Autoimmunity

  • 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
  • Article
    | Open Access

    How antibody reaches tissues from circulation is critical for understanding antibody-mediated immunity. Here the authors show that IgG extravasation in the skin is mediated by endothelial caveolin transport independently of FcR, and is targetable by imatinib, which reduces IgG-dependent pathology in a mouse model of pemphigus.

    • Sachiko Ono
    • , Gyohei Egawa
    •  & Kenji Kabashima
  • Article
    | Open Access

    B cell response and antibody production are generally facilitated by CD4+ follicular helper (Tfh) cells. Here the authors identify a subset of CXCR5+PD1+CD8+ Tfh cells that is normally suppressed by STAT5 signaling, so that STAT5 deficiency in mice increases the number of these CD8+ Tfh cells and induces concomitant production of autoantibodies.

    • Yuhong Chen
    • , Mei Yu
    •  & Demin Wang
  • Article
    | Open Access

    Complex traits associate with genetic variation and environment and their interaction. Here, the authors study the influence of different diets on trait variability in 1154 outbred mice from an advanced intercross line and find gene-diet interactions associated with spontaneous autoimmunity development in these animals.

    • Artem Vorobyev
    • , Yask Gupta
    •  & Ralf J. Ludwig
  • Article
    | Open Access

    Statistical fine-mapping to pinpoint likely causal variants in a genomic region is complicated by linkage disequilibrium (LD). Here, Asimit et al. compare stepwise and stochastic approaches to fine-mapping and propose a Bayesian multinomial stochastic search method which they apply to six immune-mediated diseases.

    • Jennifer L. Asimit
    • , Daniel B. Rainbow
    •  & Chris Wallace
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Tissue signals that prime autoreactive T cells at the onset of autoimmunity remain enigmatic. Here the authors show NK and ILC1 cells are increased in vitiligo patients, and induce melanocyte apoptosis via CXCR3B, which in turn leads to increased priming of T cell responses in cell culture.

    • Meri K. Tulic
    • , Elisa Cavazza
    •  & Thierry Passeron
  • Article
    | Open Access

    Monozygotic (MZ) twins are ideal to study the influence of non-genetic factors on complex phenotypes. Here, Souren et al. perform an EWAS in peripheral blood mononuclear cells from 45 MZ twins discordant for multiple sclerosis and identify disease and treatment-associated epigenetic markers.

    • Nicole Y. Souren
    • , Lisa A. Gerdes
    •  & Jörn Walter
  • Article
    | Open Access

    CXCL4 is an inflammatory chemokine signaling through CXCR3 receptor. Here the authors show a CXCR3-independent function of CXCL4: it forms liquid crystals with DNA, potentiating mammalian and bacterial DNA recognition by TLR9, thereby amplifying interferon-a production in systemic sclerosis.

    • Roberto Lande
    • , Ernest Y. Lee
    •  & Loredana Frasca
  • Article
    | Open Access

    The inhibitory receptor, FcγRIIb, is reported to limit autoimmune B cell response. Here the authors show that FcγRIIb has a dual role in both human and mouse, with reduced FcγRIIb expression or function associated with enhanced pre-immune B cell tolerance, yet defective control of mature autoreactive B cells in the germinal center.

    • Marion Espéli
    • , Rachael Bashford-Rogers
    •  & Kenneth G. C. Smith
  • Article
    | Open Access

    Antiphospholipid syndrome is characterised by increased neutrophil extracellular trap formation (NETosis) and, consequently, increased thrombotic events. Here Ali et al. show that treatment with adenosine receptor agonists suppresses NETosis and venous thrombosis in mouse models of antiphospholipid syndrome.

    • Ramadan A. Ali
    • , Alex A. Gandhi
    •  & Jason S. Knight
  • Article
    | Open Access

    Interleukin-2 (IL-2) signaling is required for regulatory T (Treg) cell differentiation in the thymus, but its function in peripheral Tregs is still unclear. Here the authors show, using inducible deletion of IL-2 receptor subunit CD25, that IL-2 signaling is essential for maintaining peripheral Treg homeostasis, but dispensable for lineage stability.

    • Kevin H. Toomer
    • , Jen Bon Lui
    •  & Thomas R. Malek
  • Article
    | Open Access

    Autoreactive T cells are suspected to destroy hypocretin-producing neurons in narcolepsy. Here the authors detect CD8 T cells recognizing narcolepsy-related proteins in healthy individuals and in patients with narcolepsy, and show that the frequency of self-reactive CD8 T cells differs between patients and controls sharing the same HLA-II risk allele.

