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    Circadian rhythms and renal pathophysiology. Mohandas Rajesh,Douma Lauren G,Scindia Yogesh,Gumz Michelle L The Journal of clinical investigation The reality of life in modern times is that our internal circadian rhythms are often out of alignment with the light/dark cycle of the external environment. This is known as circadian disruption, and a wealth of epidemiological evidence shows that it is associated with an increased risk for cardiovascular disease. Cardiovascular disease remains the top cause of death in the United States, and kidney disease in particular is a tremendous public health burden that contributes to cardiovascular deaths. There is an urgent need for new treatments for kidney disease; circadian rhythm-based therapies may be of potential benefit. The goal of this Review is to summarize the existing data that demonstrate a connection between circadian rhythm disruption and renal impairment in humans. Specifically, we will focus on chronic kidney disease, lupus nephritis, hypertension, and aging. Importantly, the relationship between circadian dysfunction and pathophysiology is thought to be bidirectional. Here we discuss the gaps in our knowledge of the mechanisms underlying circadian dysfunction in diseases of the kidney. Finally, we provide a brief overview of potential circadian rhythm-based interventions that could provide benefit in renal disease. 10.1172/JCI148277
    Complement activation precedes classifiable SLE. Nature reviews. Rheumatology 10.1038/s41584-019-0310-y
    A new model to study BAFF-independent SLE. Nature reviews. Rheumatology 10.1038/s41584-019-0313-8
    Putting the brakes on T cell hyperactivity in SLE. Nature reviews. Rheumatology 10.1038/s41584-019-0317-4
    Targeting mitochondrial dysfunction in SLE. Nature reviews. Rheumatology 10.1038/s41584-019-0332-5
    Pathogenicity of neutrophils linked to maturation stage in SLE. Clarke Joanna Nature reviews. Rheumatology 10.1038/s41584-019-0358-8
    Risk variant in long noncoding RNA linked to SLE. Clarke Joanna Nature reviews. Rheumatology 10.1038/s41584-020-0382-8
    CD38: Modulating Histone Methyltransferase EZH2 Activity in SLE. Chakraborty Paramita,Mehrotra Shikhar Trends in immunology To keep autoreactive T cells under control in SLE patients, immunosuppressive regimens are used, which can increase susceptibility to bacterial and viral infections. Recently, Katsuyama et al., demonstrated that the CD38/NAD/Sirtuin1/EZH2 axis reduces cytolytic CD8 T cell function and might be targeted to overcome incidence of infections. 10.1016/j.it.2020.01.008
    Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory. Chan Kelvin,Nestor Jacquelyn,Huerta Tomás S,Certain Noele,Moody Gabrielle,Kowal Czeslawa,Huerta Patricio T,Volpe Bruce T,Diamond Betty,Wollmuth Lonnie P Nature communications Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of autoantibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B. Accordingly, GluN2A-specific antagonists provide greater protection from DNRAb-mediated neuronal cell death than GluN2B antagonists. Using transgenic mice to perturb expression of either GluN2A or GluN2B in vivo, we find that DNRAb-mediated disruption of spatial memory characterized by early neuronal cell death and subsequent microglia-dependent pathologies requires GluN2A-containing NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction. 10.1038/s41467-020-15224-w
    B cell-intrinsic TLR9 expression is protective in murine lupus. Tilstra Jeremy S,John Shinu,Gordon Rachael A,Leibler Claire,Kashgarian Michael,Bastacky Sheldon,Nickerson Kevin M,Shlomchik Mark J The Journal of clinical investigation Toll-like receptor 9 (TLR9) is a regulator of disease pathogenesis in systemic lupus erythematosus (SLE). Why TLR9 represses disease while TLR7 and MyD88 have the opposite effect remains undefined. To begin to address this question, we created 2 alleles to manipulate TLR9 expression, allowing for either selective deletion or overexpression. We used these to test cell type-specific effects of Tlr9 expression on the regulation of SLE pathogenesis. Notably, Tlr9 deficiency in B cells was sufficient to exacerbate nephritis while extinguishing anti-nucleosome antibodies, whereas Tlr9 deficiency in dendritic cells (DCs), plasmacytoid DCs, and neutrophils had no discernable effect on disease. Thus, B cell-specific Tlr9 deficiency unlinked disease from autoantibody production. Critically, B cell-specific Tlr9 overexpression resulted in ameliorated nephritis, opposite of the effect of deleting Tlr9. Our findings highlight the nonredundant role of B cell-expressed TLR9 in regulating lupus and suggest therapeutic potential in modulating and perhaps even enhancing TLR9 signals in B cells. 10.1172/JCI132328
    MicroRNA-125a-Loaded Polymeric Nanoparticles Alleviate Systemic Lupus Erythematosus by Restoring Effector/Regulatory T Cells Balance. Zhang Jiali,Chen Chuanrong,Fu Hao,Yu Jian,Sun Ying,Huang Hui,Tang Yuanjia,Shen Nan,Duan Yourong ACS nano Systemic lupus erythematosus (SLE), a common lethal autoimmune disease, is characterized by effector/regulatory T cells imbalance. Current therapies are either inefficient or have severe side effects. MicroRNA-125a (miR-125a) can stabilize Treg-mediated self-tolerance by targeting effector programs, but it is significantly downregulated in peripheral T cells of patients with SLE. Therefore, overexpression of miR-125a may have therapeutic potential to treat SLE. Considering the stability and targeted delivery of miRNA remains a major challenge , we constructed a monomethoxy (polyethylene glycol)-poly(d,l-lactide--glycolide)-poly(l-lysine) (mPEG-PLGA-PLL) nanodelivery system to deliver miR-125a into splenic T cells. Results demonstrate that miR-125a-loaded mPEG-PLGA-PLL (PEAL) nanoparticles (NPs) exhibit good biocompatibility and protect miR-125a from degradation, thereby prolonging the circulatory time of miRNA . In addition, PEAL NPs are preferentially enriched in a pathological spleen and efficiently deliver miR-125a into the splenic T cells in SLE mice models. The PEAL NPs treatment significantly alleviates SLE disease progression by reversing the imbalance of effector/regulatory T cells. Collectively, the PEAL NPs show excellent therapeutic efficacy and safety, which may provide an effective treatment for SLE. 10.1021/acsnano.9b09998
    Increased risk of infection-related death in SLE. Onuora Sarah Nature reviews. Rheumatology 10.1038/s41584-020-0438-9
    Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA. Soni Chetna,Perez Oriana A,Voss William N,Pucella Joseph N,Serpas Lee,Mehl Justin,Ching Krystal L,Goike Jule,Georgiou George,Ippolito Gregory C,Sisirak Vanja,Reizis Boris Immunity Class-switched antibodies to double-stranded DNA (dsDNA) are prevalent and pathogenic in systemic lupus erythematosus (SLE), yet mechanisms of their development remain poorly understood. Humans and mice lacking secreted DNase DNASE1L3 develop rapid anti-dsDNA antibody responses and SLE-like disease. We report that anti-DNA responses in Dnase1l3 mice require CD40L-mediated T cell help, but proceed independently of germinal center formation via short-lived antibody-forming cells (AFCs) localized to extrafollicular regions. Type I interferon (IFN-I) signaling and IFN-I-producing plasmacytoid dendritic cells (pDCs) facilitate the differentiation of DNA-reactive AFCs in vivo and in vitro and are required for downstream manifestations of autoimmunity. Moreover, the endosomal DNA sensor TLR9 promotes anti-dsDNA responses and SLE-like disease in Dnase1l3 mice redundantly with another nucleic acid-sensing receptor, TLR7. These results establish extrafollicular B cell differentiation into short-lived AFCs as a key mechanism of anti-DNA autoreactivity and reveal a major contribution of pDCs, endosomal Toll-like receptors (TLRs), and IFN-I to this pathway. 10.1016/j.immuni.2020.04.015
    Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients-emanating from vascular endothelial cells outwards-in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis. 10.1038/s41586-020-2222-z
    Complement genes contribute sex-biased vulnerability in diverse disorders. Kamitaki Nolan,Sekar Aswin,Handsaker Robert E,de Rivera Heather,Tooley Katherine,Morris David L,Taylor Kimberly E,Whelan Christopher W,Tombleson Philip,Loohuis Loes M Olde, ,Boehnke Michael,Kimberly Robert P,Kaufman Kenneth M,Harley John B,Langefeld Carl D,Seidman Christine E,Pato Michele T,Pato Carlos N,Ophoff Roel A,Graham Robert R,Criswell Lindsey A,Vyse Timothy J,McCarroll Steven A Nature Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men, whereas schizophrenia affects men with greater frequency and severity relative to women. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses. 10.1038/s41586-020-2277-x
    Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells. Li Hao,Adamopoulos Iannis E,Moulton Vaishali R,Stillman Isaac E,Herbert Zach,Moon James J,Sharabi Amir,Krishfield Suzanne,Tsokos Maria G,Tsokos George C Nature communications Mature double negative (DN) T cells are a population of αβ T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8 T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE. 10.1038/s41467-020-16636-4
    Complement: the missing genetic link for SLE and pSS? Clarke Joanna Nature reviews. Rheumatology 10.1038/s41584-020-0456-7
    A highly potent lymphatic system-targeting nanoparticle cyclosporine prevents glomerulonephritis in mouse model of lupus. Science advances Cyclosporine A (CsA) is a powerful immunosuppressant, but it is an ineffective stand-alone treatment for systemic lupus erythematosus (SLE) due to poor target tissue distribution and renal toxicity. We hypothesized that CD71 (transferrin receptor 1)-directed delivery of CsA to the lymphatic system would improve SLE outcomes in a murine model. We synthesized biodegradable, ligand-conjugated nanoparticles [P2Ns-gambogic acid (GA)] targeting CD71. GA conjugation substantially increased nanoparticle association with CD3 or CD20 lymphocytes and with intestinal lymphoid tissues. In orally dosed MRL- mice, P2Ns-GA-encapsulated CsA increased lymphatic drug delivery 4- to 18-fold over the ligand-free formulation and a commercial CsA capsule, respectively. Improved lymphatic bioavailability of CsA was paralleled by normalization of anti-double-stranded DNA immunoglobulin G titer, plasma cytokines, and glomerulonephritis. Thus, this study demonstrates the translational potential of nanoparticles that enhance the targeting of lymphatic tissues, transforming CsA into a potent single therapeutic for SLE. 10.1126/sciadv.abb3900
    Quantitative planar array screen of 1000 proteins uncovers novel urinary protein biomarkers of lupus nephritis. Vanarsa Kamala,Soomro Sanam,Zhang Ting,Strachan Briony,Pedroza Claudia,Nidhi Malavika,Cicalese Pietro,Gidley Christopher,Dasari Shobha,Mohan Shree,Thai Nathan,Truong Van Thi Thanh,Jordan Nicole,Saxena Ramesh,Putterman Chaim,Petri Michelle,Mohan Chandra Annals of the rheumatic diseases OBJECTIVE:The goal of these studies is to discover novel urinary biomarkers of lupus nephritis (LN). METHODS:Urine from systemic lupus erythematosus (SLE) patients was interrogated for 1000 proteins using a novel, quantitative planar protein microarray. Hits were validated in an independent SLE cohort with inactive, active non-renal (ANR) and active renal (AR) patients, in a cohort with concurrent renal biopsies, and in a longitudinal cohort. Single-cell renal RNA sequencing data from LN kidneys were examined to deduce the cellular origin of each biomarker. RESULTS:Screening of 1000 proteins revealed 64 proteins to be significantly elevated in SLE urine, of which 17 were ELISA validated in independent cohorts. Urine Angptl4 (area under the curve (AUC)=0.96), L-selectin (AUC=0.86), TPP1 (AUC=0.84), transforming growth factor-β1 (TGFβ1) (AUC=0.78), thrombospondin-1 (AUC=0.73), FOLR2 (AUC=0.72), platelet-derived growth factor receptor-β (AUC=0.67) and PRX2 (AUC=0.65) distinguished AR from ANR SLE, outperforming anti-dsDNA, C3 and C4, in terms of specificity, sensitivity and positive predictive value. In multivariate regression analysis, urine Angptl4, L-selectin, TPP1 and TGFβ1 were highly associated with disease activity, even after correction for demographic variables. In SLE patients with serial follow-up, urine L-selectin (followed by urine Angptl4 and TGFβ1) were best at tracking concurrent or pending disease flares. Importantly, several proteins elevated in LN urine were also expressed within the kidneys in LN, either within resident renal cells or infiltrating immune cells, based on single-cell RNA sequencing analysis. CONCLUSION:Unbiased planar array screening of 1000 proteins has led to the discovery of urine Angptl4, L-selectin and TGFβ1 as potential biomarker candidates for tracking disease activity in LN. 10.1136/annrheumdis-2019-216312
    The (Orf)ull truth about IRF5 and type I interferons in SLE. Elkon Keith B,Briggs Tracy A Nature reviews. Rheumatology 10.1038/s41584-020-0472-7
    New insights into the role of antinuclear antibodies in systemic lupus erythematosus. Pisetsky David S,Lipsky Peter E Nature reviews. Rheumatology Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by antinuclear antibodies (ANAs) that form immune complexes that mediate pathogenesis by tissue deposition or cytokine induction. Some ANAs bind DNA or associated nucleosome proteins, whereas other ANAs bind protein components of complexes of RNA and RNA-binding proteins (RBPs). Levels of anti-DNA antibodies can fluctuate widely, unlike those of anti-RBP antibodies, which tend to be stable. Because anti-DNA antibody levels can reflect disease activity, repeat testing is common; by contrast, a single anti-RBP antibody determination is thought to suffice for clinical purposes. Experience from clinical trials of novel therapies has provided a new perspective on ANA expression during disease, as many patients with SLE are ANA negative at screening despite previously testing positive. Because trial results suggest that patients who are ANA negative might not respond to certain agents, screening strategies now involve ANA and anti-DNA antibody testing to identify patients with so-called 'active, autoantibody-positive SLE'. Evidence suggests that ANA responses can decrease over time because of the natural history of disease or the effects of therapy. Together, these findings suggest that, during established disease, more regular serological testing could illuminate changes relevant to pathogenesis and disease status. 10.1038/s41584-020-0480-7
