Human Systemic Lupus Erythematosus Research Articles

The IL-12-STAT4 axis in the pathogenesis of human systemic lupus erythematosus.

Generation of autoantibodies is a hallmark of systemic lupus erythematosus (SLE). As demonstrated in a number of lupus mouse models, recent evidence suggests that both GC and extrafollicular pathways contribute to the generation of autoantibodies also in human SLE, and that CD11c+ IgD- CD27- (double negative:DN) B cells play a central role in the latter pathway. In this mini-review, the author will first briefly summarize the features of CD11c+ DN B cells in human SLE, and discuss how the IL-12-STAT4 axis might contribute to the generation of autoantibodies in SLE. In addition, various types of CD4+ helper T cell subsets promoting the generation of autoantibodies in SLE will be described, and finally it will be discussed how these recent discoveries contribute to understanding of SLE pathogenesis and treatment of SLE patients.

MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus.

T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt–AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt–AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE.

Lupus Autoimmunity and Metabolic Parameters Are Exacerbated Upon High Fat Diet-Induced Obesity Due to TLR7 Signaling.

Systemic lupus erythematosus (SLE) patients have increased prevalence of metabolic syndrome but the underlying mechanisms are unknown. Toll-like receptor 7 (TLR7) that detects single stranded-RNA plays a key role in antimicrobial host defense and also contributes to the initiation and progression of SLE both in mice and humans. Here, we report the implication of TLR7 signaling in high fat diet (HFD)-induced metabolic syndrome and exacerbation of lupus autoimmunity in TLR8-deficient (TLR8ko) mice, which develop spontaneous lupus-like disease due to increased TLR7 signaling by dendritic cells (DCs). The aggravated SLE pathogenesis in HFD-fed TLR8ko mice was characterized by increased overall immune activation, anti-DNA autoantibody production, and IgG/IgM glomerular deposition that were coupled with increased kidney histopathology. Moreover, upon HFD TLR8ko mice developed metabolic abnormalities, including liver inflammation. In contrast, upon HFD TLR7/8ko mice did not develop SLE and both TLR7ko and TLR7/8ko mice were fully protected from metabolic abnormalities, including body weight gain, insulin resistance, and liver inflammation. Interestingly, HFD led to an increase of TLR7 expression in WT mice, that was coupled with increased TNF production by DCs, and this phenotype was more profound in TLR8ko mice. Our study uncovers the implication of TLR7 signaling in the interconnection of SLE and metabolic abnormalities, indicating that TLR7 might be a novel approach as a tailored therapy in SLE and metabolic diseases.

AhR-ROR-γt complex is a therapeutic target for MAP4K3/GLKhighIL-17Ahigh subpopulation of systemic lupus erythematosus.

The cytokine IL-17A plays critical roles in the pathogenesis of autoimmune diseases. The frequencies of MAP kinase kinase kinase kinase 3 [also named germinal center kinase–like kinase (GLK)]-overexpressing T cells are correlated with disease severity of systemic lupus erythematosus (SLE). T-cell–specific GLK-transgenic mice develop spontaneous autoimmune responses through IL-17A. GLK signaling selectively stimulates IL-17A production in murine T cells through inducing aryl hydrocarbon receptor (AhR)–retinoic acid receptor–related orphan nuclear receptor-γt (ROR-γt) complex formation. Here, we investigated whether GLK-induced AhR–ROR-γt complex in T cells is a therapeutic target for human SLE. The population of GLK+IL-17A+ T cells was enhanced in the peripheral blood from patients with SLE compared with that of healthy controls using flow cytometry. The receiver operating characteristic curve analysis showed that increased GLK+IL-17A+ T-cell population in peripheral blood reflected an active stage of SLE. In addition, peripheral blood T cells from patients with SLE displayed induction of ROR-γt phosphorylation and the AhR–ROR-γt (and AhR–phosphorylated ROR-γt) complex. Moreover, we identified a small-molecule inhibitor, verteporfin, that inhibited GLK kinase activity and AhR–ROR-γt interaction. The small-molecule inhibitor verteporfin suppressed the disease severity in autoimmune mouse models and IL-17A production in T cells from patients with SLE. Collectively, the GLK-induced AhR–ROR-γt (and AhR–phosphorylated ROR-γt) complex is a therapeutic target for the GLKhighIL-17Ahigh subpopulation of human patients with SLE.—Chuang, H.-C., Chen, Y.-M., Chen, M.-H., Hung, W.-T., Yang, H.-Y., Tseng, Y.-H., Tan, T.-H. AhR–ROR-γt complex is a therapeutic target for MAP4K3/GLKhighIL-17Ahigh subpopulation of systemic lupus erythematosus.