    • Natasja Wulff Pedersen
    • , Anja Holm
    •  & Birgitte Rahbek Kornum
  • Article
    | Open Access

    Short-chain fatty acids (SCFAs) have immunomodulatory effects, but the underlying mechanisms are still unclear. Here the authors show that a SCFA, pentanoate, suppresses autoimmune inflammation in mouse models of colitis and multiple sclerosis via epigenetic modulation of immune cell metabolic and functional pathways.

    • Maik Luu
    • , Sabine Pautz
    •  & Alexander Visekruna
  • Article
    | Open Access

    Ubiquitination may control protein stability or function. Here the authors show that an ubiquitination enzyme, Hectd3, ubiquitinates Stat3 and Malt1 to modulate their function but not degradation in T cells, and thereby promoting the differentiation of pathogenic Th17 cells and susceptibility to a mouse model of multiple sclerosis.

    • Jonathan J. Cho
    • , Zhiwei Xu
    •  & Dorina Avram
  • Article
    | Open Access

    A chromatin remodelling factor Satb1 is essential for T cell lineage development in the thymus. Here the authors show that while Satb1 is dispensable for the differentiation of Th17 cells and their response to gut commensals, it plays a critical role in pathogenic Th17 effector function in EAE by directly activating Bhlhe40 and modulating PD-1.

    • Keiko Yasuda
    • , Yohko Kitagawa
    •  & Keiji Hirota
  • Article
    | Open Access

    Natural killer (NK) cells are functionally calibrated against self MHC during a process termed education. Here the authors show that NK cell education is associated with the accumulation of dense-core secretory lysosomes for expedited release of granzyme B and Ca2+ flux upon target recognition and NK cell activation.

    • Jodie P. Goodridge
    • , Benedikt Jacobs
    •  & Karl-Johan Malmberg
  • Article
    | Open Access

    The transcription factor Foxp3 and Stat5 modulate lineage stability and function of regulatory T (Treg) cells to promote immune homeostasis. Here the authors show that O-GlcNAcylation of Foxp3 and Stat5, mediated by O-GlcNAc transferase (OGT), is essential for Treg-mediate immune balance, with Treg-specific deficiency of OGT leading to severe autoimmunity.

    • Bing Liu
    • , Oscar C. Salgado
    •  & Hai-Bin Ruan
  • Article
    | Open Access

    B cells produce antibodies to mediate various immune functions, but are also reported to negatively regulate immune responses. Here, the authors show that a subset of mature B cells expressing low levels of IgD, present in both mice and human, may pursue this regulatory function indirectly by inducing the proliferation of regulatory T cells via GITRL.

    • Avijit Ray
    • , Mohamed I. Khalil
    •  & Bonnie N. Dittel
  • Article
    | Open Access

    Regulatory T (Treg) cells are developed in the thymus, and are essential for suppressing detrimental autoimmunity. Here the authors show, using mice with dampened interleukin 2 (IL-2) signaling, that IL-2 helps position the pioneer factor SATB1 to control genome-wide chromatin accessibility to facilitate Treg cell lineage commitment in the thymus.

    • Laurent Chorro
    • , Masako Suzuki
    •  & Grégoire Lauvau
  • Article
    | Open Access

    It is unclear if multiple sclerosis (MS) genetic susceptibility can be mediated through perturbations of CNS-intrinsic pathways. Authors show that the rs7665090 risk variant is associated with astrocyte responses that enhance lymphocyte recruitment, and with increased lymphocyte infiltration and lesion sizes in MS lesions.

    • Gerald Ponath
    • , Matthew R. Lincoln
    •  & David Pitt
  • Article
    | Open Access

    Regulatory T (Treg) cells need to be differentiated into effector Treg (eTreg), with the transcription factor IRF4 implicated during this process. Here the authors show that an AP-1 family transcription factor, JunB, is expressed in eTreg to promote the IRF4 transcription program, and regulate eTreg homeostasis and function.

    • Shin-ichi Koizumi
    • , Daiki Sasaki
    •  & Hiroki Ishikawa
  • Article
    | Open Access

    Autoantibodies are implicated in autoimmunity, but may also be present in healthy individuals. Here the authors find that the autoantibody specificity signatures against various G protein-coupled receptors are associated with multiple parameters, including disease states, to imply a physiological function in maintaining immune homeostasis.

    • Otavio Cabral-Marques
    • , Alexandre Marques
    •  & Gabriela Riemekasten
  • Article
    | Open Access

    Natural killer (NK) cells eliminate damaged cells, but spare healthy ones by recognizing their expressed ligands via NK inhibitory receptors. Here the authors solve the structure of an NK inhibitory receptor, NKR-P1B, bound to its ligand, Clr-b, with further data suggesting a weak interaction and informing on the basis of missing-self recognition.

    • Gautham R. Balaji
    • , Oscar A. Aguilar
    •  & Richard Berry
  • Article
    | Open Access

    T cell functions depend on distinct metabolic fluxes. Here the authors show different metabolic requirements of humoral responses to self versus microbial antigens: while glucose is dispensable for antiviral Tfh and antibody responses, it is essential to mount these responses against autoantigens.