    Proteomic, biomechanical and functional analyses define neutrophil heterogeneity in systemic lupus erythematosus. Bashant Kathleen R,Aponte Angel M,Randazzo Davide,Rezvan Sangsari Paniz,Wood Alexander Jt,Bibby Jack A,West Erin E,Vassallo Arlette,Manna Zerai G,Playford Martin P,Jordan Natasha,Hasni Sarfaraz,Gucek Marjan,Kemper Claudia,Conway Morris Andrew,Morgan Nicole Y,Toepfner Nicole,Guck Jochen,Mehta Nehal N,Chilvers Edwin R,Summers Charlotte,Kaplan Mariana J Annals of the rheumatic diseases OBJECTIVES:Low-density granulocytes (LDGs) are a distinct subset of proinflammatory and vasculopathic neutrophils expanded in systemic lupus erythematosus (SLE). Neutrophil trafficking and immune function are intimately linked to cellular biophysical properties. This study used proteomic, biomechanical and functional analyses to further define neutrophil heterogeneity in the context of SLE. METHODS:Proteomic/phosphoproteomic analyses were performed in healthy control (HC) normal density neutrophils (NDNs), SLE NDNs and autologous SLE LDGs. The biophysical properties of these neutrophil subsets were analysed by real-time deformability cytometry and lattice light-sheet microscopy. A two-dimensional endothelial flow system and a three-dimensional microfluidic microvasculature mimetic (MMM) were used to decouple the contributions of cell surface mediators and biophysical properties to neutrophil trafficking, respectively. RESULTS:Proteomic and phosphoproteomic differences were detected between HC and SLE neutrophils and between SLE NDNs and LDGs. Increased abundance of type 1 interferon-regulated proteins and differential phosphorylation of proteins associated with cytoskeletal organisation were identified in SLE LDGs relative to SLE NDNs. The cell surface of SLE LDGs was rougher than in SLE and HC NDNs, suggesting membrane perturbances. While SLE LDGs did not display increased binding to endothelial cells in the two-dimensional assay, they were increasingly retained/trapped in the narrow channels of the lung MMM. CONCLUSIONS:Modulation of the neutrophil proteome and distinct changes in biophysical properties are observed alongside differences in neutrophil trafficking. SLE LDGs may be increasingly retained in microvasculature networks, which has important pathogenic implications in the context of lupus organ damage and small vessel vasculopathy. 10.1136/annrheumdis-2020-218338
    IL-17 sustains plasma cells in SLE. Clarke Joanna Nature reviews. Rheumatology 10.1038/s41584-020-00519-5
    Structural analysis reveals TLR7 dynamics underlying antagonism. Tojo Shingo,Zhang Zhikuan,Matsui Hiroyuki,Tahara Masahiro,Ikeguchi Mitsunori,Kochi Mami,Kamada Mami,Shigematsu Hideki,Tsutsumi Akihisa,Adachi Naruhiko,Shibata Takuma,Yamamoto Masaki,Kikkawa Masahide,Senda Toshiya,Isobe Yoshiaki,Ohto Umeharu,Shimizu Toshiyuki Nature communications Toll-like receptor 7 (TLR7) recognizes both microbial and endogenous RNAs and nucleosides. Aberrant activation of TLR7 has been implicated in several autoimmune diseases including systemic lupus erythematosus (SLE). Here, by modifying potent TLR7 agonists, we develop a series of TLR7-specific antagonists as promising therapeutic agents for SLE. These compounds protect mice against lethal autoimmunity. Combining crystallography and cryo-electron microscopy, we identify the open conformation of the receptor and reveal the structural equilibrium between open and closed conformations that underlies TLR7 antagonism, as well as the detailed mechanism by which TLR7-specific antagonists bind to their binding pocket in TLR7. Our work provides small-molecule TLR7-specific antagonists and suggests the TLR7-targeting strategy for treating autoimmune diseases. 10.1038/s41467-020-19025-z
    Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Aranow Cynthia,Atish-Fregoso Yemil,Lesser Martin,Mackay Meggan,Anderson Erik,Chavan Sangeeta,Zanos Theodoros P,Datta-Chaudhuri Timir,Bouton Chad,Tracey Kevin J,Diamond Betty Annals of the rheumatic diseases OBJECTIVES:Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. METHODS:18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. RESULTS:taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. CONCLUSION:taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted. 10.1136/annrheumdis-2020-217872
    FcγRIIA expression accelerates nephritis and increases platelet activation in systemic lupus erythematosus. Melki Imene,Allaeys Isabelle,Tessandier Nicolas,Mailhot Benoit,Cloutier Nathalie,Campbell Robert A,Rowley Jesse W,Salem David,Zufferey Anne,Laroche Audrée,Lévesque Tania,Patey Natalie,Rauch Joyce,Lood Christian,Droit Arnaud,McKenzie Steven E,Machlus Kellie R,Rondina Matthew T,Lacroix Steve,Fortin Paul R,Boilard Eric Blood Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by deposits of immune complexes (ICs) in organs and tissues. The expression of FcγRIIA by human platelets, which is their unique receptor for immunoglobulin G antibodies, positions them to ideally respond to circulating ICs. Whereas chronic platelet activation and thrombosis are well-recognized features of human SLE, the exact mechanisms underlying platelet activation in SLE remain unknown. Here, we evaluated the involvement of FcγRIIA in the course of SLE and platelet activation. In patients with SLE, levels of ICs are associated with platelet activation. Because FcγRIIA is absent in mice, and murine platelets do not respond to ICs in any existing mouse model of SLE, we introduced the FcγRIIA (FCGR2A) transgene into the NZB/NZWF1 mouse model of SLE. In mice, FcγRIIA expression by bone marrow cells severely aggravated lupus nephritis and accelerated death. Lupus onset initiated major changes to the platelet transcriptome, both in FcγRIIA-expressing and nonexpressing mice, but enrichment for type I interferon response gene changes was specifically observed in the FcγRIIA mice. Moreover, circulating platelets were degranulated and were found to interact with neutrophils in FcγRIIA-expressing lupus mice. FcγRIIA expression in lupus mice also led to thrombosis in lungs and kidneys. The model recapitulates hallmarks of human SLE and can be used to identify contributions of different cellular lineages in the manifestations of SLE. The study further reveals a role for FcγRIIA in nephritis and in platelet activation in SLE. 10.1182/blood.2020004974
    SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression. Hou Guojun,Harley Isaac T W,Lu Xiaoming,Zhou Tian,Xu Ning,Yao Chao,Qin Yuting,Ouyang Ye,Ma Jianyang,Zhu Xinyi,Yu Xiang,Xu Hong,Dai Dai,Ding Huihua,Yin Zhihua,Ye Zhizhong,Deng Jun,Zhou Mi,Tang Yuanjia,Namjou Bahram,Guo Ya,Weirauch Matthew T,Kottyan Leah C,Harley John B,Shen Nan Nature communications Since most variants that impact polygenic disease phenotypes localize to non-coding genomic regions, understanding the consequences of regulatory element variants will advance understanding of human disease mechanisms. Here, we report that the systemic lupus erythematosus (SLE) risk variant rs2431697 as likely causal for SLE through disruption of a regulatory element, modulating miR-146a expression. Using epigenomic analysis, genome-editing and 3D chromatin structure analysis, we show that rs2431697 tags a cell-type dependent distal enhancer specific for miR-146a that physically interacts with the miR-146a promoter. NF-kB binds the disease protective allele in a sequence-specific manner, increasing expression of this immunoregulatory microRNA. Finally, CRISPR activation-based modulation of this enhancer in the PBMCs of SLE patients attenuates type I interferon pathway activation by increasing miR-146a expression. Our work provides a strategy to define non-coding RNA functional regulatory elements using disease-associated variants and provides mechanistic links between autoimmune disease risk genetic variation and disease etiology. 10.1038/s41467-020-20460-1
    Platelets release mitochondrial antigens in systemic lupus erythematosus. Melki Imene,Allaeys Isabelle,Tessandier Nicolas,Lévesque Tania,Cloutier Nathalie,Laroche Audrée,Vernoux Nathalie,Becker Yann,Benk-Fortin Hadrien,Zufferey Anne,Rollet-Labelle Emmanuelle,Pouliot Marc,Poirier Guy,Patey Natacha,Belleannee Clemence,Soulet Denis,McKenzie Steven E,Brisson Alain,Tremblay Marie-Eve,Lood Christian,Fortin Paul R,Boilard Eric Science translational medicine The accumulation of DNA and nuclear components in blood and their recognition by autoantibodies play a central role in the pathophysiology of systemic lupus erythematosus (SLE). Despite the efforts, the sources of circulating autoantigens in SLE are still unclear. Here, we show that in SLE, platelets release mitochondrial DNA, the majority of which is associated with the extracellular mitochondrial organelle. Mitochondrial release in patients with SLE correlates with platelet degranulation. This process requires the stimulation of platelet FcγRIIA, a receptor for immune complexes. Because mice lack FcγRIIA and murine platelets are completely devoid of receptor capable of binding IgG-containing immune complexes, we used transgenic mice expressing FcγRIIA for our in vivo investigations. FcγRIIA expression in lupus-prone mice led to the recruitment of platelets in kidneys and to the release of mitochondria in vivo. Using a reporter mouse with red fluorescent protein targeted to the mitochondrion, we confirmed platelets as a source of extracellular mitochondria driven by FcγRIIA and its cosignaling by the fibrinogen receptor α2bβ3 in vivo. These findings suggest that platelets might be a key source of mitochondrial antigens in SLE and might be a therapeutic target for treating SLE. 10.1126/scitranslmed.aav5928