CD4+CD69+ T cells and CD4+CD25+FoxP3+ Treg cells imbalance in peripheral blood, spleen and peritoneal lavage from pristane-induced systemic lupus erythematosus (SLE) mice

BackgroundAdaptive immune cells, including CD4+CD69+ and CD4+CD25+FoxP3+ regulatory T (Treg) cells, are important for maintaining immunological tolerance. In human systemic lupus erythematosus (SLE), CD4+CD25+FoxP3+ Treg cells are reduced, whereas CD69 expression is increased, resulting in a homeostatic immune imbalance that may intensify autoreactive T cell activity. To analyze the mechanisms implicated in autotolerance failure, we evaluated CD4+CD69+ and CD4+CD25+FoxP3+ T cells and interleukin profiles in a pristane-induced SLE experimental model.MethodsFor lupus induction, 26 female Balb/c mice received a single intraperitoneal 0.5 ml dose of pristane, and 16 mice received the same dose of saline. Blood and spleen samples were collected from euthanized mice 90 and 120 days after pristane or saline inoculation. Mononuclear cells from peripheral blood (PBMC), peritoneal lavage (PL) and splenocytes were obtained by erythrocyte lysis and cryopreserved for further evaluation by flow cytometry using the GuavaEasyCyte TM HT. After thawing, cells were washed and stained with monoclonal antibodies against CD3, CD4, CD8, CD25, CD28, CD69, FoxP3, CD14 and Ly6C (BD Pharmingen TM). Interleukins were quantified using Multiplex® MAP. The Mann-Whitney test and the Pearson coefficient were used for statistical analysis, and p < 0.05 considered significant.ResultsCompared with the controls, SLE-induced animals presented increased numbers of CD4+CD69+ T cells in the blood on T90 and T120 (p = 0.022 and p = 0.008) and in the spleen on T120 (p = 0.049), but there were decreased numbers in the PL (p = 0.049) on T120. The percentage of Treg was lower in blood (p < 0.005 and p < 0.012) on T90 and T120, in spleen (p = 0.043) on T120 and in PL (p = 0.001) on T90. Increased numbers of CD4 + CD69+ T cells in the PL were positively associated with high IL-2 (p = 0.486) and IFN-γ (p = 0.017) levels, whereas reduced Treg cells in the blood were negatively correlated with TNFα levels (p = 0.043) and positively correlated with TGFβ1 (p = 0.038).ConclusionIncreased numbers of CD4+CD69+ T cells and reduced numbers of CD4+CD25+FoxP3+ Treg cells with an altered interleukin profile suggests loss of autotolerance in pristane-induced lupus mice, which is similar to human lupus. Therefore, this model is useful in evaluating mechanisms of cellular activation, peripheral tolerance and homeostatic immune imbalance involved in human SLE.

Metformin Inhibits the Type 1 IFN Response in Human CD4+ T Cells.

In systemic lupus erythematosus, defective clearance of apoptotic debris and activation of innate cells result in a chronically activated type 1 IFN response, which can be measured in PBMCs of most patients. Metformin, a widely used prescription drug for Type 2 diabetes, has a therapeutic effect in several mouse models of lupus through mechanisms involving inhibition of oxidative phosphorylation and a decrease in CD4+ T cell activation. In this study, we report that in CD4+ T cells from human healthy controls and human systemic lupus erythematosus patients, metformin inhibits the transcription of IFN-stimulated genes (ISGs) after IFN-α treatment. Accordingly, metformin inhibited the phosphorylation of pSTAT1 (Y701) and its binding to IFN-stimulated response elements that control ISG expression. These effects were independent of AMPK activation or mTORC1 inhibition but were replicated using inhibitors of the electron transport chain respiratory complexes I, III, and IV. This indicates that mitochondrial respiration is required for ISG expression in CD4+ T cells and provides a novel mechanism by which metformin may exert a therapeutic effect in autoimmune diseases.

