Murine Model Of Systemic Lupus Erythematosus Research Articles

Effects of Dietary Oleacein Treatment on Endothelial Dysfunction and Lupus Nephritis in Balb/C Pristane-Induced Mice.

Systemic lupus erythematosus (SLE) is a chronic immune-inflammatory disease characterized by multiorgan affectation and lowered self-tolerance. Additionally, epigenetic changes have been described as playing a pivotal role in SLE. This work aims to assess the effects of oleacein (OLA), one of the main extra virgin olive oil secoiridoids, when used to supplement the diet of a murine pristane-induced SLE model. In the study, 12-week-old female BALB/c mice were injected with pristane and fed with an OLA-enriched diet (0.01 % (w/w)) for 24 weeks. The presence of immune complexes was evaluated by immunohistochemistry and immunofluorescence. Endothelial dysfunction was studied in thoracic aortas. Signaling pathways and oxidative-inflammatory-related mediators were evaluated by Western blotting. Moreover, we studied epigenetic changes such as DNA methyltransferase (DNMT-1) and micro(mi)RNAs expression in renal tissue. Nutritional treatment with OLA reduced the deposition of immune complexes, ameliorating kidney damage. These protective effects could be related to the modulation of mitogen-activated protein kinases, the Janus kinase/signal transducer and transcription activator of transcription, nuclear factor kappa, nuclear-factor-erythroid-2-related factor 2, inflammasome signaling pathways, and the regulation of miRNAs (miRNA-126, miRNA-146a, miRNA-24-3p, and miRNA-123) and DNMT-1 expression. Moreover, the OLA-enriched diet normalized endothelial nitric oxide synthase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 overexpression. These preliminary results suggest that an OLA-supplemented diet could constitute a new alternative nutraceutical therapy in the management of SLE, supporting this compound as a novel epigenetic modulator of the immunoinflammatory response.

CAR T Cell Therapy: A New Hope for Refractory Lupus?

Systemic lupus erythematosus (SLE) is a complex multisystem, autoimmune disorder. The disease involves multiple inflammatory and immune pathways, posing several treatment challenges. The role of B cells in the pathogenesis and disease activity of SLE is well described, and treatments targeting B cells are now well established. Despite advances in therapeutics for SLE, the clinical course of SLE can be associated with significant morbidity and mortality. For many individuals, the management of SLE requires lifelong immunosuppression. Chimeric antigen receptor (CAR) T cell therapy is an emerging treatment for haematological malignancies that uses CAR T cells to target CD19+ B lymphocytes. CAR T cell therapy has shown promising results in murine models of SLE, and a case report and subsequent case series in people with SLE reporting drug-free remission following CAR T cell therapy against CD19+ B cells have recently been published. This review discusses CAR T cell therapy, comparing it with established B cell depletion therapies, such as rituximab, and exploring its safety, limitations and promise in the management of patients with SLE.

Endothelin receptor antagonism improves glucose tolerance and adipose tissue inflammation in an experimental model of systemic lupus erythematosus.

Endothelin-1 (ET-1) is elevated in patients with systemic lupus erythematosus (SLE), an autoimmune disease characterized by high rates of hypertension, renal injury, and cardiovascular disease. SLE is also associated with an increased prevalence of obesity and insulin resistance compared to the general population. In the present study, we tested the hypothesis that elevated ET-1 in SLE contributes to obesity and insulin resistance. For these studies, we used the NZBWF1 mouse model of SLE, which develops obesity and insulin resistance on a normal chow diet. To test this hypothesis, we treated control (NZW) and SLE (NZBWF1) mice with vehicle, atrasentan (ETA receptor antagonist, 10 mg/kg/day), or bosentan (ETA/ETB receptor antagonist, 100 mg/kg/day) for 4 wk. Neither treatment impacted circulating immunoglobulin levels, but treatment with bosentan lowered anti-dsDNA IgG levels, a marker of SLE disease activity. Treatment with atrasentan and bosentan decreased glomerulosclerosis, and atrasentan lowered renal T-cell infiltration. Body weight was lower in SLE mice treated with atrasentan or bosentan. Endothelin receptor antagonism also improved hyperinsulinemia, homeostatic model assessment for insulin resistance, and glucose tolerance in SLE mice. Adipose tissue inflammation was also improved by endothelin receptor blockade. Taken together, these data suggest a potential therapeutic benefit for SLE patients with obesity and insulin resistance.NEW & NOTEWORTHY SLE is an autoimmune disease that is associated with obesity, insulin resistance, and elevated endothelin-1. The present study demonstrated that pharmacological inhibition of endothelin receptors decreased body weight, insulin resistance, and adipose tissue inflammation in a murine model of SLE. The therapeutic potential of endothelin receptor antagonists to treat obesity-related diseases and pathophysiological conditions, such as autoimmune diseases and insulin resistance, has become increasingly clear.