    Experience with milatuzumab, an anti-CD74 antibody against immunomodulatory macrophage migration inhibitory factor (MIF) receptor, for systemic lupus erythematosus (SLE). Wallace Daniel J,Figueras Florence,Wegener William A,Goldenberg David M Annals of the rheumatic diseases 10.1136/annrheumdis-2020-219803
    Interaction between the rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus. Reid Sarah,Hagberg Niklas,Sandling Johanna K,Alexsson Andrei,Pucholt Pascal,Sjöwall Christopher,Lerang Karoline,Jönsen Andreas,Gunnarsson Iva,Syvänen Ann-Christine,Troldborg Anne Margrethe,Voss Anne,Bengtsson Anders A,Molberg Øyvind,Jacobsen Søren,Svenungsson Elisabet,Rönnblom Lars,Leonard Dag Annals of the rheumatic diseases OBJECTIVE:To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations. METHODS:Patients with SLE (n=776, n=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p<5.0×10) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in stimulated peripheral blood mononuclear cells from healthy controls (n=45). RESULTS:In the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)).Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively).The interaction between smoking and the risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063).Lastly, the rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively). CONCLUSIONS:Smoking in the presence of the risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12-STAT4 pathway in SLE-cardiovascular morbidity. 10.1136/annrheumdis-2020-219727
    Platelets highlighted as a potential source of autoantigens in SLE. McHugh Jessica Nature reviews. Rheumatology 10.1038/s41584-021-00609-y
    Type I interferons affect the metabolic fitness of CD8 T cells from patients with systemic lupus erythematosus. Nature communications The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4 and CD8 T cells. CD8 T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8 T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these 'SLE-like' conditions increase CD8 T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8 T cell death via metabolic rewiring. 10.1038/s41467-021-22312-y
    Long-Term Cardiovascular Outcomes in Systemic Lupus Erythematosus. Yafasova Adelina,Fosbøl Emil L,Schou Morten,Baslund Bo,Faurschou Mikkel,Docherty Kieran F,Jhund Pardeep S,McMurray John J V,Sun Guoli,Kristensen Søren L,Torp-Pedersen Christian,Køber Lars,Butt Jawad H Journal of the American College of Cardiology BACKGROUND:Data on long-term cardiovascular outcomes in systemic lupus erythematosus (SLE) are sparse. OBJECTIVES:This study sought to examine the long-term risk and prognosis associated with cardiovascular outcomes, including heart failure (HF), in patients with SLE. METHODS:Using Danish administrative registries, risks of outcomes were compared between SLE patients (diagnosed 1996 to 2018, no history of cardiovascular disease) and age-, sex-, and comorbidity-matched control subjects from the background population (matched 1:4). Furthermore, mortality following HF diagnosis was compared between SLE patients developing HF and age- and sex-matched non-SLE control subjects with HF (matched 1:4). RESULTS:A total of 3,411 SLE patients (median age: 44.6 years [25th to 75th percentile: 31.9 to 57.0 years]; 14.1% men) were matched with 13,644 control subjects. The median follow-up was 8.5 years (25th to 75th percentile: 4.0 to 14.4 years). Absolute 10-year risks of outcomes were: HF, 3.71% (95% confidence interval [CI]: 3.02% to 4.51%) for SLE patients, 1.94% (95% CI: 1.68% to 2.24%) for control subjects; atrial fibrillation, 4.35% (95% CI: 3.61% to 5.18%) for SLE patients, 2.82% (95% CI: 2.50% to 3.16%) for control subjects; ischemic stroke, 3.75% (95% CI: 3.06% to 4.54%) for SLE patients, 1.92% (95% CI: 1.66% to 2.20%) for control subjects; myocardial infarction, 2.17% (95% CI: 1.66% to 2.80%) for SLE patients, 1.49% (95% CI: 1.26% to 1.75%) for control subjects; venous thromboembolism, 6.03% (95% CI: 5.17% to 6.98%) for SLE patients, 1.68% (95% CI: 1.44% to 1.95%) for control subjects; and the composite of implantable cardioverter-defibrillator implantation/ventricular arrhythmias/cardiac arrest, 0.89% (95% CI: 0.58% to 1.31%) for SLE patients, 0.30% (95% CI: 0.20% to 0.43%) for control subjects. SLE with subsequent HF was associated with higher mortality compared with HF without SLE (adjusted hazard ratio: 1.50; 95% CI: 1.08 to 2.08). CONCLUSIONS:SLE patients had a higher associated risk of HF and other cardiovascular outcomes compared with matched control subjects. Among patients developing HF, a history of SLE was associated with higher mortality. 10.1016/j.jacc.2021.02.029
    IFNs disrupt T cell metabolism in SLE. McHugh Jessica Nature reviews. Rheumatology 10.1038/s41584-021-00622-1
    Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis. Scherlinger Marc,Guillotin Vivien,Douchet Isabelle,Vacher Pierre,Boizard-Moracchini Andréa,Guegan Jean-Philippe,Garreau Anne,Merillon Nathalie,Vermorel Agathe,Ribeiro Emmanuel,Machelart Irène,Lazaro Estibaliz,Couzi Lionel,Duffau Pierre,Barnetche Thomas,Pellegrin Jean-Luc,Viallard Jean-François,Saleh Maya,Schaeverbeke Thierry,Legembre Patrick,Truchetet Marie-Elise,Dumortier Hélène,Contin-Bordes Cécile,Sisirak Vanja,Richez Christophe,Blanco Patrick Science translational medicine Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (T) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with T cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of T cells and particularly follicular T cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on T cells induced a down-regulation of the transforming growth factor-β axis, altering the phenotype of T cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin-dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue. 10.1126/scitranslmed.abi4994
    B cell X-chromosome inactivation is faulty in SLE. Clarke Joanna Nature reviews. Rheumatology 10.1038/s41584-021-00660-9
    Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease. Ban Tatsuma,Kikuchi Masako,Sato Go R,Manabe Akio,Tagata Noriko,Harita Kayo,Nishiyama Akira,Nishimura Kenichi,Yoshimi Ryusuke,Kirino Yohei,Yanai Hideyuki,Matsumoto Yoshiko,Suzuki Shuichi,Hihara Hiroe,Ito Masashi,Tsukahara Kappei,Yoshimatsu Kentaro,Yamamoto Tadashi,Taniguchi Tadatsugu,Nakajima Hideaki,Ito Shuichi,Tamura Tomohiko Nature communications The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors. 10.1038/s41467-021-24609-4
    Selectins block T cells in SLE. Otto Grant Nature reviews. Rheumatology 10.1038/s41584-021-00671-6
    Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE. Caielli Simone,Cardenas Jacob,de Jesus Adriana Almeida,Baisch Jeanine,Walters Lynnette,Blanck Jean Philippe,Balasubramanian Preetha,Stagnar Cristy,Ohouo Marina,Hong Seunghee,Nassi Lorien,Stewart Katie,Fuller Julie,Gu Jinghua,Banchereau Jacques F,Wright Tracey,Goldbach-Mansky Raphaela,Pascual Virginia Cell Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE. 10.1016/j.cell.2021.07.021
    Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity. Nature immunology The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-α present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMα to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations. 10.1038/s41590-021-00993-3
