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| Open AccessAntigen presentation by B cells enables epitope spreading across an MHC barrier
Increasing evidence suggests that antigen presentation by B cells is critical to the initiation of autoimmunity. Here, the authors demonstrate that tolerance breakdown is initiated outside of germinal centres and that B cells can directly instruct T cells to break tolerance and propagate autoimmune responses.
- Cecilia Fahlquist-Hagert
- , Thomas R. Wittenborn
- & Søren E. Degn
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| Open AccessAffinity maturation generates pathogenic antibodies with dual reactivity to DNase1L3 and dsDNA in systemic lupus erythematosus
Antibodies directed against DNA in systemic lupus erythematosus are functionally diverse. This study demonstrates that DNAse1L3 is the primary target of a subset of autoantibodies previously considered specific for double-stranded DNA.
- Eduardo Gomez-Bañuelos
- , Yikai Yu
- & Felipe Andrade
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| Open AccessSingle-cell sequencing shows cellular heterogeneity of cutaneous lesions in lupus erythematosus
Discoid lupus erythematosus (DLE) and systemic LE (SLE) can present as cutaneous lesions. Here the authors characterise an scRNA dataset of cutaneous lesions from these patients and compare these to healthy controls showing differential immune cell recruitment, cell type and gene expression.
- Meiling Zheng
- , Zhi Hu
- & Ming Zhao
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| Open AccessLupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery
The functional effects of genetic loci associated with autoimmune disease are not well understood. By dissecting an autoimmune disease genetic locus, the authors define an immune cell-type-specific enhancer and the molecular mechanisms underlying the dysregulation of IRF8 expression by lupus risk variants.
- Tian Zhou
- , Xinyi Zhu
- & Nan Shen
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| Open AccessAdenosine receptor 2a agonists target mouse CD11c+T-bet+ B cells in infection and autoimmunity
CD11c+T-bet+ B cells have been linked with different autoimmune diseases, but targeting these cells has been challenging. Here the authors use an adenosine 2A receptor agonist to deplete these B cells and to inhibit or reverse autoimmune symptoms and pathology in mice.
- Russell C. Levack
- , Krista L. Newell
- & Gary M. Winslow
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| Open AccessAltered function and differentiation of age-associated B cells contribute to the female bias in lupus mice
Autoimmunity mediated by age-associated B cells (ABC) can affect males and females differently. Here, using a lupus-like mouse model that affects females more severely, the authors observe an ABC mediated and guanine nucleotide exchange factor (GEF) restrained pathogenic process involving TLR7.
- Edd Ricker
- , Michela Manni
- & Alessandra B. Pernis
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| Open AccessPhase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus
Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.
- Sarfaraz A. Hasni
- , Sarthak Gupta
- & Mariana J. Kaplan
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| Open AccessType I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus
Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8+ T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis.
- Norzawani Buang
- , Lunnathaya Tapeng
- & Marina Botto
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| Open AccessGlobal discovery of lupus genetic risk variant allelic enhancer activity
Thousands of genetic variants have been associated with lupus, but causal variants and mechanisms are unknown. Here, the authors combine a massively parallel reporter assay with genome-wide ChIP experiments to identify risk variants with allelic enhancer activity mediated through transcription factor binding.
- Xiaoming Lu
- , Xiaoting Chen
- & Leah C. Kottyan
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Article
| Open AccessIdentification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups
The presentation of systemic lupus erythematosus has been known to differ by ancestry, but the underlying genetic factors remain unclear. Here, the authors report ancestry-specific susceptibility loci and better risk prediction when using data from matched ancestral groups.
- Yong-Fei Wang
- , Yan Zhang
- & Wanling Yang
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Article
| Open AccessFunctionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity
Type I interferon drives autoimmune pathology in SLE and has been assumed to come predominantly from plasmacytoid dendritic cells (pDCs). Here, the authors show that prior to the onset of SLE, pDCs lose multiple immunogenic functions and, instead, non-hematopoietic cells such as keratinocytes are a major source of type I interferons.
- Antonios Psarras
- , Adewonuola Alase
- & Edward M. Vital
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Article
| Open AccessSystemic lupus erythematosus favors the generation of IL-17 producing double negative T cells
Splenic marginal zone macrophages can establish immune tolerance and limit the development of systemic lupus erythematosus (SLE). Here the authors show that these cells do this by clearing apoptotic cells, and defects in these cells result in the generation of self-reactive double negative T cells that are known to contribute to SLE pathogenesis.
- Hao Li
- , Iannis E. Adamopoulos
- & George C. Tsokos
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| Open AccessLupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory
Systemic lupus erythematosus (SLE) is an autoimmune disorder which can have neurological manifestations, including autoantibody targeting of the NMDA receptor. In this study, the authors GluN2A subunit is a target of SLE autoantibodies, using sample derived from patient.
- Kelvin Chan
- , Jacquelyn Nestor
- & Lonnie P. Wollmuth
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| Open AccessA phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease of substantial phenotypic heterogeneity in different ethnic groups. Here, using data from a multi-ethnic cohort, the authors describe an approach based on clinical and molecular data to subtype SLE patients into three clusters of severity.
