Immunological disorders

  • Article
    | Open Access

    Frontal fibrosing alopecia (FFA) features lichenoid cutaneous inflammation and scarring hair loss. Here, Tziotzios et al. identify four genetic loci associated with FFA by GWAS followed by Bayesian fine-mapping, co-localisation and HLA imputation which highlights HLA-B*07:02 as a risk factor.

    • Christos Tziotzios
    • , Christos Petridis
    •  & John A. McGrath
  • Article
    | Open Access

    The JAK-STAT signaling pathway is important for cytokine responses and CD4 T-cell differentiation. Here the authors show that Stat1 also serves to protect CD4 T cells from natural killer cell-mediated killing, potentially by promoting the expression of Nlrc5 and MHC-I, to preserve the induction of experimental colitis via the adoptive transfer of CD4 T cells.

    • Yu Hui Kang
    • , Amlan Biswas
    •  & Scott B. Snapper
  • Article
    | Open Access

    GWAS have led to the identification of 49 genetic loci associated with vitiligo. Here, the authors observe a bimodal distribution of age-of-onset and find a novel genetic locus specifically associated with early-onset vitiligo, located in a regulatory element in the MHC class II region.

    • Ying Jin
    • , Genevieve H. L. Roberts
    •  & Richard A. Spritz
  • Article
    | Open Access

    Obesity is associated with low-grade chronic inflammation. Here the authors show that the activation of anti-inflammatory M2a-subtype macrophages requires the IL4/Irs2/Akt pathway. Due to decreased Irs2 expression this pathway is impaired in obese mice thus leading to a defect in M2a activation.

    • Tetsuya Kubota
    • , Mariko Inoue
    •  & Takashi Kadowaki
  • Article
    | Open Access

    Mutations in genes encoding NAPDH oxidase subunits are known to be causative for the primary immunodeficiency chronic granulomatous disease (CGD). Here, the authors identify CYBC1 mutations in patients with CGD and show that CYBC1 is important for formation of the NADPH complex and respiratory burst.

    • Gudny A. Arnadottir
    • , Gudmundur L. Norddahl
    •  & Kari Stefansson
  • Article
    | Open Access

    Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here the authors use ~40 nm cationic nanoparticles to scavenge cfDNA, and demonstrate the potential for nanomedicine to relieve debilitating RA symptoms.

    • Huiyi Liang
    • , Bo Peng
    •  & Yongming Chen
  • Article
    | Open Access

    Activation of the NLRP3 inflammasome triggers the production of inflammatory cytokines. Here, the authors inactivate NLRP3 in macrophages using CRISPR/Cas9 encapsulated in nanoparticles, and show that administration in mice is effective in preventing septic shock and peritonitis, and in improving diabetes-associated inflammation and insulin resistance.

    • Congfei Xu
    • , Zidong Lu
    •  & Jun Wang
  • Article
    | Open Access

    The driver mutations for the two main molecular subgroups of diffuse large B-cell lymphoma (DLBCL) are poorly defined. Here, an integrative genomics analysis identifies 3′ UTR NFKBIZ mutations within the activated B-cell DLBCL subgroup and small FCGR2B amplifications in the germinal centre B-cell DLBCL subgroup.

    • Sarah E. Arthur
    • , Aixiang Jiang
    •  & Ryan D. Morin
  • 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

    At inflammatory sites, ectopic lymphoid-like structures (ELS) can be induced through the function of chemokine CXCL13 produced by CD4+ T cells. Here the authors show that a transcription factor, Sox4, induces the expression of CXCL13 in CD4 T cells in vitro, and is associated with ELS formation in patients with rheumatoid arthritis.

    • Hiroyuki Yoshitomi
    • , Shio Kobayashi
    •  & Junya Toguchida
  • Article
    | Open Access

    The microbial metabolite sensor GPR43 has been previously shown to be a crucial modulator of immune responses. Here the authors show GPR43 is required for controlling disease pathology severity in the context of experimental models of GVHD.