Abstract 097: Seasonal Travel Stressors Modulates Hypertension In Adult Female Lupus Mice

Systemic lupus erythematosus (SLE) is an autoimmune disorder linked to chronic renal inflammation and prevalent hypertension. We use an established murine model of SLE (NZBWF1) to mechanistically link renal inflammation to the development of hypertension. SLE mice travel to our university pre-puberty (3-6 weeks), develop autoantibodies by 20 weeks, and are consistently hypertensive by 35 weeks. We observed that when mice travel in the summer, autoantibody production is higher as the mice age vs. those that travel in the winter. This association was heightened in a subset of SLE mice that traveled to our university as adults (18-19 weeks), suggesting a role of seasonal factors, travel stressors, and age in altering disease severity. It is unknown whether these seasonal and environmental stressors can also alter blood pressure and inflammatory processes. Thus, we hypothesized that travel-induced seasonal stressors exacerbate hypertension and renal inflammation in adult SLE-prone mice. Female SLE mice traveled to our university in summer or winter at 3-6 or 18-19 weeks and were implanted with carotid catheters once they reached 35 weeks to assess mean arterial pressure (MAP). Mice were then euthanized and tissues collected to monitor plasma and renal interleukin (IL)-6, a proinflammatory cytokine. No seasonal differences were found in MAP of mice that traveled pre-puberty in summer (n = 17) and winter (n = 39) (143.6 ± 3.5 vs. 140.2 ± 2.2 mmHg; p = 0.4096) nor in plasma IL-6 (26.06 ± 7.25 vs. 15.54 ± 8.622 pg/mL; p = 0.2370) or renal IL-6 (0.01156 ± 0.00603 vs. 0.01099 ± 0.00523 pg/μg; p = 0.9445). Conversely, adult SLE mice that traveled in summer had higher MAP than those that traveled in winter (136.12 ± 2.63 vs. 128.81 ± 1.55 mmHg; p = 0.0339; n = 5-7), as well as higher plasma IL-6 (723.28 ± 220.72 vs. 280.73 ± 67.99 pg/mL; p = 0.0339) and renal IL-6 (0.078956 ± 0.017192 vs. 0.023413 ± 0.003801 pg/μg; p < 0.0001). Together, our data indicate that hypertension and renal inflammation in mice subjected to travel stress as adults is seasonally dependent. Since there were no seasonal differences in hypertension in SLE mice that traveled pre-puberty, there may be a factor related to age, seasonal environmental factors, and/or timing of the stressors that is causing the detrimental effect.

Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus.

We describe a mechanism responsible for systemic lupus erythematosus (SLE). In humans with SLE and in 2 SLE murine models, there was marked enrichment of isolevuglandin-adducted proteins (isoLG adducts) in monocytes and dendritic cells. We found that antibodies formed against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduced transcription of all C1q subunits. Treatment of SLE-prone mice with the specific isoLG scavenger 2-hydroxybenzylamine (2-HOBA) ameliorated parameters of autoimmunity, including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowered blood pressure, attenuated renal injury, and reduced inflammatory gene expression uniquely in C1q-expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE.

Vascular Inflammation in Mouse Models of Systemic Lupus Erythematosus.