Epigenetic programming underpins B cell dysfunction in human SLE.

Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naïve cells. Although these cells express distinct markers, their epigenetic architecture and how it contributes to SLE remains poorly understood. To address this, we determined the DNA methylomes, chromatin accessibility and transcriptomes from five human B cell subsets, including a newly defined effector B cell subset from SLE and healthy subjects. Our data define a differentiation hierarchy between the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Importantly, an SLE molecular signature was already established in resting naïve cells and was dominated by accessible chromatin enriched in AP-1 and EGR transcription factor motifs. Together, these factors acted in synergy with T-BET to shape the epigenome of expanded SLE effector B cell subsets. Thus, our data define the molecular foundation of pathogenic B cell dysfunction in SLE.

RP220, a Renalase Peptide, Attenuates Lupus Nephritis by Anti-Inflammatory in MRL/lpr Mice

Background: Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus (SLE), which inflammation plays an important role in the progression of the disease. RP220, an active peptide of renalase, was proved previously to be effective in protecting kidney against ischemic and toxic injury by anti-inflammatory effect. We aimed to investigate the therapeutic effect of RP220 in lupus nephritis and its possible mechanism. Methods: MRL/lpr mice were treated by RP220, cyclophosphamide (CP) and saline respectively. Urine albumin creatinine ratio, serum creatinine and blood urea nitrogen, circulating autoantibody levels and renal histopathological assessment was done to evaluate the renal damage and immunology status for all the mice. Renal pro-inflammatory cytokines including IL-1β, IL-6, CCL-2, TNF-α and NLRP3 inflammasome were assessed by real-time PCR and western blotting. Mouse macrophage cell line (RAW264.7) were treated by renalase-siRNA and RP220 to verify its antiinflammatory effects in vitro. Results: Urinary albumin creatinine ratio, blood urea nitrogen (BUN) and serum anti-dsDNA antibody were significantly lower in RP220 and CP group compared with saline group at the end of the experiment. Renal immune complex deposition and the injury score of glomerular, tubular and perivascular were significantly lower in RP220 and CP treated group as well as inflammatory cytokines such as TNF-α, IL-6 and IL-1β and NLRP3. The increase of renal expression of NLRP3, ASC and caspase-1 was reversed by RP220 but not by CP. Moreover, RP220 treated mice has no significant adverse effect such as body weight loss, bone marrow arrest and immune over inhibition in CP group. In vitro study of macrophage cell found that the expression of TNF-α, IL-6, IL-1β and CCL-2 induced by LPS were significantly aggravated by RP220 targeted siRNA and the effects were reversed by RP220 administration. Conclusion: Administration of RP220 ameliorated proteinuria, renal injury and inflammatory status in LN murine model without adverse effects. The renal protective effect of RP220 might be associated with NLRP3-IL1 β pathway. Development of pharmacologic peptide would be helpful in providing novel therapeutic strategies for human SLE. Funding Statement: This work was supported by the National Science and Technology Major Project (No. 81770666), Shanghai Municipal Health Commission Project (ZY(2018-2020)-FWTX-1001, 20154Y0003) and research funding to LING WANG from Shanghai Shenkang Hospital Development Center(16CR3022A). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All experiments were approved by the Institutional Animal Care Committee of Shanghai Jiaotong University.

High TLR7 Expression Drives the Expansion of CD19+CD24hiCD38hi Transitional B Cells and Autoantibody Production in SLE Patients.