    Are DNA-HLA class II interactions the missing link in SLE? Pisetsky David S Nature reviews. Rheumatology 10.1038/s41584-021-00684-1
    Rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren's syndrome shared megakaryocyte expansion in peripheral blood. Wang Yukai,Xie Xuezhen,Zhang Chengpeng,Su Miaotong,Gao Sini,Wang Jing,Lu Changhao,Lin Qisheng,Lin Jianqun,Matucci-Cerinic Marco,Furst Daniel E,Zhang Guohong Annals of the rheumatic diseases OBJECTIVES:Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) share many clinical manifestations and serological features. The aim of this study was to identify the common transcriptional profiling and composition of immune cells in peripheral blood in these autoimmune diseases (ADs). METHODS:We analysed bulk RNA-seq data for enrichment of biological processes, transcription factors (TFs) and deconvolution-based immune cell types from peripheral blood mononuclear cells (PBMCs) in 119 treatment-naive patients (41 RA, 38 pSS, 28 SLE and 12 polyautoimmunity) and 20 healthy controls. The single-cell RNA-seq (scRNA-seq) and flow cytometry had been performed to further define the immune cell subsets on PBMCs. RESULTS:Similar transcriptional profiles and common gene expression signatures associated with nucleosome assembly and haemostasis were identified across RA, SLE, pSS and polyautoimmunity. Distinct TF ensembles and gene regulatory network were mainly enriched in haematopoiesis. The upregulated cell-lineage-specific TFs , , and demonstrated a strong gene expression signature of megakaryocyte (MK) expansion. Gene expression-based cell type enrichment revealed elevated MK composition, specifically, CD41bCD42b and CD41bCD61 MKs were expanded, further confirmed by flow cytometry in these ADs. In scRNA-seq data, MKs were defined by TFs and pre-T-cell antigen receptor gene, . Cellular heterogeneity and a distinct immune subpopulation with functional enrichment of antigen presentation were observed in MKs. CONCLUSIONS:The identification of MK expansion provided new insights into the peripheral immune cell atlas across RA, SLE, pSS and polyautoimmunity. Aberrant regulation of the MK expansion might contribute to the pathogenesis of these ADs. 10.1136/annrheumdis-2021-220066
    Human SLE variant -R90H promotes kidney damage and murine lupus through enhanced Tfh2 responses induced by defective efferocytosis of macrophages. Geng Linyu,Zhao Jian,Deng Yun,Molano Ivan,Xu Xue,Xu Lingxiao,Ruiz Phillip,Li Quanzhen,Feng Xuebing,Zhang Miaojia,Tan Wenfeng,Kamen Diane L,Bae Sang-Cheol,Gilkeson Gary S,Sun Lingyun,Tsao Betty P Annals of the rheumatic diseases OBJECTIVES:We previously identified a hypomorphic variant, p.Arg90His (p.R90H) of neutrophil cytosolic factor 1 ( a regulatory subunit of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 complex), as an putative causal variant for systemic lupus erythematosus (SLE), and established a knock-in (KI) H90 variant in the C57BL/6 background to study how this variant promotes lupus development. METHODS:Wild type (WT) and KI littermates were assessed for immune profiles and lupus-like features. Disease activity and renal damage of patients with SLE were assessed by systemic lupus erythematosus disease activity index (SLEDAI) and renal items of systemic lupus international collaborating clinics (SLICC), respectively. RESULTS:Compared with WT littermates, 5-week-old homozygous KI mice had reduced oxidative burst, splenomegaly, elevated type I interferon (IFN-I) scores, increased ratios of splenic follicular T helper 2 (Tfh2) to either T follicular regulatory (Tfr) or Tfh1 cells, increased ANA follicular, germinal centre and plasma cells without spontaneous kidney disease up to 1 year of age. Pristane treatment exacerbated the immune dysregulation and induced IFN-I-dependent kidney disease in 36-week-old H90 KI female mice. Decreased efferocytosis of macrophages derived from KI mice and patients with homozygous H90 SLE promoted elevated ratios of Tfh2/Tfr and Tfh2/Tfh1 as well as dysregulated humoral responses due to reduced voltage-gated proton channel 1 (Hv1)-dependent acidification of phagosome pH to neutralise the decreased electrogenic effect of the H90 variant, resulting in impaired maturation and phagosome proteolysis, and increased autoantibody production and kidney damage in mice and patients with SLE of multiple ancestries. CONCLUSIONS:A lupus causal variant, NCF1-H90, reduces macrophage efferocytosis, enhances Tfh2 responses and promotes autoantibody production and kidney damage in both mice and patients with SLE. 10.1136/annrheumdis-2021-220793
    Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus. Chuang Huai-Chia,Hung Wei-Ting,Chen Yi-Ming,Hsu Pu-Ming,Yen Jeng-Hsien,Lan Joung-Liang,Tan Tse-Hua Annals of the rheumatic diseases OBJECTIVES:MAP4K3 (GLK) overexpression in T cells induces interleukin (IL)-17A production and autoimmune responses. GLK overexpressing T-cell population is correlated with severity of human systemic lupus erythematosus (SLE); however, it is unclear how GLK is upregulated in patients with SLE. METHODS:We enrolled 181 patients with SLE and 250 individuals without SLE (93 healthy controls and 157 family members of patients with SLE) in two independent cohorts from different hospitals/cities. Genomic DNAs of peripheral blood mononuclear cells were subjected to next-generation sequencing to identify GLK gene variants. The functional consequences of the identified GLK germline or somatic variants were investigated using site-directed mutagenesis and cell transfection, followed by reporter assays, mass spectrometry, immunoblotting, coimmunoprecipitation, and in situ proximity ligation assays. RESULTS:We identified 58 patients with SLE from Cohort #1 and #2 with higher frequencies of a somatic variant (chr2:39 477 124 A>G) in GLK 3'-untranslated region (UTR); these patients with SLE showed increased serum anti-double-stranded DNA levels and decreased serum C3/C4 levels. This somatic variant in 3'-UTR enhanced GLK mRNA levels in T cells. In addition, we identified five patients with SLE with GLK (A410T) germline variant in Cohort #1 and #2, as well as two other patients with SLE with GLK (K650R) germline variant in Cohort #1. Another GLK germline variant, A579T, was also detected in one patient with SLE from Cohort #2. Both GLK (A410T) and GLK (K650R) mutants inhibited GLK ubiquitination induced by the novel E3 ligase makorin ring-finger protein 4 (MKRN4), leading to GLK protein stabilisation. CONCLUSIONS:Multiple GLK germline and somatic variants cause GLK induction by increasing mRNA or protein stability in patients with SLE. 10.1136/annrheumdis-2021-221010
    Erythrocyte-derived mitochondria: an unexpected interferon inducer in lupus. Morel Laurence Trends in immunology Type 1 interferon (IFN) is a major contributor to the pathogenesis of systemic lupus erythematosus (SLE). A landmark study by Caielli et al. now shows that erythrocytes from lupus patients that fail to switch from glycolysis to oxidative phosphorylation during differentiation retain their mitochondria. These mitochondria-containing erythrocytes represent a novel source of IFN when phagocytosed by macrophages. 10.1016/j.it.2021.10.010
    The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses. Chalmers Samantha A,Ayilam Ramachandran Rajalakshmy,Garcia Sayra J,Der Evan,Herlitz Leal,Ampudia Jeanette,Chu Dalena,Jordan Nicole,Zhang Ting,Parodis Ioannis,Gunnarsson Iva,Ding Huihua,Shen Nan,Petri Michelle,Mok Chi Chiu,Saxena Ramesh,Polu Krishna R,Connelly Stephen,Ng Cherie T,Mohan Chandra,Putterman Chaim The Journal of clinical investigation 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. 10.1172/JCI147334
    Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes. The Journal of clinical investigation BACKGROUNDFasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODSWe explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE).RESULTSRNA-Seq of unstimulated and LPS-activated monocytes implicated NR in the regulation of autophagy and type I IFN signaling. In primary monocytes, NR blunted LPS-induced IFN-β production, and genetic or pharmacological disruption of autophagy phenocopied this effect. Given that NAD+ is a coenzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased the inosine level. Inosine supplementation similarly blunted autophagy and IFN-β release. Finally, because SLE exhibits type I IFN dysregulation, we assessed the NR effect on monocytes from patients with SLE and found that NR reduced autophagy and IFN-β release.CONCLUSIONWe conclude that NR, in an NAD+-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for SLE management.TRIAL REGISTRATIONClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372.FUNDINGThis work was supported by the NHLBI and NIAMS Intramural Research divisions. 10.1172/JCI139828
    Up-regulation of proBDNF/p75 signaling in antibody-secreting cells drives systemic lupus erythematosus. Science advances Inappropriate expansion of antibody-secreting cells (ASCs) is typical of systemic lupus erythematosus (SLE), but the regulatory signaling of pathogenic ASCs is unclear. The present study shows that brain-derived neurotrophic factor precursor (proBDNF) and its high-affinity pan-75 neurotrophin receptor (p75) are highly expressed in CD19CD27CD38 ASCs in patients with SLE and in CD19CD44CD138 ASCs in lupus-like mice. The increased proBDNF ASCs were positively correlated with clinical symptoms and higher titers of autoantibodies in SLE. Administration of monoclonal antibodies against proBDNF or specific knockout of p75 in CD19 B cells exerted a therapeutic effect on lupus mice by limiting the proportion of ASCs, reducing the production of autoantibodies and attenuating kidney injury. Blocking the biological function of proBDNF or p75 also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75 signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction. 10.1126/sciadv.abj2797
    Anti-RNP antibodies are associated with the interferon gene signature but not decreased complement levels in SLE. Annals of the rheumatic diseases OBJECTIVES:The goals of these studies were to elucidate the inter-relationships of specific anti-nuclear antibody (ANA), complement, and the interferon gene signature (IGS) in the pathogenesis of systemic lupus erythematosus (SLE). METHODS:Data from the Illuminate trials were analysed for antibodies to dsDNA as well as RNA-binding proteins (RBP), levels of C3, C4 and various IGS. Statistical hypothesis testing, linear regression analyses and classification and regression trees analysis were employed to assess relationships between the laboratory features of SLE. RESULTS:Inter-relationships of ANAs, complement and the IGS differed between patients of African Ancestry (AA) and European Ancestry (EA); anti-RNP and multiple autoantibodies were more common in AA patients and, although both related to the presence of the IGS, relationships between autoantibodies and complement differed. Whereas, anti-dsDNA had an inverse relationship to C3 and C4, levels of anti-RNP were not related to these markers. The IGS was only correlated with anti-dsDNA in EA SLE and complement was more correlated to the IGS in AA SLE. Finally, autoantibodies occurred in the presence and absence of the IGS, whereas the IGS was infrequent in anti-dsDNA/anti-RBP-negative SLE patients. CONCLUSION:There is a complex relationship between autoantibodies and the IGS, with anti-RNP associated in AA and both anti-dsDNA and RNP associated in EA. Moreover, there was a difference in the relationship between anti-dsDNA, but not anti-RBP, with complement levels. The lack of a relationship of anti-RNP with C3 and C4 suggests that anti-RNP immune complexes (ICs) may drive the IGS without complement fixation, whereas anti-dsDNA ICs involve complement consumption. 10.1136/annrheumdis-2021-221662
    Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus. Annals of the rheumatic diseases OBJECTIVE:Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease. While the long-term prognosis has greatly improved, better long-term survival is still necessary. The type I interferon (IFN) signature, a prominent feature of SLE, is not an ideal therapeutic target or outcome predictor. To explore immunological pathways in SLE more precisely, we performed transcriptomic, epigenomic and genomic analyses using 19 immune cell subsets from peripheral blood. METHODS:We sorted 19 immune cell subsets and identified the mRNA expression profiles and genetic polymorphisms in 107 patients with SLE and 92 healthy controls. Combined differentially expressed genes and expression quantitative trait loci analysis was conducted to find key driver genes in SLE pathogenesis. RESULTS:We found transcriptomic, epigenetic and genetic importance of oxidative phosphorylation (OXPHOS)/mitochondrial dysfunction in SLE memory B cells. Particularly, we identified an OXPHOS-regulating gene, (peroxiredoxin 6), as a key driver in SLE B cells. deficient B cells showed upregulated mitochondrial respiration as well as antibody production. We revealed OXPHOS signature was associated with type I IFN signalling-related genes (ISRGs) signature in SLE memory B cells. Furthermore, the gene sets related to innate immune signalling among ISRGs presented correlation with OXPHOS and these two signatures showed associations with SLE organ damage as well as specific clinical phenotypes. CONCLUSION:This work elucidated the potential prognostic marker for SLE. Since OXPHOS consists of the electron transport chain, a functional unit in mitochondria, these findings suggest the importance of mitochondrial dysfunction as a key immunological pathway involved in SLE. 10.1136/annrheumdis-2021-221464
    The complement system as a potential therapeutic target in rheumatic disease. Trouw Leendert A,Pickering Matthew C,Blom Anna M Nature reviews. Rheumatology Complement activation is associated with common rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic vasculitis. Evidence linking complement activation to these diseases includes the presence of complement deposition in affected tissues, decreased levels of complement proteins and high levels of complement activation fragments in the blood and/or synovial fluid of patients with these diseases, as well as data from experimental models. Eculizumab, a monoclonal antibody that inhibits the complement component C5, is now approved for the treatment of rare conditions involving complement hyperactivation, and the success of this therapy has renewed interest in understanding the utility of complement inhibition in rheumatological practice, particularly for SLE. For example, inhibiting C5 is a potential means of reducing glomerular inflammation in lupus nephritis or treating thrombotic microangiopathy in SLE. The complement system is one of multiple mediators of tissue injury in complex diseases such as SLE, and identifying the disease context in which complement activation has a predominant role is a challenge. An added difficulty in RA is identifying a role for therapeutic complement inhibition within the diverse treatment modalities already available. In this Review, evidence for the therapeutic potential of complement manipulation in rheumatology practice is evaluated. 10.1038/nrrheum.2017.125
    The role of semaphorins in immune responses and autoimmune rheumatic diseases. Nishide Masayuki,Kumanogoh Atsushi Nature reviews. Rheumatology Semaphorins have a well-characterized role in guiding axon repulsion during development; however, the important contribution of these proteins in immunity is becoming increasingly clear. Immunoregulatory semaphorins, termed 'immune semaphorins', have roles in regulating immune cell activation, differentiation, mobility and migration. These proteins are also intimately associated with the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This Review discusses the pathogenic functions of immune semaphorins, as well as the potential use of these molecules as diagnostic markers and therapeutic targets for the treatment of autoimmune diseases. 10.1038/nrrheum.2017.201