Vascular inflammation mediated by overly activated immune cells is a significant cause of morbidity and mortality in systemic lupus erythematosus (SLE). Several mouse models to study the pathogenesis of SLE are currently in use, many of which have different mechanisms of pathogenesis. The diversity of these models allows interrogation of different aspects of the disease pathogenesis. To better determine the mechanisms by which vascular inflammation occurs in SLE, and to assist future researchers in choosing the most appropriate mouse models to study cardiovascular complications in SLE, we suggest that direct comparisons of vascular inflammation should be conducted among different murine SLE models. We also propose the use of in vitro vascular assays to further investigate vascular inflammation processes prevalent among different murine SLE models.

T Cells, Interleukin-2 and Systemic Lupus Erythematosus-From Pathophysiology to Therapy.

The phenotypic and functional complexities of T cells engender complicated and often confusing concepts as to how T cells ignite, accelerate and brake the inflammatory processes involved in systemic lupus erythematosus (SLE), let alone the plasticity of T cells that takes place under different immunological contexts. Nevertheless, being one of the prime survival factors of T cells, interleukin (IL)-2 plays a potentially critical role in many immunological scenarios during the pathophysiological process of SLE. Here, the pathophysiology of lupus T cells and current, as well as ongoing, therapeutic approaches of SLE that involve low-dose IL-2 administration will be highlighted. The mechanisms of IL-2 deficiency in SLE pathophysiology, the effects of low-dose IL-2 on T cells and restoration of lupus manifestations in murine SLE models, as well as the efficacy and safety of clinical trials that evaluated low-dose IL-2-containing regimens in patients with SLE will be discussed.

Phenotypic and functional alterations of peritoneal macrophages in lupus-prone mice

BackgroundSeveral studies have demonstrated the contribution of innate immune cells, including macrophages, in promoting systemic lupus erythematosus (SLE). Macrophages, one of the most abundant cell populations in the peritoneal cavity, are considered multifunctional cells with phenotypic plasticity. However, the functional properties of peritoneal macrophages in steady-state and during the progression of SLE remain poorly defined.Methods and resultsUsing the [NZB × NZW]F1 (BWF1) murine model of SLE, we analyzed the phenotype and function of peritoneal macrophages during the disease’s onset. We found a higher frequency of peritoneal macrophages and B1a cells in BWF1-diseased mice than age-matched controls. Additionally, macrophages from diseased animals expressed lower levels of CD206, MHC-II, and Sirpα. RNAseq analysis identified 286 differentially expressed genes in peritoneal macrophages from diseased-BWF1 mice compared to control mice. Functional experiments demonstrate that peritoneal macrophages from diseased-BWF1 mice secrete higher levels of pro-inflammatory cytokines when activated with TLR7 and TLR9 agonists, and they were less efficient in suppressing the activation and proliferation of peritoneal LPS-activated B cells. These data demonstrate that peritoneal macrophages from BWF1-diseased mice present phenotypic and functional alterations shifting to a more pro-inflammatory state.ConclusionsThe increase of macrophages with an altered phenotype and function together with the accumulation of B1a cells in the peritoneal cavity of diseased-BWF1 mice may promote the progression of the disease. Advancing awareness of the role and phenotype of peritoneal macrophages in SLE may contribute to a better understanding of these types of diseases and the development of novel therapies.

The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses.

T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6+ and ALCAM+ cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.

The effect of rose hip on experimental anti-GBM glomerulonephritis in systemic lupus erythematosus murine models

Background: Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease with ominous end organ manifestations significantly affecting the kidneys and joints. One of the most frequent manifestations is glomerulonephritis (GN), a renal disease distinguished by inflammation of the glomeruli that often leads to end stage kidney failure. Treatments often have severe side effects. Rose hip (RH) is derived from Rosa canina L. and has been used as a medicinal plant for centuries; it contains numerous beneficial constituents, and has the capacity to counter lipid peroxidation, oxidative stress, and inflammation. Methods: Nephritis was induced in 129/svJ strain mice using anti-glomerular basement membrane antibodies (anti-GBM). The experimental group was fed whole RH preparation (100mg/kg body weight per day) by oral gavage from D5 to D10; the control group was fed the diluent used to dissolve RH (10 mice per group). Mice were sacrificed on D11 and phenotyped for disease. Blood urea nitrogen (BUN) and proteinuria were measured; flow cytometry of kidneys was performed on both groups. Results: RH treatment decreased proteinuria, blood urea nitrogen, CD4+, CD8+, CD11b+Gr-1+ (neutrophil), and CD11b+CD11c+ (myeloid cells) compared with nephritis control. The presence of vitamin C was confirmed. RH largely maintained its total antioxidant capacity and some vitamin C content for 24 hours, as well as at least 7 days after preparation. Conclusion: Our preliminary results confirmed that RH has antioxidative properties, significant anti-inflammatory effects, and may be useful in managing glomerulonephritisKeywords: Rose hip, glomerulonephritis, systemic lupus erythematosus, lupus, proteinuria, blood urea nitrogen, CD4+, CD8+, CD11b+Gr-1+(neutrophil), and CD11b+CD11c+ (myeloid cells)