Signaling through Toll-like receptor 7 (TLR7) drives the production of type I IFN and promotes the activation of autoreactive B cells and is implicated in the pathogenesis of systemic lupus erythematosus (SLE). While TLR7 has been extensively studied in murine lupus, much less is known about its role in the pathogenesis of human SLE. Genetic studies support a link between the TLR7 rs3853839 C/G polymorphism, which affects TLR7 mRNA turnover, and SLE susceptibility; however, the effects of this polymorphism on B cells have not been studied. Here we determined how changes in TLR7 expression affect peripheral B cells and auto-Ab production in SLE patients. High TLR7 expression in SLE patients driven by TLR7 rs3853839 C/G polymorphism was associated with more active disease and upregulation of IFN-responsive genes. TLR7hi SLE patients showed an increase in peripheral B cells. Most notably, the percentage and numbers of CD19+CD24++CD38++ newly-formed transitional (TR) B cells were increased in TLR7hi SLE patients as compared to HCs and TLR7norm/lo SLE patients. Using auto-Ab arrays, we found an increase and enrichment of auto-Ab specificities in the TLR7hi SLE group, including the production of anti-RNA/RNP-Abs. Upon in vitro TLR7 ligand stimulation, TR B cells isolated from TLR7hi but not TLR7norm/lo SLE patients produced anti-nuclear auto-Abs (ANA). Exposure of TR B cells isolated from cord blood to IFNα induced the expression of TLR7 and enabled their activation in response to TLR7 ligation in vitro. Our study shows that overexpression of TLR7 in SLE patients drives the expansion of TR B cells. High TLR7 signaling in TR B cells promotes auto-Ab production, supporting a possible pathogenic role of TR B cells in human SLE.

Dendritic cell-associated B7-H3 suppresses the production of autoantibodies and renal inflammation in a mouse model of systemic lupus erythematosus

B7-H3 immune modulatory molecule has been implicated in the generation and pathogenesis of autoimmune diseases, the mechanism of action is less known. We explored the role of B7-H3 in the induction of autoantibodies and organ-directed inflammation in a murine systemic lupus erythematosus (SLE) model in which the immunization with DNA extracted from activated T cells induced the production of anti-DNA autoantibodies and subsequent glomerulonephritis, two hallmarks of human SLE. Mice deficient of B7-H3 or treated with a B7-H3 specific antibody produced significantly higher levels of anti-DNA autoantibodies and more severe glomerulonephritis than wild-type mice, indicating an inhibitory function of B7-H3 in this model. Interestingly, immunization of mice with DNA-pulsed dendritic cells induced severe SLE symptoms while B7-H3 on dendritic cells is required in this process. Importantly, treatment of mice with recombinant B7-H3Ig fusion protein effectively ameliorated progression of murine SLE, accompanied with decreased level of anti-DNA autoantibodies and alleviated glomerulonephritis, decreased autoantibody deposition and complement deposition in kidney. Our findings implicate a potential role of B7-H3 on dendritic cells in the induction of SLE and as a potential target for the treatment of autoimmune diseases.

Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA.

The mitochondrion supplies energy to the cell and regulates apoptosis. Unlike other mammalian organelles, mitochondria are formed by binary fission and cannot be directly produced by the cell. They contain numerous copies of a compact circular genome that encodes RNA molecules and proteins involved in mitochondrial oxidative phosphorylation. Whereas, mitochondrial DNA (mtDNA) activates the innate immune system if present in the cytosol or the extracellular milieu, it is also the target of circulating autoantibodies in systemic lupus erythematosus (SLE). However, it is not known whether mitochondrial RNA is also recognized by autoantibodies in SLE. In the present study, we evaluated the presence of autoantibodies targeting mitochondrial RNA (AmtRNA) in SLE. We quantified AmtRNA in an inducible model of murine SLE. The AmtRNA were also determined in SLE patients and healthy volunteers. AmtRNA titers were measured in both our induced model of murine SLE and in human SLE, and biostatistical analyses were performed to determine whether the presence and/or levels of AmtRNA were associated with clinical features expressed by SLE patients. Both IgG and IgM classes of AmtRNA were increased in SLE patients (n = 86) compared to healthy controls (n = 30) (p < 0.0001 and p = 0.0493, respectively). AmtRNA IgG levels correlated with anti-mtDNA-IgG titers (rs = 0.54, p < 0.0001) as well as with both IgG and IgM against β-2-glycoprotein I (anti-β2GPI; rs = 0.22, p = 0.05), and AmtRNA-IgG antibodies were present at higher levels when patients were positive for autoantibodies to double-stranded-genomic DNA (p < 0.0001). AmtRNA-IgG were able to specifically discriminate SLE patients from healthy controls, and were negatively associated with plaque formation (p = 0.04) and lupus nephritis (p = 0.03). Conversely, AmtRNA-IgM titers correlated with those of anti-β2GPI-IgM (rs = 0.48, p < 0.0001). AmtRNA-IgM were higher when patients were positive for anticardiolipin antibodies (aCL-IgG: p = 0.01; aCL-IgM: p = 0.002), but AmtRNA-IgM were not associated with any of the clinical manifestations assessed. These findings identify mtRNA as a novel mitochondrial antigen target in SLE, and support the concept that mitochondria may provide an important source of circulating autoantigens in SLE.

