Experimental Model Of Systemic Lupus Erythematosus Research Articles

Leptin antagonism attenuates hypertension and renal injury in an experimental model of autoimmune disease.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by B- and T-lymphocyte dysfunction and altered cytokine production, including elevated levels of the adipocytokine leptin. Leptin has various immunomodulatory properties, including promoting the expansion of proinflammatory T lymphocytes and the proliferation and survival of B cells. In the present study, we hypothesized that leptin antagonism would improve B- and T-cell dysfunction and attenuate hypertension in an experimental model of SLE, the NZBWF1 mouse. To test this hypothesis, 28-week-old female control and SLE mice were administered 5 mg/kg of murine leptin superantagonist (LA) or vehicle via ip injection every other day for four weeks. Analysis of peripheral blood immune cell populations showed no changes in total CD45R+ B and CD3+ T cell percentages after treatment with LA. However, SLE mice treated with LA had an improved CD4/CD8 ratio and decreased CD3+CD4-CD8- double negative (DN) T cells. Blood pressure was higher in SLE than in control, and treatment with LA decreased blood pressure in SLE mice. Treatment with LA also delayed the onset of albuminuria and decreased glomerulosclerosis in SLE mice. Renal immune cell infiltration was significantly higher in SLE mice as compared with control, but LA treatment was associated with decreased levels of renal CD4+ T cells. In conclusion, these data suggest that leptin plays a pathogenic role in the development of hypertension in SLE, in part, by promoting the expansion of inflammatory DN T cells and the infiltration of T cells into the kidneys.

Fecal microbiota transplantation attenuates hypertension in a female mouse model of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototypic multisystem autoimmune disorder that disproportionately affects women. SLE is characterized by a breach of immunological self-tolerance and the expansion of autoreactive T and B lymphocytes, leading to the production of autoantibodies. Autoantibody production leads to downstream chronic inflammation resulting in high rates of hypertension, renal injury, and cardiovascular disease. Alterations in the gut microbiota, or gut dysbiosis, is associated with many autoimmune diseases, including SLE. In the present study, we hypothesized that gut dysbiosis in SLE may play a role in the development of immune system dysfunction and hypertension in an experimental model of SLE, and that fecal microbiota transplantation (FMT) with microbes from control mice may improve these parameters. To test this hypothesis, we treated 26-week-old female control (NZW, n=19) and SLE (NZBWF1, n=19) mice with broad spectrum antibiotics (0.4 g/L ampicillin, 0.4 g/L neomycin sulfate, 0.4 g/L metronidazole, and 0.2 g/L vancomycin) in drinking water for one week to deplete the existing microbiota. Subsequently, mice were given 0.1 mL of fecal microbes via oral gavage two times per week for four weeks in the following groups (n=9-10 mice/group): Control-vehicle, Control-SLE microbes, SLE-vehicle, SLE-Control microbes. Changes in the gut microbiome before and after FMT were assessed by 16S rRNA analysis of the microbiome. Mean arterial pressure (MAP, mmHg), measured in conscious mice by carotid artery catheter was higher in SLE mice that received SLE microbes (Control: 112±3 vs. SLE: 140 ±2 mmHg, p<0.0001). SLE mice that received FMT with control microbes had lower blood pressure (SLE-Control microbes: 126±4 mmHg, p=0.03). Renal injury, as assessed by urinary albumin excretion at the conclusion of the study, was not significantly different among the groups (p=0.3523). Circulating autoantibodies and immunoglobulins were also measured at the conclusion of the study. Anti-dsDNA IgG was elevated in SLE mice compared to control (Control: 149±38 vs. SLE: 527±114 kU/mL, p=0.02), and were significantly lower in SLE mice treated with control microbes (SLE-Control microbes: 126±4 mmHg, p=0.03). Circulating IgM was also elevated in SLE mice (Control: 0.053±0.008 vs. SLE: 0.32±0.04 mg/mL, p<0.0001), and FMT lowered IgM in SLE mice that received FMT (0.19±0.03 mg/mL, p=0.0069). These data suggest that gut microbiota present in NZBWF1 mice contribute to both autoantibody production and the development of hypertension, and that interventions to alter the microbiora could have a beneficial impact on disease activity in SLE patients. NIH NIGMS P20GM104357 to UMMC Department of Physiology and Biophysics, NIH NHLBI R00HL146888 to Erin Taylor This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Long‐term Gut Microbiota Depletion Exacerbates Hypertension and Renal Injury in an Experimental Model of Autoimmune Disease