Lactobacillus acidophilus Supplementation Exerts a Synergistic Effect on Tacrolimus Efficacy by Modulating Th17/Treg Balance in Lupus-Prone Mice via the SIGNR3 Pathway.

ObjectiveTacrolimus (Tac) is an immunosuppressant used in the treatment of systemic lupus erythematosus (SLE); however, it induces T cell subset imbalances by reducing regulatory T (Treg) cells. Lactobacillus acidophilus (LA) is reported to have therapeutic efficacy in immune-mediated diseases via T cell regulation.MethodsThis study investigated whether a combination therapy of LA and Tac improves the therapeutic efficacy of Tac by modulating T cell subset populations in an animal model of SLE. Eight-week-old MRL/lpr mice were orally administered with 5 mg/kg of Tac and/or 50 mg/kg of LA daily for 8 weeks. Cecal microbiota compositions, serum autoantibodies levels, the degree of proteinuria, histological changes in the kidney, and populations of various T cell subsets in the spleen were analyzed.ResultsMice presented with significant gut dysbiosis, which were subsequently recovered by the combination treatment of Tac and LA. Double negative T cells in the peripheral blood and spleens of MRL/lpr mice were significantly decreased by the combination therapy. The combination treatment reduced serum levels of anti-dsDNA antibodies and Immunoglobulin G2a, and renal pathology scores were also markedly alleviated. The combination therapy induced Treg cells and decreased T helper 17 (Th17) cells both in vitro and in vivo. In vitro treatment with LA induced the production of indoleamine-2,3-dioxygenase, programmed death-ligand 1, and interleukin-10 via the specific intracellular adhesion molecule-3 grabbing non-integrin homolog-related 3 receptor signals.ConclusionThe present findings indicate that LA augments the therapeutic effect of Tac and modulates Th17/Treg balance in a murine model of SLE.

T Cell Homeostatic Proliferation Promotes a Redox State That Drives Metabolic and Epigenetic Upregulation of Inflammatory Pathways in Lupus.

Significance: Numerous abnormalities in T cells have been described in patients with systemic lupus erythematosus (SLE), including lymphopenia, DNA demethylation, expression of endogenous retroviruses (ERVs), increased cell death, enlarged mitochondria, production of reactive oxygen species (ROS), and the appearance of unusual CD4-CD8- T cells. Our studies propose a model in which accelerated homeostatic proliferation of T cells promotes an epigenetic and metabolic program, leading to this cluster of abnormalities. Recent Advances: Growing knowledge of the innate immune disorders in SLE has included increased mitochondrial size and ROS production that induces oligomerization of the mitochondrial antiviral signaling (MAVS) protein and type I interferon production, as well as DNA demethylation, upregulation of inflammatory genes, and expression of certain ERVs in SLE peripheral blood mononuclear cells. All these events are part of the cellular program that occurs during homeostatic proliferation of T cells. Evidence from a murine model of SLE as well as in human SLE reveals that increased T cell homeostatic proliferation may be a driving factor in these processes. Critical Issues: Despite extensive knowledge of the myriad autoantibodies in SLE and other immune abnormalities, a cogent model has been lacking to link the numerous and seemingly disparate immune aberrations. This may partly explain the general lack of new drugs specifically for SLE in over 50 years. A more coherent model of SLE would not only unify the variety of immune abnormalities is SLE but would also suggest new therapies. Future Directions: The model of augmented homeostatic proliferation leading to increased mitochondrial mass, ROS, DNA demethylation, and upregulation of inflammatory genes suggests strategic new targets for SLE, including antioxidants and certain inhibitors of metabolism. Antioxid. Redox Signal. 36, 410-422.

