Autoimmunity

  • Article
    | Open Access

    The Cia21 locus on chromosome 3 has been associated with rheumatoid arthritis severity in females. Here the authors show this locus houses a non-coding polymorphic estrogen receptor binding site and how it regulates neighbouring gene expression of CD2, implicating CD2 signalling in the sexual dimorphism of a variety of T cell-dependent autoimmune diseases.

    • Gonzalo Fernandez Lahore
    • , Michael Förster
    •  & Rikard Holmdahl
  • Article
    | Open Access

    Infection with SARS-CoV2 and the development of Coronavirus disease 2019 (COVID-19) has been linked to induction of autoimmunity and autoantibody production. Here the authors characterise the new-onset IgG autoantibody response in hospitalised patients with COVID-19 which they correlate to the magnitude of the SARS-CoV2 response.

    • Sarah Esther Chang
    • , Allan Feng
    •  & Paul J. Utz
  • Article
    | Open Access

    Epitopes formed by fusion of more than one self peptide, such as proinsulin and other β cell proteins, can result in the formation of non-self hybrid peptides that can potentially trigger autoimmune responses. Here the authors show how TRBV5 + T cell receptors are geared towards recognition of HLA-DQ8 bound hybrid peptides in patients with type 1 diabetes.

    • Mai T. Tran
    • , Pouya Faridi
    •  & Hugh H. Reid
  • Article
    | Open Access

    There are dynamic interactions between immune cells and β cells that lead to β cell destruction in the context of autoimmune diabetes. Here the authors show that TET2, a methylcytosine dioxygenase, can regulate this interaction and deletion of TET2 can prevent the autoimmune destruction of β cells in mice.

    • Jinxiu Rui
    • , Songyan Deng
    •  & Kevan C. Herold
  • Article
    | Open Access

    Patients with rheumatoid arthritis are commonly stratified by ACPA serology, with positivity being associated with more severe disease and joint destruction. Here the authors present a single cell RNA sequencing resource comparing peripheral blood and synovial tissue cells from patients with ACPA+ versus ACPA- rheumatoid arthritis.

    • Xunyao Wu
    • , Yi Liu
    •  & Xuan Zhang
  • Article
    | Open Access

    3-hydroxy-L-kynurenamine (3-HKA) is a metabolite deriving from a lateral pathway of tryptophan catabolism. Here the authors identify 3-HKA as a biogenic amine and show it has anti-inflammatory properties that can protect mice against psoriasis and nephrotoxic nephritis.

    • Cristina C. Clement
    • , Angelo D’Alessandro
    •  & Laura Santambrogio
  • Article
    | Open Access

    IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.

    • Tatsuma Ban
    • , Masako Kikuchi
    •  & Tomohiko Tamura
  • Article
    | Open Access

    Development of the T cells requires functions from thymic epithelial cells, whose development and function are epigenetically regulated. Here the authors show that inactivation of the polycomb repressive complex 2 (PRC2) alters the H3K27me3 configuration, reduces TEC functions, reveals a specific TEC subset, and hampers T cell development.

    • Thomas Barthlott
    • , Adam E. Handel
    •  & Georg A. Holländer
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Immune cells are known to aggravate the inflammatory impact of Duchene muscular dystrophy. Here, the authors describe impaired thymic development and suggest thymic involution in this model of disease is linked to disease acceleration due to impaired immunological tolerance.

    • Andrea Farini
    • , Clementina Sitzia
    •  & Yvan Torrente
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Regulatory B (Breg) cells suppress excessive inflammation primary via the production of interleukin 10 (IL-10). Here the authors show that the function and homeostasis of mouse and human IL-10+ Breg cells are negatively regulated by the cell surface receptor, SLAMF5, to impact experimental autoimmunity, thereby hinting SLAMF5 as a potential target for immunotherapy.

    • Lihi Radomir
    • , Matthias P. Kramer
    •  & Idit Shachar
  • Article
    | Open Access

    The thymus supports T cell immunity by providing the environment for thymocyte differentiation. Here the authors profile human thymic stroma at the single cell level, identifying ionocytes as a new medullary population and defining tissue specific antigen expression in multiple stromal cell types.