The gut microbiota plays an indispensable role in the development and maintenance of both the innate and adaptive immune systems. Alterations in the gut microbiota, or gut dysbiosis, is associated with many autoimmune disorders, including those without gastrointestinal manifestations, such as rheumatoid arthritis and systemic lupus erythematosus (SLE). SLE is a multisystem autoimmune disorder that primarily affects women and is characterized by high rates of hypertension, renal injury, and cardiovascular disease. Recent studies in several animal models have also posited a possible causative role of the gut dysbiosis in the development of hypertension. In the present study, we hypothesized that the gut dysbiosis in SLE may play a role in the development of immune system dysfunction and hypertension in an experimental model of SLE, the NZBWF1 mouse. To test this hypothesis, we treated 18‐week‐old female control (NZW, n=14) and SLE (NZBWF1, n=14) mice with broad spectrum antibiotics (Abx: 0.4 g/L ampicillin, 0.4 g/L neomycin sulfate, 0.4 g/L metronidazole, and 0.2 g/L vancomycin) in drinking water for 16 weeks. Additional groups of control and SLE mice received normal drinking water (control, n=14; SLE, n=14) over the course of the study. At the conclusion of the treatment, we confirmed successful gut microbiome depletion in the feces of control and SLE mice by qPCR of 16S rRNA. Mean arterial pressure (MAP; mmHg), measured in conscious mice by carotid artery catheter, was higher in SLE mice than in control mice (110±4 mmHg control vs. 131±6 mmHg SLE, p<0.01). Unexpectedly, treatment with antibiotics further increased blood pressure in SLE mice (SLE‐Abx: 151±4 mmHg, p<0.01 vs. SLE), but had no impact on blood pressure in control animals (110±4 mmHg control vs. 106±4 mmHg control‐Abx, p=0.91). Urinary albumin excretion, a marker of renal injury, was assessed by ELISA at the conclusion of the study. Albumin excretion was increased in SLE mice (0.22±0.08 mg/day control vs. 25.1±15.7 mg/day SLE, p=0.08), and urinary albumin remained elevated in SLE mice administered antibiotics (43.6±17.3 mg/day, p=0.68 vs. SLE‐Abx). Additionally, renal immune cell infiltration was assessed using flow cytometry. SLE mice had significantly higher levels of renal CD4+ T cells as compared to control mice (0.46±0.04% control vs. 0.84±0.1% SLE, p<0.05), but treatment with antibiotics elevated renal CD4+ T cells further (2.9±0.5%, p<0.001 vs. SLE). An additional pilot study (n=7‐9 mice/group) of short‐term antibiotic treatment from 26‐32 weeks of age had no impact on blood pressure in SLE mice (120±4 mmHg SLE vs. 122±3 mmHg SLE‐Abx, p=0.97). These data suggest that a long‐term loss of the microbiome in SLE actually further exacerbate disease progression and the development of hypertension.