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus.

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

Characterization of the mechanism of action of lanraplenib, a novel spleen tyrosine kinase inhibitor, in models of lupus nephritis

BackgroundB cells are critical mediators of systemic lupus erythematosus (SLE) and lupus nephritis (LN), and antinuclear antibodies can be found in the serum of approximately 98% of patients with SLE. Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that mediates signaling from immunoreceptors, including the B cell receptor. Active, phosphorylated SYK has been observed in tissues from patients with SLE or cutaneous lupus erythematosus, and its inhibition is hypothesized to ameliorate disease pathogenesis. We sought to evaluate the efficacy and characterize the mechanism of action of lanraplenib, a selective oral SYK inhibitor, in the New Zealand black/white (NZB/W) murine model of SLE and LN.MethodsLanraplenib was evaluated for inhibition of primary human B cell functions in vitro. Furthermore, the effect of SYK inhibition on ameliorating LN-like disease in vivo was determined by treating NZB/W mice with lanraplenib, cyclophosphamide, or a vehicle control. Glomerulopathy and immunoglobulin G (IgG) deposition were quantified in kidneys. The concentration of proinflammatory cytokines was measured in serum. Splenocytes were analyzed by flow cytometry for B cell maturation and T cell memory maturation, and the presence of T follicular helper and dendritic cells.ResultsIn human B cells in vitro, lanraplenib inhibited B cell activating factor-mediated survival as well as activation, maturation, and immunoglobulin M production. Treatment of NZB/W mice with lanraplenib improved overall survival, prevented the development of proteinuria, and reduced blood urea nitrogen concentrations. Kidney morphology was significantly preserved by treatment with lanraplenib as measured by glomerular diameter, protein cast severity, interstitial inflammation, vasculitis, and frequency of glomerular crescents; treatment with lanraplenib reduced glomerular IgG deposition. Mice treated with lanraplenib had reduced concentrations of serum proinflammatory cytokines. Lanraplenib blocked disease-driven B cell maturation and T cell memory maturation in the spleen.ConclusionsLanraplenib blocked the progression of LN-like disease in NZB/W mice. Human in vitro and murine in vivo data suggest that lanraplenib may be efficacious in preventing disease progression in patients with LN at least in part by inhibiting B cell maturation. These data provide additional rationale for the use of lanraplenib in the treatment of SLE and LN.

CGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE.

Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGASKOFaslpr mice on a pure MRL/Faslpr background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity.

The enrichment of neutrophil extracellular traps impair the placentas of systemic lupus erythematosus through accumulating decidual NK cells

Despite the advances made in the management of pregnancies in women with systemic lupus erythematosus (SLE), the rate of adverse pregnancy outcomes is still higher than that in the general population. In the last few years, neutrophil extracellular traps (NETs) were proven to be detrimental in both autoimmune diseases and placental injury. We investigated whether NETs could be detected in the placentas of pregnant individuals with SLE and explored the relationship between NETs and decidual natural killer cells (dNKs), which comprise the majority of immune cells at the maternal–fetal interface, using clinical samples and animal models. In this study, we found that the infiltration of NETs and dNKs, especially CD56+CD16+ NK cells, was significantly increased in pregnant individuals with SLE with placental insufficiency. In the murine models of SLE, the number of dNKs was significantly decreased due to the decreased formation of NETs affected by Ly6G. Moreover, the histopathological placental injury was reduced, with a remarkable increase in fetal birth weight. This study shows that NETs may contribute to immunological disorder in the placenta and the pathological changes in pregnancies with SLE, which provides a research basis for further explorations of the mechanism of SLE in placental impairment.

Immunotherapeutic effects of allogeneic mesenchymal stem cells on systemic lupus erythematosus.