Validation of lanthionine synthetase C-like 2 (LANCL2) as a therapeutic target for systemic lupus erythematosus

Abstract Lanthionine synthetase C-like 2 (LANCL2) is a membrane receptor with downstream effects on immunity and metabolism including the differentiation of regulatory CD4+ T cells. Its natural ligand, abscisic acid (ABA), has been shown to be decreased in autoimmune and inflammatory disease. Given the implication of the LANCL2 pathway in autoimmune disease and the progression of LANCL2-specific ligands, such as BT-11, into clinical stage development, we assessed the role of LANCL2 in systemic lupus erythematosus (SLE). In a TLR7/8 resiquimod-induced model of SLE, the loss of LANCL2 significantly decreases survival (P = 0.0008) relative to wild-type, resulting in less than 10% survival and a greater than 60% reduction relative to wild-type. Similarly, LANCL2−/− displayed greater serum anti-dsDNA antibodies and higher proteinuria. Within spleens, the loss of LANCL2 resulted in greater IL-6 and TNF, higher proportions of T follicular helper cells and lower ratios of regulatory CD4+ T cells relative to IFNγ producing cells. The greater inflammation was also mirrored in transcriptional changes at the splenic level indicating a greater susceptibility to severe disease. These results merit further exploration into the implication of LANCL2 signaling in human SLE and characterization of the therapeutic efficacy of LANCL2-specific agonists for future SLE development. Thus, LANCL2 is a novel promising therapeutic target for SLE.

MAP4K3/GLK-induced AhR-RORγt complex is a novel therapeutic target for GLKhighIL-17Ahigh subpopulation of SLE patients

Abstract The cytokine IL-17A plays critical roles in the pathogenesis of autoimmune diseases. The frequencies of MAP4K3 (also named GLK)-overexpressing T cells are correlated with disease severity of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and adult-onset Still’s disease. T-cell specific GLK transgenic mice develop spontaneous autoimmune responses. GLK signaling selectively stimulates IL-17A production in murine T cells through inducing AhR-RORγt complex formation. Here, we investigated whether GLK-induced AhR-RORγt complex in T cell is a therapeutic target for human SLE or RA. The population of GLK+IL-17A+ T cells was enhanced in the peripheral blood from SLE patients compared to that of healthy controls using flow cytometry. The ROC curve analyses showed that increased GLK+IL-17A+ T cell population in peripheral blood reflected an active stage of SLE. In addition, peripheral blood T cells from SLE or RA patients displayed induction of RORγt phosphorylation and the AhR-RORγt complex. Moreover, we identified a small-molecule GLK inhibitor that inhibited GLK kinase activity and AhR-RORγt interaction. The GLK inhibitor suppressed the disease severity in autoimmune mouse models and IL-17A production in T cells from SLE or RA patients. Collectively, GLK-induced AhR-RORγt complex is a therapeutic target for the GLKhighIL-17Ahigh subpopulation of SLE or RA patients.