Leptin Antagonism Attenuates Hypertension in a Rodent Model of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that predominately affects women and is associated with high rates of hypertension and cardiovascular disease. SLE is characterized by B and T lymphocyte dysfunction and altered cytokine production, including elevated levels of the adipocytokine leptin. Leptin has various immunomodulatory properties, including promoting the expansion of proinflammatory T lymphocytes as well as the proliferation and survival of B cells. Because B and T lymphocytes have been implicated in the development of autoimmune‐associated hypertension by our laboratory, we hypothesized that leptin antagonism would attenuate hypertension and renal injury in an experimental model of SLE. To test this hypothesis, 28 week old female SLE (NZBWF1, n=27) and control (NZW, n=25) mice were administered 3 mg/kg of murine leptin superantagonist (LA) or vehicle (0.2% NaHCO3, pH 8.0) every 48 hours for four weeks. At the conclusion of the study, immune cell populations in the peripheral blood were analyzed using flow cytometry. The percentages of CD45R+ B lymphocytes were not significantly different between vehicle and LA‐treated SLE mice (17.4±3.0% SLE‐vehicle vs. 11.7±1.9% SLE‐LA, p=0.1). Similarly, there were no significant changes in CD3+CD4+or CD3+CD8+T cells; however, double negative T cells (CD3+CD4−CD8−) were significantly decreased in SLE mice administered LA as compared to vehicle treated SLE mice (25.1±2.0% SLE‐vehicle vs. 16.4±2.9% SLE‐LA, p=0.03). Increased numbers of these proinflammatory T cells have been previously shown in both patients with SLE and in the NZBWF1 mouse. Mean arterial pressure (MAP; mmHg), measured in conscious mice by carotid artery catheter, was higher in SLE mice than in control mice (115±4 mmHg Controlvehicle vs. 131±2 mmHg SLE‐vehicle, p=0.01), and treatment with LA decreased blood pressure in SLE mice (SLE‐LA: 121±3 mmHg; p=0.03 vs. SLE‐vehicle). Urinary albumin excretion, a marker of renal injury, was assessed by ELISA at the conclusion of the study. Albumin excretion was increased in SLE mice (0.064±0.01 mg/day Control‐vehicle vs. 20.7±9.7 mg/day SLE‐vehicle, p=0.12), but urinary albumin remained elevated in SLE mice administered LA (16.4±6.8 mg/day, p=0.96 vs. SLE‐vehicle). An additional indicator of renal injury, B and T lymphocyte infiltration, was assessed by flow cytometry. SLE mice had significantly higher levels of renal CD45+B cells and CD3+T cells as compared to control mice, but SLE mice treated with LA had lower percentages of renal CD3+T cells as compared to SLE‐vehicle treated mice (2.7±0.6% SLE‐vehicle vs. 1.3±0.2% SLE‐LA, p=0.04). In conclusion, these data suggest that leptin plays a pathogenic role in the development of hypertension in SLE, in part by promoting the expansion of inflammatory T cells and the infiltration of T cells into the kidneys.Support or Funding InformationResearch supported by: VA Merit Award BX002604‐01A2 to MJR, NIH P01HL051971 and P20GM104357 to UMMC‐Department of Physiology and Biophysics, and NIH NHLBI F32HL137393 to EBT.

Human recombinant relaxin-2 does not attenuate hypertension or renal injury but exacerbates vascular dysfunction in a female mouse model of SLE

Systemic lupus erythematosus (SLE) is an autoimmune disease that disproportionately affects women of reproductive age and increases their risk for developing hypertension, vascular, and renal disease. Relaxin has potential beneficial therapeutic effects in cardiovascular disease through direct actions on the vasculature. The potential therapeutic benefit of relaxin on SLE-associated cardiovascular and renal risk factors like hypertension has not previously been tested. We hypothesized that relaxin would attenuate hypertension, renal injury, and vascular dysfunction in an established female mouse model of SLE (NZBWF1 mice). Serelaxin (human recombinant relaxin-2, 0.5 mg·kg-1·day-1) or vehicle was administered via osmotic mini-pump for 4 wk in female control (NZW) or SLE mice between 28 and 31 wk of age. Serelaxin treatment increased uterine weights in both groups, suggesting that the Serelaxin was bioactive. Mean arterial pressure, measured by carotid artery catheter, was significantly increased in vehicle-treated SLE mice compared with vehicle-treated controls, but was not changed by Serelaxin treatment. Albumin excretion rate, measured by ELISA, was similar between vehicle- and Serelaxin-treated SLE mice and between vehicle- and Serelaxin-treated control mice. Wire myography was performed using isolated carotid arteries to assess endothelial-independent and -dependent vasodilation, and data confirm that SLE mice have impaired endothelium-independent and -dependent relaxation compared with control mice. Serelaxin treatment did not affect endothelium-independent vasodilation, but exacerbated the endothelium-dependent dysfunction. These data suggest that, contrary to our hypothesis, Serelaxin infusion does not attenuate hypertension, renal injury, or vascular dysfunction in SLE, but worsens underlying vascular endothelial dysfunction in this experimental model of SLE. These data do not support the use of human recombinant relaxin-2 as an antihypertensive in the SLE patient population. NEW & NOTEWORTHY Relaxin is a peptide hormone commonly known for its role in pregnancy and for its use in recent clinical trials for the treatment of heart failure. Evidence suggests that relaxin has immunomodulatory effects; however, the potential therapeutic impact of relaxin in chronic immune mediated disease is unclear. This study tests whether recombinant human relaxin (Serelaxin) attenuates the progression of autoimmunity, and the associated cardiovascular consequences, in an experimental model of systemic lupus erythematosus.