    • Hideaki Fujiwara
    • , Melissa D. Docampo
    •  & Pavan Reddy
  • Article
    | Open Access

    Understanding how regulators of inflammation affect nucleic acid sensing is important for targeting research against inflammatory diseases and conditions. Here, the authors identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells.

    • David Olagnier
    • , Aske M. Brandtoft
    •  & Christian K. Holm
  • Article
    | Open Access

    Antibody mediated immune responses to Streptococcus pneumoniae are crucial for the immune response to infection. Here the authors show hyper-activation of PI3Kδ promotes development of a subset of B cells that exacerbate infection in an antibody-independent manner and can be reversed by therapeutic targeting in vivo.

    • Anne-Katrien Stark
    • , Anita Chandra
    •  & Klaus Okkenhaug
  • Article
    | Open Access

    Disease risk variants can exert their influence on phenotypes by altering epigenome function. Here, Pelikan et al. show that variants inducing allelic imbalance in histone marks in lymphoblastoid cell lines from lupus patients are enriched in autoimmune disease haplotypes and influence gene expression.

    • Richard C. Pelikan
    • , Jennifer A. Kelly
    •  & Patrick M. Gaffney
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Neuromyelitis optica (NMO) is a rare autoimmune condition characterized by inflammation and demyelination of the optic nerve and the spinal cord. Here, Estrada et al. identify NMO susceptibility variants in the MHC region and find that autoantibody-positive NMO genetically overlaps with lupus.

    • Karol Estrada
    • , Christopher W. Whelan
    •  & Daniel G. MacArthur
  • Article
    | Open Access

    Allergen-specific immunotherapy is used to treat patients affected by acute immunoglobulin E (IgE) responses, but the function mechanism is unclear. Here the authors show that the administration of two cat allergen-specific IgGs reduces allergic responses in mouse models and helps ameliorate clinical symptoms in a phase 1b clinical trial.

    • J. M. Orengo
    • , A. R. Radin
    •  & G. D. Yancopoulos
  • Article
    | Open Access

    Matrix metalloproteinases (MMP) are involved in vascular remodeling associated with plaque progression. Little is known about their immune regulatory role in vascular disorders. Here, the authors report that MT4-MMP-deficiency increases the recruitment of patrolling monocytes to early atherosclerotic lesions, which accelerates atherosclerosis.

    • Cristina Clemente
    • , Cristina Rius
    •  & Alicia G. Arroyo
  • Article
    | Open Access

    XLP-2 syndrome is caused by XIAP mutation. Here the authors show that mouse and human XIAP-deficient regulatory T cells have defective suppressive function as a result of conversion to proinflammatory cytokine producing cells, an effect that can be prevented by blocking the IL-6 receptor.

    • Wan-Chen Hsieh
    • , Tzu-Sheng Hsu
    •  & Ming-Zong Lai
  • 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

    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
  • Article
    | Open Access

    Colonization of commensal bacteria is thought to impact immune development, especially in the earliest years of life. Here, the authors show, by analyzing the development of the gut microbiome of 690 children, that microbial composition at the age of 1 year is associated with asthma diagnosed in the first 5 years of life.

    • Jakob Stokholm
    • , Martin J. Blaser
    •  & Hans Bisgaard
  • Article
    | Open Access

    The pathogenesis of paradoxical psoriasis in patients receiving anti-TNF treatments for classical psoriasis is unclear. Here, the authors show that anti-TNF drugs enhance the production of type I interferon by plasmacytoid dendritic cells, causing skin lesions that, unlike classical psoriasis, lack T- cell autoimmunity.

    • Curdin Conrad
    • , Jeremy Di Domizio
    •  & Michel Gilliet
  • Article
    | Open Access

    IgE is linked to allergic diseases and there is a great interest in developing anti-IgE therapeutics. Here the authors characterize the binding of human IgE Fc to a single domain antibody (sdab) and show that the sdab induces a closed conformation, which prevents and disrupts IgE binding to its receptor FcεRI and abrogates allergen mediated activation.

    • Frederic Jabs
    • , Melanie Plum
    •  & Edzard Spillner
  • Article
    | Open Access

    Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.