    • Jhoanne L. Bautista
    • , Nathan T. Cramer
    •  & Audrey V. Parent
  • Article
    | Open Access

    The transcriptional adaptation processes of harmful self-reactive CD8+ T cells in the central nervous system are not well understood. Here the authors use a system in which self-reactive and virally generated CD8+ T cells are directly compared in vivo and demonstrate that TOX expression contributes to maintenance of auto-reactive CD8+ T cells through alteration of chromatin accessibility.

    • Nicolas Page
    • , Sylvain Lemeille
    •  & Doron Merkler
  • Article
    | Open Access

    The autoimmune disorder, rheumatoid arthritis (RA), has been associated with multiple pathophysiological factors. Here the authors show that deficiency in endophilin A2 in rodents protects them from experimental arthritis by altering T cell activation threshold and effector functions, thereby hinting a potential target for RA therapy.

    • Ulrika Norin
    • , Carola Rintisch
    •  & Rikard Holmdahl
  • Article
    | Open Access

    CTLA-4 is an important co-inhibitory receptor for T cells. Here, the authors show that CTLA-4 also has a function on B-1a cells, as conditional deletion results in activation of these cells and knockout mice develop an autoimmune profile.

    • Yang Yang
    • , Xiao Li
    •  & Leonore A. Herzenberg
  • Article
    | Open Access

    T helper 17 (Th17) cells are important mediators of inflammatory diseases and fungal infection protection, and are critically regulated by the transcription factor (TF), RORγt. Here the authors identify a new enhancer for RORγt, RORCE2, which synergizes with another TF, Sox5, for binding with RORγt promoter and thereby modulation of RORγt expression.

    • Yi Tian
    • , Chao Han
    •  & Yuzhang Wu
  • Article
    | Open Access

    Pemphigoid diseases involve autoimmune mediated blistering and immunopathology of the upper dermis. Here, the authors implicate granzyme B in the immunopathology in multiple in vivo models of pemphigoid diseases and utilise a topical granzyme B inhibitor that attenuates disease phenotypes in vivo.

    • Sho Hiroyasu
    • , Matthew R. Zeglinski
    •  & David J. Granville
  • Article
    | Open Access

    Enhancers shape gene expression patterns and are involved in disease pathogenesis. Here the authors demonstrate a strategy to screen functional regulatory elements for non-coding RNAs ― illustrated with miR-146a ― and link autoimmune disease risk genetic variants to autoimmune disease etiology.

    • Guojun Hou
    • , Isaac T. W. Harley
    •  & Nan Shen
  • Article
    | Open Access

    Early life trauma has been associated with multiple sclerosis, but the causal link is unclear. Here the authors show in mice that early life trauma can result in IFN-β-resistant EAE as a result of β-adrenergic desensitization in immune cells and that a β1 adrenergic receptor agonist can reverse this susceptibility.

    • Yee Ming Khaw
    • , Danish Majid
    •  & Makoto Inoue
  • Article
    | Open Access

    TARM1 is a LILR family member that drives cell signalling via interactions with FcRγ. Here the authors show that TARM1 binds collagens to activate dendritic cells and thereby is an effector of inflammatory arthritis, plus provide a soluble TARM-Fc fusion protein that can limit collagen-induced arthritis in mice.

    • Rikio Yabe
    • , Soo-Hyun Chung
    •  & Yoichiro Iwakura
  • Article
    | Open Access

    Unlike RORα, which has been thought to be somewhat redundant, RORγt has been well characterized in its function and contribution to the development of Th17 cells. Here the authors show that RORα is important in Th17 differentiation and that RORα deletion or a small molecule inhibitor of RORα can reduce disease in EAE and colitis mouse models.

    • Ran Wang
    • , Sean Campbell
    •  & Laura A. Solt
  • Article
    | Open Access

    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
  • Article
    | Open Access

    CD39 is an ectonucleotidase associated with immunoregulatory function. Here authors show regulation of CD39 expression by an endogenous antisense RNA moiety transcribed from the 3‘ end of CD39/ENTPD1 which when itself is silenced results in amelioration of pathology in an animal model of colitis.