Cyclophosphamide treatment for hypertension and renal injury in an experimental model of systemic lupus erythematosus.

Cardiovascular disease is the major cause of mortality among patients with the autoimmune disorder systemic lupus erythematosus (SLE). Our laboratory previously reported that immunosuppression with mycophenolate mofetil, a common therapy in patients with SLE, attenuates the development of hypertension in an experimental model of SLE. Cyclophosphamide (CYC) is another common therapy for patients with SLE that has contributed to improved disease management; however, its impact on the development of hypertension associated with SLE is not clear. We tested whether treatment with CYC (25 mg/kg, once/week, IP injection) for 4 weeks would attenuate hypertension in an established female mouse model of SLE with hypertension (30‐week‐old NZBWF1 females). Plasma anti‐dsDNA IgG levels, pathogenic for the disease, were lower in CYC‐treated SLE mice compared to vehicle‐treated SLE mice, suggesting efficacy of the therapy to suppress aberrant immune system function. Mean arterial pressure (MAP) was assessed by carotid artery catheters in conscious mice. Treatment did not attenuate the development of hypertension when compared to vehicle‐treated SLE mice; however, urinary albumin excretion was lower in CYC‐treated animals. Corresponding with the reduction in autoantibodies, data suggest that CYC treatment lowered circulating CD45R+ B cells. Paradoxically, circulating CD11b+Ly6G+ neutrophils were increased in CYC‐treated SLE mice compared to vehicle treated. Estrus cycling data also suggest that CYC treatment had an impact on ovarian function that may be consistent with reduced circulating estrogen levels. Taken together, these data suggest that CYC treatment attenuates autoantibody production and renal disease during SLE, but that the potential to affect MAP may be blunted by the increase in circulating neutrophils and CYC's impact on ovarian function.

030 IRF7 and IRF8 have distinct effects on the pathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the loss of tolerance against nuclear autoantigens in which the production of autoantibodies leads to tissue damages through the formation and deposition of immune complexes. Recent genome-wide association studies of SLE patients have revealed that polymorphisms of interferon regulatory factor (IRF) 7 and IRF8 are associated with an increased risk of SLE but the precise role of these IRFs in SLE development is not fully understood. IRF7 and IRF8 belong to the IRF family of transcription factors that regulate transcription of type I Interferon (IFN) and the expression of IFN-stimulated genes. Using a murine model of SLE induced by 2,6,10,14-tetramethylpentadecane (TMPD), we previously reported that IRF7 knockout (KO) mice failed to produce autoantibodies such as anti-dsDNA, ssDNA, nRNP and Sm antibodies but developed glomerulonephritis. In contrast, we found that IRF8KO mice showed no production of autoantibodies along with reduced glomerulonephritis after TMPD injection. TMPD induced apoptosis similarly in wild-type (WT), IRF7KO, and IRF8KO mice, suggesting that the dysregulation of apoptosis was not involved in the pathogenesis of SLE-like symptoms in these mice. These results suggest that type I IFN pathway is critical for autoantibody production but not development of glomerulonephritis. In order to explore the mechanism responsible for tissue damage including glomerulonephritis in this experimental model of SLE, we analyzed the peritoneal cell infiltrate in these mice. We found that inflammatory monocytes were recruited into the peritoneum in WT and IRF7KO mice but not in IRF8KO mice 2 weeks after TMPD injection. Inflammatory monocytes are known to be recruited to inflamed tissue and contribute to tissue damage. These results suggest that inflammatory monocytes trafficking to the peritoneum might be important event leading to tissue damage in this model.