Patrolling monocytes promote the pathogenesis of early lupus-like glomerulonephritis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with genetic and environmental contributions. Hallmarks of the disease are the appearance of immune complexes (IC) containing autoreactive Abs and TLR-activating nucleic acids, whose deposition in kidney glomeruli is suspected to promote tissue injury and glomerulonephritis (GN). Here, using a mouse model based on the human SLE susceptibility locus TNFAIP3-interacting protein 1 (TNIP1, also known as ABIN1), we investigated the pathogenesis of GN. We found that GN was driven by TLRs but, remarkably, proceeded independently of ICs. Rather, disease in 3 different mouse models and patients with SLE was characterized by glomerular accumulation of patrolling monocytes (PMos), a cell type with an emerging key function in vascular inflammation. Consistent with such function in GN, monocyte-specific deletion of ABIN1 promoted kidney disease, whereas selective elimination of PMos provided protection. In contrast to GN, PMo elimination did not protect from reduced survival or disease symptoms such as IC generation and splenomegaly, suggesting that GN and other inflammatory processes are governed by distinct pathogenic mechanisms. These data identify TLR-activated PMos as the principal component of an intravascular process that contributes to glomerular inflammation and kidney injury.

Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations

Mitochondria are organelles that govern energy supply and control cell death. Mitochondria also express bacterial features, such as the presence of inner membrane cardiolipin and a circular genome rich in hypomethylated CpG motifs. While mitochondrial extrusion by damaged organs or activated cells is thought to trigger innate immunity, it is unclear whether extracellular mitochondria also stimulate an adaptive immune response. We describe the development of novel assays to detect autoantibodies specific to two distinct components of the mitochondrion: the mitochondrial outer membrane and mitochondrial DNA. Antibodies to these two mitochondrial constituents were increased in both human and murine systemic lupus erythematosus (SLE), compared to controls, and were present at higher levels than in patients with antiphospholipid syndrome or primary biliary cirrhosis. In both bi- and multi-variate regression models, antibodies to mitochondrial DNA, but not whole mitochondria, were associated with increased anti-dsDNA antibodies and lupus nephritis. This study describes new and optimized methods for the assessment of anti-mitochondrial antibodies, and demonstrates their presence in both human and murine SLE. These findings suggest that different mitochondrial components are immunogenic in SLE, and support the concept that extracellular mitochondria may provide an important source of circulating autoantigens in SLE.

CGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model

TREX1 encodes a major cellular DNA exonuclease. Mutations of this gene in human cause cellular accumulation of DNA that triggers autoimmune diseases including Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE). We created a lupus mouse model by engineering a D18 N mutation in the Trex1 gene which inactivates the enzyme and has been found in human patients with lupus-like disorders. The Trex1D18N/D18N mice exhibited systemic inflammation that consistently recapitulates many characteristics of human AGS and SLE. Importantly, ablation of cGas gene in the Trex1D18N/D18N mice rescued the lethality and all detectable pathological phenotypes, including multi-organ inflammation, interferon stimulated gene induction, autoantibody production and aberrant T-cell activation. These results indicate that cGAS is a key mediator in the autoimmune disease associated with defective TREX1 function, providing additional insights into disease pathogenesis and guidance to the development of therapeutics for human systemic autoimmune disorders.

Extrafollicular responses in humans and SLE.

Chronic autoimmune diseases, and in particular Systemic Lupus Erythematosus (SLE), are endowed with a long-standing autoreactive B-cell compartment that is presumed to reactivate periodically leading to the generation of new bursts of pathogenic antibody-secreting cells (ASC). Moreover, pathogenic autoantibodies are typically characterized by a high load of somatic hypermutation and in some cases are highly stable even in the context of prolonged B-cell depletion. Long-lived, highly mutated antibodies are typically generated through T-cell-dependent germinal center (GC) reactions. Accordingly, an important role for GC reactions in the generation of pathogenic autoreactivity has been postulated in SLE. Nevertheless, pathogenic autoantibodies and autoimmune disease can be generated through B-cell extrafollicular (EF) reactions in multiple mouse models and human SLE flares are characterized by the expansion of naive-derived activated effector B cells of extrafollicular phenotype. In this review, we will discuss the properties of the EF B-cell pathway, its relationship to other effector B-cell populations, its role in autoimmune diseases, and its contribution to human SLE. Furthermore, we discuss the relationship of EF B cells with Age-Associated B cells (ABCs), a TLR-7-driven B-cell population that mediates murine autoimmune and antiviral responses.