    • Rasika P. Harshe
    • , Anyan Xie
    •  & Maria Serena Longhi
  • Article
    | Open Access

    Systemic sclerosis (SSc) is a disease with manifestation in the skin and immune etiology, but the pathogenic immune cell types remain unidentified. Here the authors use ATAC-seq to profile chromatin landscapes of skin samples from patients with SSc to implicate skin dendritic cells for having the strongest disease-associated epigenetic changes.

    • Qian Liu
    • , Lisa C. Zaba
    •  & Howard Y. Chang
  • Article
    | Open Access

    How mutations in the microbial receptor NOD2 induce Blau syndrome in humans and related uveitis is unclear. Here the authors show, using Nod2-deficient mice and experimental uveitis, that Nod2 negatively regulates T cell activation and transcription of autoimmunity-related genes to suppress Th17 responses and uveitis.

    • Ruth J. Napier
    • , Ellen J. Lee
    •  & Holly L. Rosenzweig
  • Article
    | Open Access

    SOCS1 is a potent suppressor of JAK-STAT signalling responses to IFNγ and γ-chain cytokines and thereby limits inflammation. Here the authors identify and characterize heterozygous SOCS1 mutations in 10 patients from 5 unrelated families with autoimmune diseases.

    • Jérôme Hadjadj
    • , Carla Noemi Castro
    •  & Frédéric Rieux-Laucat
  • Article
    | Open Access

    Psoriatic arthritis (PsA) commonly affects patients with skin psoriasis, but its pathogenesis is still unclear. Here the authors use two types of single-cells data, mass cytometry and RNA sequencing, to describe the expansion and diversity of synovial, but not peripheral blood, CD8 T cells from PsA patients to provide a molecular immune landscape for PsA.

    • Frank Penkava
    • , Martin Del Castillo Velasco-Herrera
    •  & M. Hussein Al-Mossawi
  • Article
    | Open Access

    How extracellular calcium can trigger Nlrp3 inflammasome activation has been somewhat controversial and unclear. Here the authors show calciprotein particles are taken up by myeloid cells via calcium-sensing receptor-dependent macropinocytosis in response to high levels of extracellular Ca2+ and this pathway might be critical to inflammatory conditions.

    • Elisabeth Jäger
    • , Supriya Murthy
    •  & Ulf Wagner
  • Article
    | Open Access

    Type I IFN has apposing effects in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Here the authors perform molecular profiling of NMOSD patients and mouse mechanistic experiments of neuro-inflammation to show that IFN-I stimulates pathogenic Th17 via IL-6 production by B cells.

    • Agnieshka M. Agasing
    • , Qi Wu
    •  & Robert C. Axtell
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Type 1 diabetes is associated with autoimmune destruction of pancreatic beta-cells. Here the authors compose a large-scale electron microscopy image data base of pancreatic organ donor tissue to enable data mining and further understanding of the disease.

    • Pascal de Boer
    • , Nicole M. Pirozzi
    •  & Ben N. G. Giepmans
  • Article
    | Open Access

    Immune tolerance is mediated by the deletion of autoreactive T cells via medullary thymic epithelial cells (mTEC) and dendritic cells (DC), and by the induction of regulatory T cells (Treg). Here the authors show that mTEC receiving toll-like receptor signaling control the recruitment of CD14+Sirpα+ DC population that is capable of inducing Treg for establishing tolerance.

    • Matouš Vobořil
    • , Tomáš Brabec
    •  & Dominik Filipp
  • Article
    | Open Access

    Intestinal dysbiosis is associated with an ever-growing list of autoimmune diseases. Here the authors show that both mice and humans with autoimmune arthritis can have dysbiosis and barrier leakiness prior to major signs of inflammatory arthritis, and treatment of mice with a zonulin antagonist can limit collagen-induced arthritis.

    • Narges Tajik
    • , Michael Frech
    •  & Mario M. Zaiss
  • Article
    | Open Access

    Moderate consumption of alcohol is associated with protection from some autoimmune diseases. Here the authors show that ethanol and its metabolite acetate can protect mice from collagen-induced arthritis and provide evidence that the mechanism of this effect might be via inhibition of the effector function of T follicular helper cells.

    • Vugar Azizov
    • , Katharina Dietel
    •  & Mario M. Zaiss
  • Article
    | Open Access

    α-Synuclein-specific T cell reactivity is preferentially associated with Parkinson’s disease (PD) patients, but the temporal relation with diagnosis was previously unknown. This study reveals that α-syn-reactive T cells are highest before and shortly after diagnosis of motor PD, and then decrease.