435 IRF7 and IRF8 have distinct effects on the pathogenesis of SLE

Recent genome-wide association studies of systemic lupus erythematosus (SLE) patients have revealed that polymorphisms of interferon regulatory factor (IRF) 7 and IRF8 are associated with an increased risk of SLE but the precise role of these IRFs in SLE development is not fully understood. IRF7 and IRF8 belong to the IRF family of transcription factors that regulate transcription of type I Interferon (IFN) and the expression of IFN-stimulated genes. Using a murine model of SLE induced by 2,6,10,14-tetramethylpentadecane (TMPD), we previously reported that IRF7 knockout (KO) mice failed to produce autoantibodies such as anti-dsDNA, ssDNA, nRNP and Sm antibodies but developed glomerulonephritis. In contrast, we found that IRF8KO mice showed no production of autoantibodies along with reduced glomerulonephritis after TMPD injection. These results suggest that type I IFN pathway is critical for autoantibody production but not development of glomerulonephritis. In order to explore the mechanism responsible for tissue damage including glomerulonephritis in this experimental model of SLE, we analyzed the peritoneal cell infiltrate in these mice. We found that inflammatory monocytes were recruited into the peritoneum in wild-type (WT) and IRF7KO mice but not in IRF8KO mice 2 weeks after TMPD injection. Inflammatory monocytes, characterized by expression of Ly6C and CCR2, are known to be recruited to inflamed tissue and contribute to tissue damage. These results suggest that inflammatory monocytes trafficking to the peritoneum might be important event leading to tissue damage in this model.

Abstract P348: Immunosuppression with Cyclophosphamide Attenuates Renal Injury but Not Hypertension in an Experimental Model of Autoimmune Disease

Cardiovascular disease is the major cause of mortality among patients with the autoimmune disorder systemic lupus erythematosus (SLE). Our laboratory previously showed that immunosuppression with mycophenolate mofetil, a common therapy in patients with SLE, attenuates the development of hypertension in an experimental model of SLE. Cyclophosphamide is another common therapy for patients with SLE that has contributed to improved disease management; however, its impact on the development of hypertension associated with SLE is not clear. We tested whether treatment with cyclophosphamide (25 mg/kg, once/week, IP injection) for four weeks attenuates hypertension in an established female mouse model of SLE with hypertension (30 week old NZBWF1 females). Plasma anti-dsDNA IgG levels, pathogenic for the disease, were lower in cyclophosphamide-treated SLE mice compared to vehicle-treated SLE mice (161 ± 43, n=19 vs 501 ± 114, n=21, p<0.05 units/mL), suggesting efficacy of the therapy to suppress aberrant immune system function. Mean arterial pressure (MAP) was assessed by carotid artery catheters in conscious mice. Treatment did not attenuate the development of hypertension (136 ± 3 mmHg, n=15) when compared to vehicle treated SLE mice (131 ± 4 mmHg, n=13, p=0.69]; however, urinary albumin excretion (72.2 ± 68 mg/day, n=21, mg/day) was lower in cyclophosphamide treated animals (0.06 ± 0.02 mg/day, n=13). Corresponding with the reduction in autoantibodies, preliminary data suggest that cyclophosphamide treatment lowered circulating CD45R + B cells (15.87 ± 8.49%, n=10 vs 26.96 ± 4.72%, n=8). Paradoxically, circulating CD11b + Ly6G + neutrophils were increased in cyclophosphamide treated SLE mice compared to vehicle treated (39.26 ± 4.92%, n=10 vs 20.58 ± 6.01%, n=8, p=0.06). These data suggest that cyclophosphamide treatment attenuates autoantibody production and renal disease during SLE, but that the potential to impact MAP may be blunted by the increase in circulating neutrophils.

SY 11-4 CONNECTIVE TISSUE DISEASE AND ITS ASSOCIATION WITH ARTERIAL HYPERTENSION

Connective tissue diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, and scleroderma, have a strong predilection for women and are associated with a marked increase in the prevalence of hypertension. The mechanisms leading to the increased risk of hypertension in these patients remain unclear; however, they are likely related to immune mediated changes in cardiovascular and renal function. Over the past several years, we have elucidated a number of factors that contribute to the development of hypertension during SLE using a widely established experimental model of SLE, the female NZBWF1 mouse. These factors include impaired systemic vascular function, altered renal hemodynamics, and increased oxidative stress and inflammatory cytokines. Recent work from our laboratory has focused on identifying fundamental immunological changes during SLE that ultimately lead to increased cardiovascular risk. This presentation will review clinical and basic evidence for the risk of hypertension during connective tissue diseases and provide experimental evidence that autoantibodies have a central mechanistic role in the pathogenesis of hypertension associated with SLE.