Neutrophils in lupus nephritis.

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease characterized by IgG-autoantibodies to nuclear antigens that can deposit in the kidney and trigger lupus nephritis. Neutrophils accumulate in the kidneys of patients with proliferative LUPUS NEPHRITIS and neutrophil products and a subset of granulocytes, called low-density granulocytes (LDG) may contribute to lupus nephritis pathogenesis. Here, we will discuss recent studies implicating neutrophils in the pathogenesis of human SLE nephritis and then examine studies that provide mechanistic insights into how these cells are recruited to the glomerulus following immune complex deposition and how their products may promote lupus nephritis. SLE patients display unique blood transcriptional signatures linked to Type I interferon and myeloblast differentiation, which could help stratify lupus nephritis progression. Multiphoton intravital microscopy of kidney glomerular capillaries revealed a role for neutrophil FcγRs in the rapid capture of neutrophils following immune complex deposition. The view that reduced degradation of neutrophil extracellular traps (NETS) contributes to lupus nephritis progression, is now challenged by experimental data in lupus-prone mice that genetically fail to produce NETS but still are afflicted. A greater understanding of the neutrophil dependent mechanisms that promote lupus nephritis may potentially inform on newer therapeutic options that target neutrophil accumulation and reactivity in the nephritic kidney.

Dnase1-deficient mice spontaneously develop a systemic lupus erythematosus-like disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease that has high morbidity and can result in multi-organ damage. SLE is characterized by dysregulated activation of T- and B-lymphocytes and the production of autoantibodies directed against nuclear components. The endonuclease deoxyribonuclease 1 (DNase1) is abundant in blood and a subset of SLE patients have mutations in DNASE1. Furthermore, a report showed that Dnase1-deficient mice develop an SLE-like disease, but these mice also carry a deletion of the gene adjacent to Dnase1, which encodes the chaperone TRAP1/HSP75. We generated a murine strain deficient in Dnase1 with an intact Trap1 gene to examine if a lack of DNase1 is responsible for the development of a spontaneous SLE-like disease. We show that the Dnase1-deficient mice do indeed develop an SLE-like phenotype with elevated autoantibody production by 9 months and kidney damage by 12 months. Notably, this model recapitulates the female bias seen in human SLE patients since female Dnase1-deficient mice produced the highest concentrations of autoantibodies and had more severe kidney damage than males. Since there is currently no cure for SLE the protective role of DNase1 as demonstrated in our study remains of great therapeutic interest.

OX40L/OX40 axis impairs follicular and natural Treg function in human SLE.

Tregs are impaired in human systemic lupus erythematosus (SLE) and contribute to effector T cell activation. However, the mechanisms responsible for the Treg deficiency in SLE remain unclear. We hypothesized that the OX40L/OX40 axis is implicated in Treg and regulatory follicular helper T (Tfr) cell dysfunction in human SLE. OX40L/OX40 axis engagement on Tregs and Tfr cells not only specifically impaired their ability to regulate effector T cell proliferation, but also their ability to suppress T follicular helper (Tfh) cell-dependent B cell activation and immunoglobulin secretion. Antigen-presenting cells from patients with active SLE mediated Treg dysfunction in an OX40L-dependent manner, and OX40L-expressing cells colocalized with Foxp3+ cells in active SLE skin lesions. Engagement of the OX40L/OX40 axis resulted in Foxp3 downregulation in Tregs, and expression in SLE Tregs correlated with the proportion of circulating OX40L-expressing myeloid DCs. These data support that OX40L/OX40 signals are implicated in Treg dysfunction in human SLE. Thus, blocking the OX40L/OX40 axis appears to be a promising therapeutic strategy.