    The non-haemostatic role of platelets in systemic lupus erythematosus. Linge Petrus,Fortin Paul R,Lood Christian,Bengtsson Anders A,Boilard Eric Nature reviews. Rheumatology Dysregulation of lymphocyte function, accumulation of autoantibodies and defective clearance of circulating immune complexes and apoptotic cells are hallmarks of systemic lupus erythematosus (SLE). Moreover, it is now evident that an intricate interplay between the adaptive and innate immune systems contributes to the pathogenesis of SLE, ultimately resulting in chronic inflammation and organ damage. Platelets circulate in the blood and are chiefly recognized for their role in the prevention of bleeding and promotion of haemostasis; however, accumulating evidence points to a role for platelets in both adaptive and innate immunity. Through a broad repertoire of receptors, platelets respond promptly to immune complexes, complement and damage-associated molecular patterns, and represent a major reservoir of immunomodulatory molecules in the circulation. Furthermore, evidence suggests that platelets are activated in patients with SLE, and that they could contribute to the circulatory autoantigenic load through the release of microparticles and mitochondrial antigens. Herein, we highlight how platelets contribute to the immune response and review evidence implicating platelets in the pathogenesis of SLE. 10.1038/nrrheum.2018.38
    2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Aringer Martin,Costenbader Karen,Daikh David,Brinks Ralph,Mosca Marta,Ramsey-Goldman Rosalind,Smolen Josef S,Wofsy David,Boumpas Dimitrios T,Kamen Diane L,Jayne David,Cervera Ricard,Costedoat-Chalumeau Nathalie,Diamond Betty,Gladman Dafna D,Hahn Bevra,Hiepe Falk,Jacobsen Søren,Khanna Dinesh,Lerstrøm Kirsten,Massarotti Elena,McCune Joseph,Ruiz-Irastorza Guillermo,Sanchez-Guerrero Jorge,Schneider Matthias,Urowitz Murray,Bertsias George,Hoyer Bimba F,Leuchten Nicolai,Tani Chiara,Tedeschi Sara K,Touma Zahi,Schmajuk Gabriela,Anic Branimir,Assan Florence,Chan Tak Mao,Clarke Ann Elaine,Crow Mary K,Czirják László,Doria Andrea,Graninger Winfried,Halda-Kiss Bernadett,Hasni Sarfaraz,Izmirly Peter M,Jung Michelle,Kumánovics Gábor,Mariette Xavier,Padjen Ivan,Pego-Reigosa José M,Romero-Diaz Juanita,Rúa-Figueroa Fernández Íñigo,Seror Raphaèle,Stummvoll Georg H,Tanaka Yoshiya,Tektonidou Maria G,Vasconcelos Carlos,Vital Edward M,Wallace Daniel J,Yavuz Sule,Meroni Pier Luigi,Fritzler Marvin J,Naden Ray,Dörner Thomas,Johnson Sindhu R Annals of the rheumatic diseases OBJECTIVE:To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS:This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects. RESULTS:The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION:These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research. 10.1136/annrheumdis-2018-214819
    T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy. Sharabi Amir,Tsokos George C Nature reviews. Rheumatology T cell subsets are critically involved in the development of systemic autoimmunity and organ inflammation in systemic lupus erythematosus (SLE). Each T cell subset function (such as effector, helper, memory or regulatory function) is dictated by distinct metabolic pathways requiring the availability of specific nutrients and intracellular enzymes. The activity of these enzymes or nutrient transporters influences the differentiation and function of T cells in autoimmune responses. Data are increasingly emerging on how metabolic processes control the function of various T cell subsets and how these metabolic processes are altered in SLE. Specifically, aberrant glycolysis, glutaminolysis, fatty acid and glycosphingolipid metabolism, mitochondrial hyperpolarization, oxidative stress and mTOR signalling underwrite the known function of T cell subsets in patients with SLE. A number of medications that are used in the care of patients with SLE affect cell metabolism, and the development of novel therapeutic approaches to control the activity of metabolic enzymes in T cell subsets represents a promising endeavour in the search for effective treatment of systemic autoimmune diseases. 10.1038/s41584-019-0356-x
    Lupus nephritis. Anders Hans-Joachim,Saxena Ramesh,Zhao Ming-Hui,Parodis Ioannis,Salmon Jane E,Mohan Chandra Nature reviews. Disease primers Lupus nephritis (LN) is a form of glomerulonephritis that constitutes one of the most severe organ manifestations of the autoimmune disease systemic lupus erythematosus (SLE). Most patients with SLE who develop LN do so within 5 years of an SLE diagnosis and, in many cases, LN is the presenting manifestation resulting in the diagnosis of SLE. Understanding of the genetic and pathogenetic basis of LN has improved substantially over the past few decades. Treatment of LN usually involves immunosuppressive therapy, typically with mycophenolate mofetil or cyclophosphamide and with glucocorticoids, although these treatments are not uniformly effective. Despite increased knowledge of disease pathogenesis and improved treatment options, LN remains a substantial cause of morbidity and death among patients with SLE. Within 10 years of an initial SLE diagnosis, 5-20% of patients with LN develop end-stage kidney disease, and the multiple comorbidities associated with immunosuppressive treatment, including infections, osteoporosis and cardiovascular and reproductive effects, remain a concern. Clearly, early and accurate diagnosis of LN and prompt initiation of therapy are of vital importance to improve outcomes in patients with SLE. 10.1038/s41572-019-0141-9
    Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Schrezenmeier Eva,Dörner Thomas Nature reviews. Rheumatology Despite widespread clinical use of antimalarial drugs such as hydroxychloroquine and chloroquine in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other inflammatory rheumatic diseases, insights into the mechanism of action of these drugs are still emerging. Hydroxychloroquine and chloroquine are weak bases and have a characteristic 'deep' volume of distribution and a half-life of around 50 days. These drugs interfere with lysosomal activity and autophagy, interact with membrane stability and alter signalling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules. These modes of action, together with the drug's chemical properties, might explain the clinical efficacy and well-known adverse effects (such as retinopathy) of these drugs. The unknown dose-response relationships of these drugs and the lack of definitions of the minimum dose needed for clinical efficacy and what doses are toxic pose challenges to clinical practice. Further challenges include patient non-adherence and possible context-dependent variations in blood drug levels. Available mechanistic data give insights into the immunomodulatory potency of hydroxychloroquine and provide the rationale to search for more potent and/or selective inhibitors. 10.1038/s41584-020-0372-x
    Harnessing SLE Autoantibodies for Intracellular Delivery of Biologic Therapeutics. Gordon Renata E,Nemeth Jennifer F,Singh Sanjaya,Lingham Russell B,Grewal Iqbal S Trends in biotechnology Intracellular delivery of therapeutic antibodies is highly desirable but remains a challenge for biomedical research and the pharmaceutical industry. Approximately two-thirds of disease-associated targets are found inside the cell. Difficulty blocking these targets with available drugs creates a need for technology to deliver highly specific therapeutic antibodies intracellularly. Historically, antibodies have not been believed to traverse the cell membrane and neutralize intracellular targets. Emerging evidence has revealed that anti-DNA autoantibodies found in systemic lupus erythematosus (SLE) patients can penetrate inside the cell. Harnessing this technology has the potential to accelerate the development of drugs against intracellular targets. Here, we dissect the mechanisms of the intracellular localization of SLE antibodies and discuss how to apply these insights to engineer successful cell-penetrating antibody drugs. 10.1016/j.tibtech.2020.07.003
