he joined the laboratory of the late Henry Kunkel at the Rockefeller University in 1982. It was there that Dr Stohl began his investigative career focused on B cells, with an emphasis on their dysfunction in systemic lupus erythematosus (SLE). In 1986, Dr Stohl joined the faculty in the Division of Rheumatology (Department of Medicine, University of Southern California, Los Angeles, CA, USA) where he has remained throughout his professional career, rising to the Chief of the Division in 2007. For the past 11 years, the major focus of Dr Stohl’s investigations has been B lymphocyte stimulator (BLyS, also known as BAFF), its role in SLE pathogenesis and its therapeutic neutralization. Dr Stohl maintains an active laboratory that studies BLyS in SLE mice an...

Regulation of T cell metabolism and autoimmunity by the orphan nuclear receptor ERRγ (123.47)

Abstract Autoreactive T cells and abnormal cytokine production are key features of human and mouse systemic lupus erythematosus (SLE). The SLE susceptibility locus Sle1c2 is associated with CD4+ T cell hyperactivation, hyperproliferation and hyperproduction of IFNγ in the NZM2410 mouse model. Sle1c2 contains two genes, only one of which, Esrrg, is expressed in mouse CD4+ T cells. qRT-PCR and Western blot analysis showed that Esrrg is expressed in CD4+ T cells, albeit at a low level. Esrrg expression is significantly decreased in B6.Sle1c2 CD4+ T cells as compared to B6, and negatively correlates with T cell activation. In vitro, Esrrg expression is dramatically decreased after CD4+ T cells are stimulated with anti-CD3/CD28. These data suggest that Esrrg is required to maintain T cells in a quiescent state. Esrrg is a key regulator of cell metabolism. Consistently, Sle1c2 is associated with increased expression of genes involved in the glycolytic pathway, such as MCT4 and Hif1a, which have been previously associated with enhanced T cell effector functions. Sle1c2 is also associated with a decreased mitochondrial mass and functions, which is consistent with Esrrg playing a key role in these processes. Furthermore, treatment of CD4+ T cells with ERRγ agonist and reverse agonist affects T cell survival, proliferation, Foxp3 expression, and IL-2 and IFNγ production. Our study suggests that decreased Esrrg expression contributes to T cell autoimmunity through regulating cell metabolism.

T lymphocytes promote autoimmune‐associated hypertension

Evidence suggests that essential hypertension has autoimmune origins. We tested whether T cells, important mediators of autoimmunity, contribute to the prevalent hypertension in the autoimmune inflammatory disorder systemic lupus erythematosus (SLE). Female mice with active SLE (NZBWF1 with albuminuria ≥ 100 mg/dL) or control mice (NZW) were treated with the T cell receptor antibody (anti‐CD3) or anti‐IgG for 3–4 weeks (intranasally; 25 μg/week). Renal cortical expression of CD3 antigen was increased in SLE mice (p=0.03) and splenic CD3+CD4+ T cells were increased in SLE mice compared to controls (19 ± 2% vs. 14 ± 1% gated, p=0.04). Spleen weight was increased in SLE mice compared to controls, and was normalized by anti‐CD3. Blood pressure (mmHg) was increased in SLE mice compared to controls (155 ± 3 vs. 112 ± 4, p=0.001), and was lower in SLE mice (137 ± 6; p=0.01) but not controls (117±2) after anti‐CD3. Albuminuria (mg/mg creatinine) was increased in SLE mice compared to controls (500 ± 290 vs. 0.05 ± 0.01; p=0.01), and was reduced in SLE mice (50 ± 37; p=0.03) but not controls (0.06 ± 0.01) after anti‐CD3. Renal cortical IL‐17 receptor expression was increased in SLE mice compared to controls, and was reduced after anti‐CD3. These data suggest that T cell‐mediated inflammation contributes to hypertension and renal injury during SLE. Support: AHA4350019 (KWM), HL085907, HL092284, HL085907S1 (MJR), HL051971 (UMMC‐Phys)

Defects within the Myeloid Derived Supressor Cells (MDSCS) Compartment may Facilitate Aberrant Immune Responses in Systemic Lupus Erythematosus (SLE)

Background and objectivesThere is a currently unmet need to define the mechanisms involved in the homeostatic control of the immune response in autoimmune diseases. MDSCs (characterised in mice as CD11b+Gr1+...

Oxidative Stress Promotes Hypertension and Albuminuria During the Autoimmune Disease Systemic Lupus Erythematosus

Several lines of evidence suggest that essential hypertension originates from an autoimmune-mediated mechanism. One consequence of chronic immune activation is the generation of oxygen-derived free radicals, resulting in oxidative stress. Renal oxidative stress has direct prohypertensive actions on renal microvascular and tubular function. Whether oxidative stress contributes to the prevalent hypertension associated with autoimmune disease is not clear. We showed previously that female NZBWF1 mice, an established model of the autoimmune disease systemic lupus erythematosus (SLE), develop hypertension associated with renal oxidative stress. In the present study we tested the hypothesis that oxidative stress contributes to autoimmune-mediated hypertension by treating SLE and control (NZW/LacJ) mice with tempol (2.0 mmol/L) and apocynin (1.5 mmol/L) in the drinking water for 4 weeks. Although the treatment did not alter SLE disease activity (assessed by plasma double-stranded DNA autoantibodies), blood pressure and renal injury (urinary albumin) were reduced in the treated SLE mice. Tempol plus apocynin-treated SLE mice had reduced expression of nitrosylated proteins in the renal cortex, as well as reduced urinary and renal cortical hydrogen peroxide, suggesting that treatment reduced renal markers of oxidative stress. These data suggest that renal oxidative stress plays an important mechanistic role in the development of autoimmune-mediated hypertension.