    • Mathieu P. Rodero
    • , Alessandra Tesser
    •  & Yanick J. Crow
  • Article
    | Open Access

    The NLRP3 inflammasome is central to a variety of inflammatory diseases, but how it is regulated to prevent excessive inflammation is not clear. Here the authors show that NLRP3 activation causes SHP2 translocation to the mitochondria to interact with and dephosphorylate ANT1, thus stabilizing the mitochondria and preventing release of proinflammatory mitochondrial DNA and ROS.

    • Wenjie Guo
    • , Wen Liu
    •  & Qiang Xu
  • Article
    | Open Access

    Rising rates of peanut allergy pose a public health problem. Here, the authors profile blood transcriptomes during double-blind, placebo-controlled oral challenge in peanut-allergic children to identify gene and cell composition changes, and construct causal networks to detect key allergic reaction drivers.

    • C. T. Watson
    • , A. T. Cohain
    •  & S. Bunyavanich
  • Article
    | Open Access

    Complement component C1q activates efferocytosis, suppresses inflammatory responses, and is thereby thought to limit autoimmune disease. Here, the authors show that macrophage transcription factor MafB regulates total serum levels of C1q, which contributes to preventing autoimmune disease in mice.

    • Mai Thi Nhu Tran
    • , Michito Hamada
    •  & Satoru Takahashi
  • Article
    | Open Access

    Wiskott-Aldrich syndrome protein (WASp) is essential for controlling the cytoskeleton, but its function in innate immunity is unclear. Here the authors show that WASp deficiency is associated with dysregulated septin cage formation, excessive inflammasome activation, elevated immune cell death and reduced bacterial clearance.

    • Pamela P. Lee
    • , Damián Lobato-Márquez
    •  & Adrian J. Thrasher
  • Article
    | Open Access

    IgE is an important mediator of protective immunity as well as allergic reaction, but how high affinity IgE antibodies are produced in memory responses is not clear. Here the authors show that IgE can be generated via class-switch recombination in IgG1 memory B cells without additional somatic hypermutation.

    • Jin-Shu He
    • , Sharrada Subramaniam
    •  & Maria A. Curotto de Lafaille
  • Article
    | Open Access

    Non-invasive cell tracking is a powerful method to visualize cells in vivo under physiological and pathophysiological conditions. Here Thunemann et al. generate a mouse model for in vivo tracking and quantification of specific cell types by combining a PET reporter gene with Cre-dependent activation that can be exploited for any cell population for which a Cre mouse line is available.

    • Martin Thunemann
    • , Barbara F. Schörg
    •  & Robert Feil
  • Article
    | Open Access

    Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.

    • Satish Ranjan
    • , Alexander Goihl
    •  & Berend Isermann
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Axl is a TAM receptor that can inhibit Toll-like receptor (TLR) -induced pro-inflammatory production by dendritic cells (DC). Here the authors show that miR-34a targets Axl to control CD1c+ DC activity in mice, and that miR-34a-deficient mice are resistant to collagen-induced arthritis, whereas DCs from patients with rheumatoid arthritis have high levels of miR- 34a.

    • Mariola Kurowska-Stolarska
    • , Stefano Alivernini
    •  & Iain B. McInnes
  • Article
    | Open Access

    TWEAK is a TNF family member that binds the NFκB signalling receptor Fn14. Here the authors show that TWEAK is central to skin inflammation in mouse models of atopic dermatitis and psoriasis and causes similar pathology when injected subcutaneously into mice.

    • Daniel Sidler
    • , Ping Wu
    •  & Michael Croft
  • Article
    | Open Access

    ARPC1B is a component of the actin-related protein 2/3 complex (Arp2/3), which is required for actin filament branching. Kahret al. show that ARPC1B deficiency in humans is associated with severe multisystem disease that includes platelet abnormalities, eosinophilia, eczema and other indicators of immune disease.

    • Walter H. A. Kahr
    • , Fred G. Pluthero
    •  & Aleixo M Muise