Abstract 535: Chronic High Sodium Diet Attenuates The Development Of Renal Injury And Inflammation In Murine Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder with prevalent renal disease, a consequence of increased and abnormal survival of B and T lymphocytes. Recent evidence suggests that dietary salt may be an important environmental factor that promotes certain autoimmune diseases by stimulating pro-inflammatory T lymphocyte differentiation. Therefore, we hypothesized that a long-term high salt diet would accelerate the progression of renal disease during SLE. In order to test this, an established experimental model of SLE (female NZBWF1 mice) was fed a standard (0.4% NaCl) or high salt (4% NaCl) diet starting at 10 weeks of age. Sodium intake (in meq/day) was measured three times throughout the study and was significantly greater in high salt fed animals at 16 weeks of age (2.9±0.6 vs. 0.5±0.06 , p=0.01), 23 weeks (4.8±0.8 vs. 0.6±0.06, p=0.004) and 29 weeks (5.7±0.6 vs. 0.6±0.05, p=0.0007). Urinary albumin was monitored monthly until 30 weeks then weekly by dipstick assay as a marker of renal injury until 34 weeks of age, at which time catheters were implanted into the carotid arteries for measurement of mean arterial pressure (MAP). Mice were then euthanized and kidneys collected. Renal cortex enriched mRNA was analyzed by qRT-PCR for inflammatory markers, and renal medullary enriched mRNA was analyzed for expression of serum glucocorticoid kinase 1 (SGK1), a salt-sensing kinase. Counter to our hypothesis, 75% (9/12) of animals on a normal diet developed albuminuria (≥ 100 mg/dL), whereas 17% (2/12) of the high salt fed animals developed albuminuria (p=0.0002). MAP was not different between groups (132±4 mmHg 0.4% NaCl vs. 144±8 mmHg 4% NaCl), nor was renal medullary expression of SGK1 mRNA (0.25±0.03 vs. 0.20±0.04). However, renal cortical interleukin-2 (IL-2), a cytokine important for T cell differentiation, expression was significantly lower in high salt fed animals (0.31±0.03 vs. 1.16±0.34, p=0.03). These data suggest that a long-term high salt diet may protect against the renal injury associated with SLE, possibly through alterations in IL-2 mediated T cell differentiation, without a significant effect on MAP. Furthermore, the data advance our overall understanding of how dietary salt may impact different autoimmune disorders.

Malarial Infection of Female BWF1 Lupus Mice Alters the Redox State in Kidney and Liver Tissues and Confers Protection against Lupus Nephritis

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by an imbalanced redox state and increased apoptosis. Tropical infections, particularly malaria, may confer protection against SLE. Oxidative stress is a hallmark of SLE. We have measured changes in the levels of nitric oxide (NO), hydrogen peroxide (H2O2), malondialdehyde (MDA), and reduced glutathione (GSH) in both kidney and liver tissues of female BWF1 lupus mice, an experimental model of SLE, after infection with either live or gamma-irradiated malaria. We observed a decrease in NO, H2O2, and MDA levels in kidney tissues after infection of lupus mice with live malaria. Similarly, the levels of NO and H2O2 were significantly decreased in the liver tissues of lupus mice after infection with live malaria. Conversely, GSH levels were obviously increased in both kidney and liver tissues after infection of lupus mice with either live or gamma-irradiated malaria. Liver and kidney functions were significantly altered after infection of lupus mice with live malaria. We further investigated the ultrastructural changes and detected the number of apoptotic cells in kidney and liver tissues in situ by electron microscopy and TUNEL assays. Our data reveal that infection of lupus mice with malaria confers protection against lupus nephritis.