Mesenchymal stem cells have been applied to treat graft versus host disease as they have immunosuppressive ability and can overcome the major histocompatibility complex-histocompatibility barrier. The potential of allogeneic mesenchymal stem cells in treating systemic lupus erythematosus (SLE) was investigated in this study. MRL/lpr mice which can develop acquired SLE-like phenotypes were selected as an animal model. Mesenchymal stem cells obtained from green fluorescent protein-transgenic ICR mice were infused into MRL/lpr mice at either the early or late stage of disease. The dosage was 1 × 106/mice per infusion. Mice were stratified into six groups including negative controls and those receiving one, two, three, four or five doses at 2-weekly intervals. The phenotypes were monitored regularly. After treatment, the spleen CD3+CD4-CD8- T and CD19+ B cells of two-dose mesenchymal stem cell-treated mice were significantly lower than those of the phosphate-buffered saline control. In terms of reducing the severity of SLE such as hair loss, skin ulcers, proteinuria and anti-dsDNA level, mesenchymal stem cells given at the early stage responded better and mice receiving two doses of mesenchymal stem cells performed better than those receiving either a lower dose (one dose) or higher doses (three, four or five doses). In conclusion, early treatment and an optimal dose of mesenchymal stem cells can effectively suppress the murine SLE model.

Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus.

Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell depletion a potential strategy for SLE treatment. The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice. Furthermore, anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention. According to our observations, compared with antibody treatment, the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice. The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression. We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif, CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment. Taken together, these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE, indicating its potential for clinical use in patients.

Thymic B Cells Promote Germinal Center-Like Structures and the Expansion of Follicular Helper T Cells in Lupus-Prone Mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the activation of autoreactive T and B cells, autoantibody production, and immune complex deposition in various organs. Previous evidence showed abnormal accumulation of B cells in the thymus of lupus-prone mice, but the role of this population in the progression of the disease remains mostly undefined. Here we analyzed the spatial distribution, function, and properties of this thymic B cell population in the BWF1 murine model of SLE. We found that in diseased animals, thymic B cells proliferate, and cluster in structures that resemble ectopic germinal centers. Moreover, we detected antibody-secreting cells in the thymus of diseased-BWF1 mice that produce anti-dsDNA IgG autoantibodies. We also found that thymic B cells from diseased-BWF1 mice induced the differentiation of thymocytes to follicular helper T cells (TFH). These data suggest that the accumulation of B cells in the thymus of BWF1 mice results in the formation of germinal center-like structures and the expansion of a TFH population, which may, in turn, activate and differentiate B cells into autoreactive plasma cells. Therefore, the thymus emerges as an important niche that supports the maintenance of the pathogenic humoral response in the development of murine SLE.

High salt diet accelerates the progression of murine lupus through dendritic cells via the p38 MAPK and STAT1 signaling pathways

The increased incidence of systemic lupus erythematosus (SLE) in recent decades might be related to changes in modern dietary habits. Since sodium chloride (NaCl) promotes pathogenic T cell responses, we hypothesize that excessive salt intake contributes to the increased incidence of autoimmune diseases, including SLE. Given the importance of dendritic cells (DCs) in the pathogenesis of SLE, we explored the influence of an excessive sodium chloride diet on DCs in a murine SLE model. We used an induced lupus model in which bone marrow-derived dendritic cells (BMDCs) were incubated with activated lymphocyte-derived DNA (ALD-DNA) and transferred into C57BL/6 recipient mice. We observed that a high-salt diet (HSD) markedly exacerbated lupus progression, which was accompanied by increased DC activation. NaCl treatment also stimulated the maturation, activation and antigen-presenting ability of DCs in vitro. Pretreatment of BMDCs with NaCl also exacerbated BMDC-ALD-DNA-induced lupus. These mice had increased production of autoantibodies and proinflammatory cytokines, more pronounced splenomegaly and lymphadenopathy, and enhanced pathological renal lesions. The p38 MAPK–STAT1 pathway played an important role in NaCl-induced DC immune activities. Taken together, our results demonstrate that HSD intake promotes immune activation of DCs through the p38 MAPK–STAT1 signaling pathway and exacerbates the features of SLE. Thus, changes in diet may provide a novel strategy for the prevention or amelioration of lupus or other autoimmune diseases.