    • Cecilia S. Lindestam Arlehamn
    • , Rekha Dhanwani
    •  & Alessandro Sette
  • Article
    | Open Access

    Circadian rhythms can alter inflammatory state and activity of inflammatory diseases such as rheumatoid arthritis. Here the authors show that extrinsic signals confer a circadian rhythm to regulatory T cell activity, which in turn drives rhythmic inflammation in collagen-induced arthritis.

    • L. E. Hand
    • , K. J. Gray
    •  & J. E. Gibbs
  • Article
    | Open Access

    Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects.

    • Jingyuan Xie
    • , Lili Liu
    •  & Krzysztof Kiryluk
  • Article
    | Open Access

    Here the authors provide a single-cell characterization of cerebrospinal fluid and blood of newly diagnosed multiple sclerosis (MS) patients, revealing altered composition of lymphocyte and monocyte subsets, validated by other methods including the interrogation of the TFH subset in mouse models of MS.

    • David Schafflick
    • , Chenling A. Xu
    •  & Gerd Meyer zu Horste
  • Article
    | Open Access

    . TGFβ is critical for limiting autoreactive responses of peripheral T cells. Here, the authors show that TGFβ signaling in thymocytes mediates elimination of self-reactive T cells and promotes the expression of self-antigens by medullary thymic epithelial cells.

    • Mark J. McCarron
    • , Magali Irla
    •  & Julien C. Marie
  • Article
    | Open Access

    Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

    • Catharina C. Gross
    • , Céline Meyer
    •  & Roland Liblau
  • Article
    | Open Access

    Dimethyl fumarate (DMF) is a therapy for multiple sclerosis (MS) with undetermined mechanism of action. Here the authors find that clinical response to DMF associates with decrease in IL-17-producing CD8+ T cells (Tc17), delineate molecular pathways involved, and show that DMF suppresses Tc17 pathogenicity in a mouse model of MS.

    • Christina Lückel
    • , Felix Picard
    •  & Magdalena Huber
  • Article
    | Open Access

    Innate immune cells can be trained by some stimuli or pathogen exposures to be metabolically and epigenetically altered such that they have different responses to subsequent exposures. Here the authors show that low-dose LPS trained macrophages and BCG-trained macrophages have opposing effects on fibrosis and inflammation in the context of systemic sclerosis.

    • Mohamed Jeljeli
    • , Luiza Gama Coelho Riccio
    •  & Frédéric Batteux
  • Article
    | Open Access

    Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder characterised by asthma, eosinophilia and vasculitis. Here, the authors describe a genome-wide association study of EGPA that reveals clinical and genetic differences between subgroups stratified by autoantibody status (ANCA).

    • Paul A Lyons
    • , James E Peters
    •  & Kenneth G. C. Smith
  • Article
    | Open Access

    MHC-I-induced signalling of various natural killer (NK) inhibitory receptors is critical for regulation NK cell education, but clear genetic evidence is still lacking. Here the authors generate multiple lines of mice differentially deficient in Ly49 family and/or NKG2A NK receptors, and find that self-MHCI specific Ly49 members and NKG2A synergize to regulate NK education.

    • Xiaoqian Zhang
    • , Jin Feng
    •  & Zhongjun Dong
  • Article
    | Open Access

    Recombinant MHC class II molecules are instrumental in antigen-specific T-cell identification assays and showed efficacy as experimental medicines. Here, the authors engineer MHC class II molecules with species-specific knob-into-hole heteromerization domains, enabling a translatable purification process with improved stability, yields, and biological potency.

    • Pau Serra
    • , Nahir Garabatos
    •  & Pere Santamaria
  • Article
    | Open Access

    Food intake shapes intestinal microbiome composition, which in turn shapes adaptive immune responses. Here the authors show that dietary tryptophan restriction (DTR) protects mice from subsequent autoimmune neuropathology challenge by altering intestinal microbiota, highlighting the potential of diet-regulated microbiota to prevent immune pathology.

    • Jana K. Sonner
    • , Melanie Keil
    •  & Michael Platten