    • Seung-Chul Choi
    • , Anton A. Titov
    •  & Laurence Morel
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Roquin targets are known to contain two types of sequence-structure motifs, the constitutive and the alternative decay elements (CDE and ADE). Here, the authors describe a linear Roquin binding element (LBE) also involved in target recognition, and show that Roquin binding affects the translation of a subset of targeted mRNAs.

    • Katharina Essig
    • , Nina Kronbeck
    •  & Vigo Heissmeyer
  • Article
    | Open Access

    Regulatory T cells are crucial for the establishment and maintenance of peripheral immune tolerance, yet the mechanisms regulating their stability and function remain to be fully elucidated. Here the authors show SENP3 maintains Treg cell stability and function via BACH2 deSUMOylation.

    • Xiaoyan Yu
    • , Yimin Lao
    •  & Qiang Zou
  • Article
    | Open Access

    Systemic lupus erythematosus (SLE) is associated with altered B cell responses but the underlying aetiology is still unclear. Here the authors show that a CD11chiT-bet+ B cell subset with a unique phenotype and transcriptome is increased in patients with SLE, can be expanded by IL-21, and may contribute to autoimmune responses in SLE.

    • Shu Wang
    • , Jingya Wang
    •  & Rachel Ettinger
  • Article
    | Open Access

    Germinal center (GC) is where B cells interact with other immune cells for optimal induction of antibody responses. Here the authors show that galectin-3 regulates GC development by modulating interferon-γ and B cell-intrinsic signaling, such that galectin-3 deficiency mice exhibit lupus-like autoimmune symptoms.

    • Cristian Gabriel Beccaria
    • , María Carolina Amezcua Vesely
    •  & Adriana Gruppi
  • Article
    | Open Access

    T help 17 (Th17) cells are important mediators for both protective and pathogenic immune reactions, but how their functions are regulated at the epigenetic level is not understood. Here the authors show that TRIM28, a cofactor for transcriptional regulation, is important for epigenetic activation of Th17-related gene loci during Th17 response.

    • Yu Jiang
    • , Ying Liu
    •  & Chen Dong
  • Article
    | Open Access

    Blocking B-cell activating factor (BAFF), an important soluble factor for B-cell responses, with specific antibodies is approved for treating autoimmune disorders. Here the authors show, with structural data, that antibody-BAFF interactions not only interrupt BAFF–receptor-binding, but also induce the formation of a less active BAFF polymer.

    • Woori Shin
    • , Hyun Tae Lee
    •  & Yong-Seok Heo
  • Article
    | Open Access

    Systemic lupus erythematosus (SLE) is an autoimmune disorder mediated by excessive autoantibodies. Here the authors show that an E3 ubiquitin ligase, Peli1, negatively modulates noncanonical NF-κB signaling to restrain lupus-like symptoms in mice, and that Peli1 expression inversely correlates with SLE severity in humans.

    • Junli Liu
    • , Xinfang Huang
    •  & Yichuan Xiao
  • Article
    | Open Access

    Regulatory B cells (Breg) are known to suppress immune responses by secreting interleukin-10 (IL-10). Here the authors show that, alternatively, Bregs may also present lipid antigens on surface CD1d to induce IFN-γ production from invariant natural killer cells to ameliorate experimental arthritis via IL-10-independent pathways.

    • K. Oleinika
    • , E. C. Rosser
    •  & C. Mauri
  • Article
    | Open Access

    Post-translational modifications are associated with autoimmune diseases but definitive evidence of their contribution to escape from central tolerance mechanisms is needed. Here, the authors show that T cells specific for post-translational modifications of type II collagen escape intrathymic tolerance induction in a mouse model of rheumatoid arthritis.

    • Bruno Raposo
    • , Patrick Merky
    •  & Johan Bäcklund
  • Article
    | Open Access

    Inflammasomes are protein complexes induced by pathogens for the secretion of pro-inflammatory cytokines IL-1β and IL-18 in immune cells. Here the authors show, using a new mouse model, that aberrant NLRC4 and ASC-dependent inflammasome activation in neutrophils contributes to systemic inflammation.

    • Randilea D. Nichols
    • , Jakob von Moltke
    •  & Russell E. Vance
  • Article
    | Open Access

    Circadian controls of immune responses by the molecular clock have been reported, but the underlying mechanisms are unclear. Here the authors show that the master circadian gene, Bmal1, is essential for modulating the homeostasis of myeloid cells to control pro-inflammatory IL-17+/IFN-γ+ T cells in autoimmunity.

    • Caroline E. Sutton
    • , Conor M. Finlay
    •  & Annie M. Curtis