    Update οn the diagnosis and management of systemic lupus erythematosus. Fanouriakis Antonis,Tziolos Nikolaos,Bertsias George,Boumpas Dimitrios T Annals of the rheumatic diseases Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is-by and large-a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents-used alone, in combination or sequentially-have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use. 10.1136/annrheumdis-2020-218272
    Toll-like receptor signalling in B cells during systemic lupus erythematosus. Fillatreau Simon,Manfroi Benoît,Dörner Thomas Nature reviews. Rheumatology B lymphocytes have a central role in autoimmune diseases, which are often defined by specific autoantibody patterns and feature a loss of B cell tolerance. A prototypic disease associated with B cell hyperactivity is systemic lupus erythematosus (SLE). In patients with SLE, the loss of B cell tolerance to autoantigens is controlled in a cell-intrinsic manner by Toll-like receptors (TLRs), which sense nucleic acids in endosomes. TLR7 drives the extrafollicular B cell response and the germinal centre reaction that are involved in autoantibody production and disease pathogenesis. Surprisingly, TLR9 seems to protect against SLE, even though it is required for the production of autoantibodies recognizing double-stranded DNA-associated antigens, which are abundant in SLE and are a hallmark of this disease. The protective function of TLR9 is at least partly mediated by its capacity to limit the stimulatory activity of TLR7. The roles of TLR7 and TLR9 in the effector function of B cells in lupus-like disease and in patients with SLE, and the unique features of TLR signalling in B cells, suggest that targeting TLR signalling in SLE might be therapeutically beneficial. 10.1038/s41584-020-00544-4
    Meant to B: B cells as a therapeutic target in systemic lupus erythematosus. Atisha-Fregoso Yemil,Toz Bahtiyar,Diamond Betty The Journal of clinical investigation B cells have a prominent role in the pathogenesis of systemic lupus erythematosus (SLE). They are mediators of inflammation through the production of pathogenic antibodies that augment inflammation and cause direct tissue and cell damage. Multiple therapeutic agents targeting B cells have been successfully used in mouse models of SLE; however, these preclinical studies have led to approval of only one new agent to treat patients with SLE: belimumab, a monoclonal antibody targeting B cell-activating factor (BAFF). Integrating the experience acquired from previous clinical trials with the knowledge generated by new studies about mechanisms of B cell contributions to SLE in specific groups of patients is critical to the development of new treatment strategies that will help to improve outcomes in patients with SLE. In particular, a sharper focus on B cell differentiation to plasma cells is warranted. 10.1172/JCI149095
    Global epidemiology of systemic lupus erythematosus. Barber Megan R W,Drenkard Cristina,Falasinnu Titilola,Hoi Alberta,Mak Anselm,Kow Nien Yee,Svenungsson Elisabet,Peterson Jonna,Clarke Ann E,Ramsey-Goldman Rosalind Nature reviews. Rheumatology Systemic lupus erythematosus (SLE) is an autoimmune disease with protean manifestations that predominantly affects young women. Certain ethnic groups are more vulnerable than others to developing SLE and experience increased morbidity and mortality. Reports of the global incidence and prevalence of SLE vary widely, owing to inherent variation in population demographics, environmental exposures and socioeconomic factors. Differences in study design and case definitions also contribute to inconsistent reporting. Very little is known about the incidence of SLE in Africa and Australasia. Identifying and remediating such gaps in epidemiology is critical to understanding the global burden of SLE and improving patient outcomes. Mortality from SLE is still two to three times higher than that of the general population. Internationally, the frequent causes of death for patients with SLE include infection and cardiovascular disease. Even without new therapies, mortality can potentially be mitigated with enhanced quality of care. This Review focuses primarily on the past 5 years of global epidemiological studies and discusses the regional incidence and prevalence of SLE and top causes of mortality. 10.1038/s41584-021-00668-1
    The role of neutrophils in rheumatic disease-associated vascular inflammation. Wang Lihui,Luqmani Raashid,Udalova Irina A Nature reviews. Rheumatology Vascular pathologies underpin and intertwine autoimmune rheumatic diseases and cardiovascular conditions, and atherosclerosis is increasingly recognized as the leading cause of morbidity in conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis. Neutrophils, important cells in the innate immune system, exert their functional effects in tissues via a variety of mechanisms, including the generation of neutrophil extracellular traps and the production of reactive oxygen species. Neutrophils have been implicated in the pathogenesis of several rheumatic diseases, and can also intimately interact with the vascular system, either through modulating endothelial barriers at the blood-vessel interface, or through associations with platelets. Emerging data suggest that neutrophils also have an important role maintaining homeostasis in individual organs and can protect the vascular system. Furthermore, studies using high-dimensional omics technologies have advanced our understanding of neutrophil diversity, and immature neutrophils are receiving new attention in rheumatic diseases including SLE and systemic vasculitis. Developments in genomic, imaging and organoid technologies are beginning to enable more in-depth investigations into the pathophysiology of vascular inflammation in rheumatic diseases, making now a good time to re-examine the full scope of roles of neutrophils in these processes. 10.1038/s41584-021-00738-4
    Bite of the wolf: innate immune responses propagate autoimmunity in lupus. Gupta Sarthak,Kaplan Mariana J The Journal of clinical investigation The etiopathogenesis of systemic lupus erythematosus (SLE), a clinically heterogeneous multisystemic syndrome that derives its name from the initial characterization of facial lesions that resemble the bite of a wolf, is considered a complex, multifactorial interplay between underlying genetic susceptibility factors and the environment. Prominent pathogenic factors include the induction of aberrant cell death pathways coupled with defective cell death clearance mechanisms that promote excessive externalization of modified cellular and nuclear debris with subsequent loss of tolerance to a wide variety of autoantigens and innate and adaptive immune dysregulation. While abnormalities in adaptive immunity are well recognized and are key to the pathogenesis of SLE, recent findings have emphasized fundamental roles of the innate immune system in the initiation and propagation of autoimmunity and the development of organ damage in this disease. This Review focuses on recent discoveries regarding the role of components of the innate immune system, specifically neutrophils and interferons, in promoting various aspects of lupus pathogenesis, with potential implications for novel therapeutic strategies. 10.1172/JCI144918