- Cristina M. Lanata
- , Ishan Paranjpe
- & Lindsey A. Criswell
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| Open AccessMesenchymal stem cell therapy induces FLT3L and CD1c+ dendritic cells in systemic lupus erythematosus patients
Promising pilot clinical trials of mesenchymal stem cells (MSCs) therapy of lupus await validation in larger, controlled trials. Here the authors show that MSCs expand CD1c+ dendritic cells in cell culture by producing FLT3L, and that in lupus patients, circulating CD1c+ dendritic cells and FLT3L are increased following MSCs therapy.
- Xinran Yuan
- , Xiaodong Qin
- & Lingyun Sun
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Article
| Open AccessFunctional rare and low frequency variants in BLK and BANK1 contribute to human lupus
Function-altering variants of immune-related genes cause rare autoimmune syndromes, whereas their contribution to common autoimmune diseases remains uncharacterized. Here the authors show that rare variants of lupus-associated genes are present in the majority of lupus patients and healthy controls, but only the variants found in lupus patients alter gene function.
- Simon H. Jiang
- , Vicki Athanasopoulos
- & Carola G. Vinuesa
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| Open AccessInterferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) shows a striking bias towards higher prevalence in females. Here, the authors perform fine-mapping of an SLE-associated locus at Xp21.2 and characterise a candidate gene, CXorf21, as IFN-responsive in immune cells that shows sexually dimorphic expression.
- Christopher A. Odhams
- , Amy L. Roberts
- & Timothy J. Vyse
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Article
| Open AccessInnate and adaptive signals enhance differentiation and expansion of dual-antibody autoreactive B cells in lupus
Conventional B cells express clonally specific antigen receptors, but a small subset of B cells from patients and mice with systematic lupus erythematosus simultaneously expresses two distinct antigen receptors. Here the authors show that these dual-specificity B cells have higher levels of MHC-II, depend on IL-21 for expansion, and mount stronger memory response.
- Allison Sang
- , Thomas Danhorn
- & Roberta Pelanda
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| Open AccessAct1 is a negative regulator in T and B cells via direct inhibition of STAT3
Adaptor for IL-17 receptors (Act1) is known to be crucial for IL-17-mediated immune responses. Here the authors show that Act1 also functions as a negative regulator of T and B cells by direct inhibition of STAT3.
- Cun-Jin Zhang
- , Chenhui Wang
- & Xiaoxia Li
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Article
| Open AccessC-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease
IFN-γ is central in inflammatory pathogenesis, response to infection and autoimmune diseases. Here the authors show that MMP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and affecting pathogenesis of mouse models of peritonitis, SLE and rheumatoid arthritis.
- Antoine Dufour
- , Caroline L. Bellac
- & Christopher M. Overall
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Article
| Open AccessDissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models
The human TNFAIP3 gene, which encodes for A20, is associated with autoimmune diseases. Here, the authors use BAC transgenics combined with CRISPR- and recombineering-mediated genome editing to dissect in vivo and in primary immune cells, the role of enhancers regulating TNFAIP3.
- Upneet K. Sokhi
- , Mark P. Liber
- & Shiaoching Gong
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Article
| Open AccessNF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus
Clinical trials of BAFF blockade with belimumab have shown partial efficacy for the treatment of systemic lupus erythematosus (SLE), so other therapeutic options are required. Here, the authors present a new small molecule inhibitor that targets NIK with a similar efficacy to BAFF inhibition in two mouse models of SLE.
- Hans D. Brightbill
- , Eric Suto
- & Nico Ghilardi
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Article
| Open AccessThe mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity
Excessive expansion of the T follicular helper (TFH) cell pool is associated with autoimmune disease and Def6 has been identified as an SLE risk variant. Here the authors show that Def6 limits proliferation of TFH cells in mice via alteration of mTORC1 signaling and inhibition of Bcl6 expression.
- Woelsung Yi
- , Sanjay Gupta
- & Alessandra B. Pernis
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Article
| Open AccessTransancestral mapping and genetic load in systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong ethnic and gender bias. In a transancestral genetic association study, Langefeldet al. identify 24 novel regions associated with risk to lupus and propose a cumulative hits hypothesis for loci conferring risk to SLE.
- Carl D. Langefeld
- , Hannah C. Ainsworth
- & Timothy J. Vyse
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| Open AccessDeath receptor 6 contributes to autoimmunity in lupus-prone mice
Germinal centre (GC) reactions are driven by T follicular helper (Tfh) cells and their dysregulation can cause autoimmune disease. Here the authors show that the orphan receptor DR6 is a Tfh cell marker that binds syndecan-1 on GC B cells driving autoimmunity in lupus-prone mice.
- Daisuke Fujikura
- , Masahiro Ikesue
- & Toshimitsu Uede
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| Open AccessTGF-β3-expressing CD4+CD25−LAG3+ regulatory T cells control humoral immune responses
B cells reactive against self antigens can cause autoimmune disease, but are normally suppressed by regulatory T cells (Tregs). Here the authors show that a subset of Tregs can suppress lupus in a mouse model by making TGF-β3 cytokine and by engaging an inhibitory PD-1 receptor on B cells.
- Tomohisa Okamura
- , Shuji Sumitomo
- & Kazuhiko Yamamoto
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Article |
The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations
Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex genetic basis. Here the authors carry out a fine-mapping analysis of the major histocompatibility complex region and identify amino acids that have a causal role in SLE aetiology.
- Kwangwoo Kim
- , So-Young Bang
- & Sang-Cheol Bae