Monocytes fromIrf5−/−Mice Have an Intrinsic Defect in Their Response to Pristane-Induced Lupus

The transcription factor IFN regulatory factor (IRF)5 has been identified as a human systemic lupus erythematosus (SLE) susceptibility gene by numerous joint linkage and genome-wide association studies. Although IRF5 expression is significantly elevated in primary blood cells of SLE patients, it is not yet known how IRF5 contributes to SLE pathogenesis. Recent data from mouse models of lupus indicate a critical role for IRF5 in the production of pathogenic autoantibodies and the expression of Th2 cytokines and type I IFN. In the present study, we examined the mechanisms by which loss of Irf5 protects mice from pristane-induced lupus at early time points of disease development. We demonstrate that Irf5 is required for Ly6C(hi) monocyte trafficking to the peritoneal cavity, which is thought to be one of the initial key events leading to lupus pathogenesis in this model. Chemotaxis assays using peritoneal lavage from pristane-injected Irf5(+/+) and Irf5(-/-) littermates support an intrinsic defect in Irf5(-/-) monocytes. We found the expression of chemokine receptors CXCR4 and CCR2 to be dysregulated on Irf5(-/-) monocytes and less responsive to their respective ligands, CXCL12 and CCL2. Bone marrow reconstitution experiments further supported an intrinsic defect in Irf5(-/-) monocytes because Irf5(+/+) monocytes were preferentially recruited to the peritoneal cavity in response to pristane. Taken together, these findings demonstrate an intrinsic role for IRF5 in the response of monocytes to pristane and their recruitment to the primary site of inflammation that is thought to trigger lupus onset in this experimental model of SLE.

Increased disease activity is associated with altered sleep architecture in an experimental model of systemic lupus erythematosus

SLEEP IS VITAL TO HEALTH AND QUALITY OF LIFE, WHEREAS POOR SLEEP IS ASSOCIATED WITH ADVERSE HEALTH CONSEQUENCES. THIS IS AN IMPORTANT issue in its own right because sleep deprivation is becoming a more frequent and more accepted occurrence in modern society. In addition, sleep disorders have been observed in a number of chronic inflammatory conditions such as autoimmune diseases. Some of the clinical states associated with sleep disturbances include rheumatoid arthritis, fibromyalgia, and systemic lupus erythematosus (SLE).1 Nevertheless, it is unclear whether the sleep disruption that is observed in patients with these diseases is a result of factors associated with the disease—such as pain, depression, and stress2—or the result of dysregulation of the relationship between sleep and the immune system. Sleep disturbances are often reported by patients with SLE, and this may be associated with fatigue,3 a symptom that affects up to 80% of patients with SLE.4 According to Valencia-Flores and colleagues,5 these patients are sleepier during the day by virtue of sleep fragmentation due to more arousals and sleep-stage transitions (SST). In addition, the disease is exacerbated by sleep disruption, resulting in decreased sleep efficiency and less delta sleep. Additional polysomnographic findings associated with disease activity include an increased percentage of stage 1 sleep and alpha intrusions into non-rapid eye movement sleep. Furthermore, sleep apnea, periodic leg movements during sleep and narcolepsy have been associated with SLE.6 Much of our current knowledge of the pathogenesis of SLE is based on inference from a murine model, the New Zealand Black/New Zealand White (NZB/NZW)F1 hybrid strain. These mice spontaneously develop an autoimmune disease that closely resembles the immunologic and clinical characteristics of human SLE, such as high titer levels of antinuclear antibodies (ANA) associated with the development of rapidly progressive and lethal glomerulonephritis. Similar to its characteristics in humans, the disease is most common in female mice. However, there is no evidence about sleep patterns in this experimental model of SLE. Recent data from our laboratory indicate the importance of adequate sleep in (NZB/NZW)F1 mice. We observed that mice submitted to sleep deprivation exhibited an earlier onset of the disease, as reflected by the increased ANA titer levels.7 The purpose of the present study was, therefore, to evaluate the sleep patterns in a spontaneous experimental model of SLE, which offers a great opportunity to study the interaction between sleep and autoimmune disease. The disease course in (NZB/NZW)F1 mice was also assessed by following the development of ANA and pain sensitivity. A characterization of the sleep architecture that is associated with the onset, progress, and severe phases of this disease is presented in this article.